Current State of Endothelial Keratoplasty by biotic.artlab

Introduction

Current State of Endothelial Keratoplasty

Suryan Dunker

Current State of Endothelial Keratoplasty

DISSERTATION

PROEFSCHRIFT door Suryan Dunker

ISBN: Print: Layout: Biotic Artlab Cover Design: Biotic Artlab Medical Illustrations: Rogier Trompert Medical Art © Suryan Dunker, 2021

Promotor First Name Last Name Copromotoren First Name Last Name First Name Last Name Beoordelingscommissie First Name Last Name First Name Last Name First Name Last Name First Name Last Name

The studies in this thesis were supported by grants from ZonMw - The Netherlands Organisation for Health Research and Development, Stichting Nederlands Oogheelkundig Onderzoek (SNOO), Dr. F.P. Fischer-Stichting, Landelijke Stichting Blinden en Slechtzienden (LSBS), and the Rotterdamse Stichting Blindenbelangen (RSB).

Table of Contents PART ONE: GENERAL INTRODUCTION 1

General Introduction Anatomy and Physiology of the Human Cornea Fuchs Endothelial Corneap Dystrophy Corneal Transplantation Determining Outcome Parameters National and European Corneal Transplant Registries Aims and Outlines of this Thesis References

13 15 19 22 31 33 34 36

Rebubbling and graft failure in Descement membrane endothelial keratoplasty: a prospective Dutch registry study Introduction Methods Results Discussion References

107 109 109 111 115 123

Practice patterns of corneal transplantion in Europe: First report by the European Cornea and Cell Transplantation Registry (ECCTR) Introduction Methods Results Discussion Value Statement References

127

PART TWO: RESEARCH ARTICLES 2

Descemet Membrane Endothelial Keratoplasty versus Ultrathin Descemet Stripping Automated Endothelial Keratoplasty: A Multicenter Randomized Controlled Clinical Trial Introduction Methods Results Discussion References

47 48 51 57 61

Quality of vision and vision-related quality of life after Descemet membrane endothelial keratoplasty: a randomized clinical trial Introduction Methods Results Discussion References

Real-World Outcomes of DMEK: A Prospective Dutch registry study Introduction Methods Results Discussion References

67 67 71 76 82

89 89 92 98 103

129 130 131 134 138 139

Outcomes of corneal transplantation in Europe: Report by the European Cornea and Cell Transplantation Registry (ECCTR) Introduction Methods Results Discussion Value Statement References

145 145 147 151 155 157

General Discussion

161

143

PART THREE: APPENDIX 9

Summary Impact Paragraph

175 178

CHAPTER 1

Introduction

CHAPTER 1 12

General Introduction

CHAPTER 1

Introduction

1.1 General Introduction For most people, navigating from place to place is a fundamental part of daily life performed without much thought or active attention. When asked how they navigate, most adults indicate a reliance on visual perception. When citizens of the United Kingdom ranked their sensory modalities, 88% identified vision as their highest-valued sense.1 Loss of vision and its impact on quality of life and independence is more negatively viewed than almost any other disease, including deafness, losing speech, HIV/AIDS, loss of limb, cancer, or heart disease.2 Sight is dependent on the eye; an optical system that transmits light before converting an image to a set of electrochemical signals. The raw data is then processed by a complex mental operation. A key structure of the eye is the outermost layer, the cornea. The cornea lacks the dynamic movement of the lens or the neurobiological complexity of the retina; yet, without its transparency, the eye would not be able to perform its functions.

1.2 ANATOMY AND PHYSIOLOGY OF THE HUMAN CORNEA The development of the cornea begins with the primitive formation of epithelium and lens, followed by waves of migration from cells of neural crest origin between these two structures to produce the stroma and endothelium. The latter secretes Descemet’s membrane, which gradually thickens over time. Its earliest form can be detected in utero as early as 12 weeks of gestation.3 The cornea has evolved to fulfill the dual function of protecting the inner contents of the eye and focusing light rays onto the retina. The average adult cornea has a slightly larger horizontal (12.5 mm to 13.0 mm) than a vertical diameter (11.5 mm to 12.0 mm).4 It is about 0.5 mm thick at its center and gradually increases to about 0.8 mm at the periphery. The cornea has a refractive index between 1.423 - 1.436 and is prolate in shape, i.e., steeper in the center and flatter in the periphery.5 This shape creates an aspheric optical system that contributes 40 – 44 Diopter (D) of refractive power (about 70% of total refraction; the remaining refractive power is provided by the crystalline

CHAPTER 1

Introduction

lens).

The cornea is densely innervated by the long and short ciliary nerves of the ophthalmic division of the fifth cranial nerve. These nerves lose their myelin sheath as they enter the cornea and serve important sensory, reflex, and trophic functions.6 The cornea is not vascularized and instead exchanges nutrients and waste products with the tear film and aqueous humour in the center and the limbus in the periphery. The lack of blood vessels ensures corneal transparency and provides immune privilege, which contributes to the success story of corneal transplantation.7 Transparency and shape are critical for the cornea’s function. The transparency is determined by the regular arrangement of collagen fibrils and a finely controlled hydration of the stroma. In addition, structural proteins play a crucial role in determining the shape of the cornea. The cornea consists of three cellular layers: the epithelium, stroma, and endothelium, separated by two interfaces: Bowman’s layer and Descemet’s membrane,8 as shown in Figure 1. The epithelium is the outermost layer of the cornea and is directly in contact with the external environment. Together with the tear film, it forms the primary barrier of the eye and provides a smooth refractive surface. It is derived from surface ectoderm between five and six weeks of gestation and comprises five to six layers of stratified, squamous, non-keratinized epithelial cells with tight junctions between cells to prevent penetration of pathogens and fluid.7 This organization is homogenous over the entire cornea. Corneal epithelial cells routinely undergo orderly involution, apoptosis, and desquamation at the anterior surface.9 Deeper cells replace the desquamating superficial cells, replacing the entire epithelium every week. The new cells are derived from mitotic activity in the limbus, where vascularized crypts (Palisades of Vogt) provide a nutrient-rich, protected environment for limbal epithelial stem cells. The deepest cellular layer of the corneal epithelium is the basal layer comprised of columnar basal cells that secrete an 0.3 µm thick epithelial basement membrane that consists of type IV collagen and laminin.10 Bowman’s layer (Figure 1) is an acellular non-regenerating layer that lies directly under the epithelial basement membrane. Its function is uncertain, but research suggests it contributes to maintaining corneal shape, promoting

FIGURE 1. Cross section of the human cornea.

stromal wound healing, recovery of anterior corneal transparency, and restoring epithelial innervation after trauma.11 The stroma makes up about 80% to 85% of corneal thickness. It is composed of dense, regularly packed collagen fibrils, measuring about 2 µm in thickness, and arranged in 200-250 orthogonal lamellae. Notably, both the distance between collagen fibrils and the thickness of fibrils are relatively uniform, measuring less than half of the wavelength of visible light (400 – 700 nm). This arrangement, combined with the intracellular corneal crystallins transketolase and aldehyde dehydrogenase classes 1 and 3, allow scattering to cancel out in every direction except forward so that all incoming light rays propagate towards the retina.12-14 If the arrangement of the fibrils is disturbed, for example due to edema, destructive interference is reduced, and the cornea becomes opaque. The spatial organization within the stroma changes from anterior to posterior. Lamellae in the anterior stroma are relatively thicker and form

CHAPTER 1

a tightly interwoven net, whereas posterior lamellae are thinner and run parallel. This hierarchy creates an anterior-posterior gradient of rigidity that supports anterior corneal curvature and redirects excessive fluid posteriorly. The lamellae are produced by keratocytes, which occupy about 3% of the stroma. Keratocytes play a crucial role in maintaining the extracellular matrix environment by producing collagen type I, III, IV, and V, proteoglycans (mainly chondroitin-, dermatan- and keratan sulfate) and matrix metalloproteases. Keratocytes also facilitate mechanical anchoring of collagen bundles and transform to myofibroblasts to promote wound healing after injury.8,15 A microscopically thin layer termed Dua’s layer lines the posterior stroma.16 It is limited by the underlying basement membrane of the corneal endothelium called Descemet’s membrane (DM), named after the French physician Jean Descemet. It measures about 3 µm at birth and gradually thickens to about 10 µm in adulthood. Descemet’s membrane is composed of an anterior banded layer developed before birth and a posterior non-banded layer continuously excreted by endothelial cells. Structurally, DM contains collagen type IV and VIII, laminin, and fibronectin.17 It adheres firmly to the posterior surface of the corneal stroma, reflects any change in the shape of the stroma, and can be peeled off from the stroma using a simple surgical technique called descemetorhexis.18 The endothelium is adjacent to DM and forms the posterior surface of the cornea.19 It is composed of a single layer of corneal endothelial cells (CECs) measuring about 20 μm in diameter and 5 μm in depth. The healthy endothelium resembles a honeycomb due to the arrangement of the hexagonal-shaped CECs. It is firmly anchored to DM and in direct contact with the aqueous humor filling the anterior chamber, which supplies the corneal endothelium with oxygen, glucose, and amino acids. The CECs contain a large nucleus and have abundant amounts of cytoplasmic organelles, including mitochondria, endoplasmic reticulum, free ribosomes, and Golgi apparatus, suggesting that they are metabolically active. The corneal endothelium regulates the water balance of the stroma according to the “pump-leak” mechanism.19 This is accomplished on the one hand by the uncontrolled influx of fluid into the stroma through apical tight junctions (“leaky barrier”) and, on the other hand, by removing excess water from the stroma into the anterior chamber via intracellular Na+ and K+ dependent adenosine triphosphatase (Na+/K+-ATPase) pumps located in the basolateral membrane of the cells at an intensity of 1.5 × 106 pump sites per cell.20 These

Introduction

pumps create a local osmotic gradient across the basolateral membrane resulting in the outflow of stromal fluid into the anterior chamber. The proper balance of the two opposing fluid pathways is crucial for deturgescence (a state of relative dehydration) and consequently for the organization of stromal lamellae and corneal transparency. Additionally, most of the corneal nutrient delivery and metabolite disposal occur through the corneal endothelium. While endothelial glucose transporters enable the uptake and transfer of glucose into the stroma, lactic acid transporters dispose of the end-product of anaerobic glycolysis. The shape and density of CECs are important markers for the health of the corneal endothelium. At birth, endothelial cell density (ECD) measures about 6000 cells/mm2, and at five years of age, ECD rapidly decreases with the expansion of the eye to about 3500 cells/mm2. From adulthood, physiological cell loss measures about 0.6% per year.21 In contrast to the corneal epithelium, the CECs are arrested in the G1-phase of the cell cycle and essentially do not proliferate in humans and exhibit almost no regenerative capacity in-vivo.22 Instead, upon cell death, surrounding cells will enlarge (polymegathism) and change shape (pleomorphism) to occupy the space of dead cells. Typically, physiological cell loss does not lead to a compromise in deturgescence and treatment is not indicated. When endothelial cell loss is accelerated, e.g., due to disease such as Fuchs endothelial corneal dystrophy (FECD), endothelial function may become critically compromised and individuals develop reduced vision and pain.23 Although ECD and cell morphology correlate to endothelial function, intervariability between individuals is large and endothelial dysfunction cannot be deduced from ECD alone.

1.3 FUCHS ENDOTHELIAL CORNEAL DYSTROPHY Fuchs endothelial corneal dystrophy (FECD) is a progressive disease characterized by the loss of corneal endothelial cells, thickening of DM, wart-like excrescences on DM called guttae (Latin: gutta=droplet), and development of corneal edema, as shown in Figure 2. Affected individuals typically experience decreased visual acuity and contrast sensitivity, increased glare, and reduced quality of life.24

CHAPTER 1

Introduction

States.27 Accordingly, it is the primary indication for corneal transplantation, accounting for 39% of all indications worldwide and 36% in the USA.29-31 Across Europe, FECD is the predominant indication, as shown in Chapter 5 of this thesis.30

FIGURE 2. Slit lamp photograph of an edematous cornea with Fuchs endothelial corneal dystrophy (left) and corresponding specular microscopy of the corneal endothelium showing irregular distributed guttae (right).

The disease is named after the Austrian ophthalmologist Ernst Fuchs who reported in 1910 on 13 patients with clouded corneas.25 Fuchs noticed changes primarily in the anterior cornea. He writes: “the first and primary site of the alterations is in the epithelium. For this reason, I name the disease ‘Dystrophia epithelialis,’ a name which can be replaced later by a better one when the true nature of the disease will be discerned.”25 The discovery of the true nature of the disease, as foreseen by professor Fuchs, followed shortly after. In 1916, after the introduction of the slit-lamp, guttae were described.26 And only four years later, the progression of endothelial changes to corneal edema was reported.27 Subsequently, the micro- and macroscopic, histopathologic, ultrastructural, and genetic features of DM and the endothelium in FECD have been described. The hallmark symptom of the initially asymptomatic disease is a diurnal shift in vision: blurry vision upon arising with progressively better vision throughout the day. This symptom is due to fluid accumulation in the stroma during sleep followed by evaporation during the day. As endothelial dysfunction progresses, barrier function is lost and more fluid enters the cornea than can be removed, resulting in permanent corneal edema, vision loss, and pain. In late-stage disease, subepithelial fibrosis, stromal vascularization, fibrous thickening of DM, and epithelial bullae develop that may rupture and trigger episodes of severe pain.28 FECD is the most common corneal dystrophy across various ethnic groups and regions, affecting 4% of the population above 40 years in the United

Based on the time of onset of the disease, FECD is divided into two clinical subtypes. The early-onset variant is rare and affects males and females equally. This variant typically manifests in the first decade of life and progresses over the next few decades. In contrast, late-onset FECD is much more common. Symptoms manifest after the fourth decade with a female predominance of about 3:1.32,33 FECD is a genetically complex and heterogeneous disorder. The early-onset variant has been linked to mutations in the alpha 2 subunit of the collagen 8 (COL8A2) gene, which encodes a key extracellular matrix protein in DM.34 Mutations in COL8A2 are associated with a markedly thickened anterior banded layer of DM, more than three times thicker than average.35 In the late-onset variant, five causal genes (TCF4, AGBL1, LOXHD1, DLC4A11, and ZEB1) and four causal loci on chromosomes 5, 9, 13, and 18 have been identified. Mutations in the transcription factor 4 (TCF4) gene appear to be the main contributor to FECD.36 A study found that 79% of FECD patients had more than 50 intronic cytosine-thymine-guanine (CTG) repeats in the third intron of the TCF4 gene compared to just 3% of unaffected individuals.37 The expanded allele appears to be the most significant global cause of FECD, conferring a 30-fold risk increase for developing FECD in Caucasians and a major causal variant across other ethnic groups. The CTG repeat extension could interfere with transcription initiation or splicing of TCF4. In addition, TCF4 regulates zinc finger E-box binding homeobox (ZEB1) protein, which regulates the expression of extracellular matrix components, including COL8A2. Recent studies suggest RNA aggregation and toxicity form the basis of corneal endothelial cell death.38 Corneal endothelial cells from FECD patients with the CTG expansion accumulate poly(CUG)n RNA in foci within the nucleus, which stimulates apoptosis. Moreover, the endothelium’s exposure to higher levels of oxidative stress may contribute to the trinucleotide repeat expansion. Notably, the number of CTG repeats correlates with the clinical severity of the disease. However, at present, genetic testing is not performed in routine clinical care in most corneal clinics.

CHAPTER 1

Introduction

Professor Fuchs postulated the earliest treatments for FECD.25 These included topical ethylmorphine, negative pressure suction, and iridectomy. Unsurprisingly with our current understanding, these remedies were not very effective. At present, medical treatments for FECD are aimed at reducing corneal edema and alleviating blurry vision. Using 5% sodium chloride eye drops or ointment to draw fluid out of the cornea has assisted with transient symptomatic visual improvement. However, medical treatments (nonsurgical) are temporary solutions to an exacerbating situation. A recent randomized controlled trial found hyperosmolar eye drops are not effective in reducing early morning stromal edema.39 The only definite treatment for FECD, outside the experimental setting is corneal transplantation (keratoplasty). Various novel treatment modalities are currently being developed and tested in laboratories and clinics around the globe. Chapter 8 will discuss these exciting therapies in more detail.

1.4 CORNEAL TRANSPLANTATION THE HISTORY OF CORNEAL TRANSPLANTATION In 1789, during the French revolution, surgeon Guillaume Pellier de Quensgy suggested replacing an opaque cornea with a transparent material to restore vision. A century later, in 1906, Dr. Eduard Zirm was the first to successfully perform a human full-thickness corneal transplant (penetrating keratoplasty [PK]), Figure 3.40 It is noteworthy that the patient was an individual suffering from a bilateral alkali burn which in modern days is among the indications with the poorest outcomes. Dr. Zirm also made several propositions for achieving successful outcomes, i.e. the usage of strict aseptic conditions, of young and healthy donor tissue, anesthesia, the von Hippel trephine, protection of the graft with physiologic saline, and overlay sutures to secure the graft. The subsequent introduction of corticosteroids and antibiotics for the prevention and treatment of allograft rejection and infection were important contributions to make this technique successful and popular among corneal surgeons. Until the turn of the 21st century, PK would remain the mainstay for the replacement of diseased corneal tissue, accounting for more than 95% of transplants performed between 1980 and 2004.41 To date, PK continues to be the treatment of choice when all layers of the cornea are affected.

FIGURE 3. Schematic drawing of various configurations of penetrating keratoplasty. The most common configuration is shown in 1.

Whilst PK can result in an optically transparent cornea, vision recovery can take up to two years after surgery.42 Suture-related complications frequently occur, including suture erosions (11%), infiltrates (9%), loose sutures with imminent wound separation in need of surgical repair (8%), infectious keratitis (3%), and the presence of an avascular graft-to-wound interface (2%).43 The cornea may have large amounts of astigmatism (in one study 49% of eyes had more than or equal to 3 Diopters) or other large refractive errors that require the patient to wear contact lenses or to undergo subsequent surgical procedures.44,45 The large amount of allogeneic tissue that is transplanted has also been linked to high rates of immunological graft rejections. In a large retrospective case series of 3,992 PKs, rejection was the second most common cause of graft failure, responsible for 27% of all failed grafts.46 Moreover, PK is a blunt one-size-fits-all solution: the technique replaces all corneal layers including healthy tissue.

CHAPTER 1

Introduction

FIGURE 5. Volume of Penetrating keratoplasty (PK) and Endothelial keratoplasty (EK) in the USA between 2005 – 2019. Data from the Statistical Report 2019, Eye Bank Association of America.51

FIGURE 4. Schematic drawing showing the various types of lamellar keratoplasty techniques. 4=Descemet membrane endothelial keratoplasty (DMEK); 5=Descemet stripping (automated) endothelial keratoplasty (DS[A]EK) and ultrathin DSAEK; 6=Anterior lamellar keratoplasty (ALK); and 7=Deep anterior lamellar keratoplasty (DALK).

In FECD, only DM and endothelium are affected. Damage to the epithelium and stroma can recover spontaneously if the endothelial function is recovered. This led to the development of partial-thickness cornea transplant procedures that selectively replace diseased corneal layers only. These techniques are known as lamellar keratoplasty.

EVOLUTION OF LAMELLAR KERATOPLASTY Lamellar keratoplasties are categorized into techniques aimed at restoring the anterior cornea (Anterior lamellar keratoplasty [ALK]) and the posterior cornea (Endothelial keratoplasty [EK]), Figure 4. The most prominent ALK technique is Deep ALK (DALK) which replaces

epithelium and stroma while sparing the patient’s Descemet’s membrane and endothelium.47 The most common indication is keratoconus, a disease in which the usually round cornea becomes thin and cone-shaped. The two most common types of EK techniques are Descemet stripping (automated) endothelial keratoplasty (DS[A]EK) and Descemet membrane endothelial keratoplasty (DMEK).29 Both replace the diseased DM and endothelium and leave the healthy stroma and epithelium of the patient intact. Compared to PK, both ALK and EK techniques avoid an open-sky procedure, preserve globe integrity, minimally impact refraction, and introduce fewer alloantigens.48-50 Since its introduction, EK has established itself as the gold standard for the treatment of corneal endothelial dysfunction and has surpassed PK as the most commonly performed corneal transplantation in the United States (Figure 5),51 and other Western countries.52,53 EARLY EXPERIENCE WITH ENDOTHELIAL KERATOPLASTY A timeline of the major steps in the evolution of EK is given in Figure 6. The potential advantages of EK have long been conceived. In 1951, Barraquer described a technique in which a superficial rectangular hinged flap was dissected and a circular opening was trephined in the remaining stroma.

CHAPTER 1

Introduction

was perceived as too complex. To overcome these challenges, Melles described a technique for blunt dissection and removal of the pathologic host Descemet membrane and endothelium through a limbal incision (“descemetorhexis”).18 This approach avoids the complexity of creating a stromal pocket and leaves a smooth posterior surface on which the donor graft can be fixed. Accordingly, this technique was popularized as Descemet stripping endothelial keratoplasty (DSEK).

OUTSOURCING GRAFT PREPARATION TO EYE BANKS: PRECUT TISSUE

FIGURE 6. Timeline of the major steps in the evolution of penetrating keratoplasty to modern endothelial keratoplasty. DLEK=Deep lamellar endothelial keratoplasty; DMEK=Descemet membrane endothelial keratoplasty; DSAEK=Descemet stripping automated endothelial keratoplasty; DSEK=Descemet stripping endothelial keratoplasty; EK=Endothelial keratoplasty; FS=Femtosecond; PK=Penetrating keratoplasty; UT=Ultrathin.

A round lenticule of donor corneal tissue containing stroma and healthy endothelium was transplanted. Then, the graft and the flap were secured with sutures.54 The first successful EK in a patient was performed by Charles Tillet in 195655 who used a partial thickness graft created by the trephination of half of the posterior donor cornea. However, these techniques were technically challenging and were not adopted by fellow surgeons. In 1998, Melles et al. dissected the posterior part of the stroma through a limbal incision and injected a donor graft consisting of posterior stroma and endothelium through the same incision, thus keeping the anterior stroma undisturbed.56 The surgery was finished with injection of air into the anterior chamber. The air presses the graft against the recipient’s stroma, replacing the need for sutures. This technique, known as Deep lamellar endothelial keratoplasty (DLEK), was also not adopted universally, because the technique

Gorovoy postulated the use of an automated microkeratome to enable standardized dissection of a donor posterior lamella from a corneoscleral button mounted on an artificial anterior chamber. The term Descemet stripping automated endothelial keratoplasty (DSAEK) was coined to differentiate it from manually dissected grafts.57 Standardized preparation of donor tissue using microkeratomes also facilitated outsourcing graft preparation to eye banks. In 2007, our research group introduced Femtosecond (FS) laser to cut DSEK lamellae (FS-DSEK). A single eye bank in the Netherlands prepared all FS-DSEK. This process relieved pressure on corneal surgeons to invest in specialized equipment and increases cost-effectiveness. Generally, using precut tissue prepared by the eye bank has several advantages for corneal surgeons including saving time in the operating theater, outsourcing complications related to donor preparation, and allowing for quality control. Studies have shown that precut tissue does not increase the risk of acute complications such as graft dislocation or iatrogenic primary graft failure compared to surgeon-cut lenticules.58,59 Consequently, precut DSAEK gained widespread popularity, replacing PK as the gold standard for the treatment of endothelial pathology.51 MODERN ENDOTHELIAL KERATOPLASTY Although DSAEK provides better globe integrity, faster visual recovery, induces less astigmatism, and has a lower rate of graft rejection compared to PK,60 the visual outcomes remain unpredictable, and many patients do not realize their full vision potential.61 An important step in the evolution of DSAEK was the trephination of thinner grafts. Busin et al. described a technique to dissect grafts with a central graft thickness (CGT) of 100 µm, called ultrathin DSAEK, compared to standard grafts with 200 µm CGT.62

CHAPTER 1

The relationship between graft thickness and visual recovery is a controversial topic.63 Factors such as graft asymmetry, surface roughness, and interface haze affect vision irrespective of graft thickness.64 Moreover, the timing of graft thickness measurement and storage method of grafts are not standardized across trials making a direct comparison unreliable. Our research group conducted a multicenter RCT that provided strong evidence that thinner grafts lead to better visual acuity. Ultrathin DSAEK resulted in significantly better best-corrected visual acuity and faster recovery of contrast sensitivity and glare disability compared to DSAEK.65,66 Recently, even thinner grafts than those used in our study have been introduced. These so-called nanothin 50 μm grafts showed excellent clinical outcomes, but the success rate of obtaining the target thickness was low, measuring only 65%, with an unacceptable risk of graft preparation failure.67,68 THE RISE OF DESCEMET MEMBRANE ENDOTHELIAL KERATOPLASTY In 1998, Melles described a technique to transplant Descemet membrane and endothelium without any stroma.69 This technique known as Descemet membrane endothelial keratoplasty (DMEK) allows selective replacement of the diseased layers only and was performed in the first patient in 2006.70 The graft is only about 10-15 μm thick and is prepared using a descemetorhexis performed on the posterior surface of the donor cornea. The DMEK graft spontaneously rolls with the endothelial cells facing inwards and can be injected into the anterior chamber of the patient. The surgeon unfolds the DMEK roll using fluidic and pneumatic manipulations before injecting gas under the graft to position it against the recipient’s stroma.71 Refinements of the technique continue to this day including surgical technique,72 graft visualization using intraoperative imaging modalities,73 improved dying agents with low endothelial toxicity,74 use of Sulfur Hexafluoride (sf6) gas instead of air tamponade to facilitate graft attachment,75 and preloading grafts in cartridges at the eye bank.76 Innovation in clinical research is mostly unregulated to let pioneers develop and test ideas. Initial case reports are typically followed by retrospective case series and non-randomized trials. By the time enough evidence is gathered to justify an RCT, the “novel” technique may have already entered the maturity stage of the technology adaptation life cycle. As such, using registry data,

Introduction

we have shown that corneal surgeons in the Netherlands widely adopted the DMEK technique before the results of the first RCT were published.31 To address this gap in evidence, our research group received funding from the Netherlands Organization for Health Research and Development (ZonMw) in 2016 to conduct a multicenter RCT comparing DMEK to ultrathin DSAEK. The scientific output of this project is presented in Chapters 2 and 3.77,78

COMPLICATIONS IN ENDOTHELIAL KERATOPLASTY Although EK provides excellent visual and refractive outcomes, early postoperative graft detachment and graft failure remain the Achilles heel of these procedures. Moreover, DMEK surgery is notorious for a steep learning curve: most surgeons need to perform about 25 procedures to learn the basic technique. Thereafter, the path to surgical proficiency continues for many years. A high-volume tertiary center reported that their complication rate in DMEK surgery continuously decreased over multiple years performing hundreds of surgeries.79 GRAFT DETACHMENT During EK surgery, once the graft is in position, the surgeon will gently inject a gas bubble into the anterior chamber to press the graft against the recipient’s cornea. After surgery, patients have to lie in a supine position during the first postoperative day. This will cause the gas tamponade to exhibit pressure on the graft and facilitate long-term attachment. During the first postoperative month, patients return frequently to assess the recovery process and check for adverse events. The most common postoperative complication is a separation from the graft and the recipient cornea. These so-called graft detachments occur after 28% of DMEK surgeries (range 2% 74%).80 Compared to complete detachments, partial detachments show both an area of attachment and detachment of varying degrees, Figure 7. This complication manifests within the first two weeks after surgery and rarely occurs after one month. Areas of detachment are typically not functional and the overlying cornea is edematous. While detachments after DS(A)EK often resolve spontaneously, graft detachments after DMEK are less likely to resolve due to the graft’s tendency to curl and pull away from the recipient’s stroma. Most surgeons define a detachment as clinically significant when

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Introduction

GRAFT FAILURE

The second most common complication after DMEK surgery is primary graft failure (PGF). PGF is an event where a graft fails to clear corneal edema from the first postoperative day without identifiable cause. The Ophthalmic Technology Assessment by the American Academy of Ophthalmology reported a PGF rate for DMEK between 0% - 12.5%.80 In some cases, grafts initially clear the overlying cornea before failing (“secondary graft failure”). Primary and secondary graft failure, unsuccessful rebubbling, and total graft detachments require a repeat transplantation which not only puts a significant burden on patient and health care but also necessitates an additional donor graft.1 Donor corneas are a rare commodity; worldwide there is only one donor cornea available for 70 eyes in need.93 It is, therefore, important to identify risk factors for graft failure to reduce the pressure on donor systems. Single-center case series suggest that a complex anterior segment architecture, such as the presence of a glaucoma drainage device, aphakia, or anterior chamber intraocular lens increases the risk of unsuccessful DMEK surgery,94 but large multicenter studies are missing. In these cases, many surgeons prefer (ultrathin) DSAEK. Using data from the NOTR Cornea, our research group identified risk factors for any type of graft failure within three months after DMEK surgery. The scientific output of this project is presented in Chapter 5.

FIGURE 5. Graft detachment after Descemet membrane endothelial keratoplasty.

the detached area is larger than one-third of the graft surface or when the central cornea is affected.81 In that case, detached grafts can be reattached by repositioning of the graft and intra-cameral injection of an air bubble (“rebubbling”).81 Although rebubbling procedures are low-risk surgical interventions, they can put significant burden on patients and healthcare. Patients have to return to the operating theater, undergo a secondary surgery, lie in a supine position for another period to facilitate graft attachment, and additional follow-up visits have to be scheduled. From a societal and healthcare perspective, a rebubbling procedure translates to costs in terms of lost productivity from patients, valuable time in the operating theater and additional hospital visits. Notably, some corneal surgeons perform a rebubbling procedure in their consultation room instead of the operating theater.82 This technique saves time and money, and reduces burden on patients, but is not widely adopted. Numerous risk factors forgraft detachment have been described, but agreement across reports is weak. These risk factors include donor characteristics, such as age83 and low ECD;84 recipient factors, such as indication,85 age,86 and lens status;87 and surgical parameters, such as descemetorhexis diameter,88 graft folding and orientation,89 graft decentration,90 anterior chamber tamponade agent,91 use of viscoelastic agent,91 postoperative intraocular pressure,91 and surgeon experience.87 In order to determine which risk factors for graft detachment are important in the real world and examine whether rebubbling leads to accelerated endothelial cell loss,92 our research group analyzed data from the Netherlands Organ Transplant Registry (NOTR) Cornea. The scientific output of this project is presented in Chapter 5.

1.5 DETERMINING OUTCOME PARAMETERS Some countries are spearheading a slow revolution in healthcare. The present fee-for-service system, in which providers are paid based on the amount of healthcare services they deliver, is slowly transitioning to a fee-for-value system. In this novel value-based healthcare model, providers are rewarded based on patient health outcomes such as improved patient health and reduced effects and incidence of disease. For this reason, outcome measures in clinical research must evolve alongside treatment modalities to provide relevant answers to patients, clinicians, and payers.95

Incidentally, corneas clear despite total graft detachment. This observation gave rise to the idea of injecting a free-floating donor Descemet membrane as an alternative to keratoplasty.

CHAPTER 1

Introduction

domains, therefore a thorough screening including visual acuity and quality of vision parameters is necessary.96

Outcome measures for corneal transplantation for endothelial dysfunction can be grouped into anatomy, physiology, and impact.95 The distribution of guttae and ECD reveal information about the anatomical state of the cornea before surgery. After transplantation, central ECD measurements give information on the health of the donor CECs. Similarly, central cornea thickness, backscatter, and Scheimpflug tomography maps are surrogate markers for corneal physiology. Before surgery, abnormal values are indicative of corneal edema and endothelial dysfunction. After transplantation, these parameters reveal information about the functionality of the transplanted donor tissue. Lastly and most importantly, clinical parameters related to vision should be measured before and after surgery as the patient sought treatment presumably due to poor vision. Vision or “poor vision” extends beyond visual acuity, which is only a measure of the small-angle domain of the retinal point-spread function. Patients are also burdened with poor contrast sensitivity96 and glare disability, which are related to the large-angle domain, Figure 8. Patients may experience disturbances in one or multiple

Value-based healthcare also relies on health outcomes reported by patients.97 It is important that the impact on visual disability and quality of life is adequately measured as postoperative changes might not always be reflected in anatomical, physiological or objective clinical parameters. Patient reported outcome measures (PROMs) are validated questionnaires that measure symptoms, functioning and disability, health status, and quality of life (QoL).98 PROMs may be generic or disease-specific, they enable comparison between different treatments of the same disease as well as (depending on the questionnaire’s architecture) between different treatments of different diseases. In the RCT performed by our research group, we asses visual acuity as well as quality of vision (glare disability and contrast sensitivity), and generic and vision-related quality of life2. The scientific output of this project is presented in Chapters 2 and 3.66,77

1.6 NATIONAL AND EUROPEAN CORNEAL TRANSPLANT REGISTRIES Registries gather real-world data to evaluate a treatment’s ability to achieve its intended use in the real world. They systematically monitor appropriateness and effectiveness of healthcare, identify benchmarks and outcome variance, and inform improvements in healthcare.99 Registry studies are observational in design and usually gather data from many sites and include a large number of subjects compared to traditional trials. The data is generalizable as it stems from routine care; however, large heterogeneity in the study population and measurement techniques may result in low internal validity. The Dutch national registry NOTR Cornea is a prospective national database founded by the Netherlands Transplantation Foundation (NTS, https:// FIGURE 8. The point spread function of the human eye shows that visual acuity (red), contrast sensitivity (dark blue), and straylight (light blue) are different domains of vision. Patients may experience symptoms in one or multiple domains. The visual angle is exaggerated for clarity.

In the last few years, more suitable questionnaires have been introduced than the generic vision-related quality of life questionnaire NEI VFQ-25 used in our study. The V-FUCHS is disease-specific for FECD and the Catquest-9SF is validated to assess outcomes after corneal transplantation. These instruments will be discussed in Chapter 8.

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www.transplantatiestichting.nl/over-de-nts). In the Netherlands, all corneal transplants are centrally allocated by the NTS and registered in NOTR Cornea. Data related to the recipient, donor, and surgical procedure are captured. After transplantation, clinical personnel complete follow-up parameters of each transplant at predefined time points. In Chapter 4 of this thesis, we evaluate the uptake of DMEK on a national level and assess the outcomes of these grafts performed in routine care. This study also provides external validity to our RCT comparing DMEK to ultrathin DSAEK (Chapter 2). The European Cornea and Cell Transplantation Registry (ECCTR) is a young registry that aims to develop a common assessment methodology and a European web-based registry in the field of corneal transplantation. The project is a consortium of seven partners, including three national registries and professional societies.30,100 The registry allows researchers, healthcare professionals, and authorities to assess and verify the safety, quality, and efficacy of corneal transplantation in Europe. Using a dataset of 12,913 corneal transplants from the ECCTR, Chapters 6 and 7 will for the first time present a birds-eye view of corneal transplantation practice patterns and outcomes in Europe.

1.7 AIM AND OUTLINE OF THIS THESIS The aim of this thesis is to report the practice pattern and outcomes of corneal transplantation in Europe, to evaluate the uptake and outcomes of DMEK in the Netherlands, and to compare the effectiveness of DMEK versus ultrathin DSAEK in the context of multicenter randomized controlled trial. Chapter 2 compares best-spectacle corrected visual acuity, endothelial cell density, refraction, and complications after ultrathin DSAEK versus DMEK in a multicenter randomized controlled trial. Chapter 3 evaluates contrast sensitivity, straylight, and vision-related quality of life after ultrathin DSAEK versus DMEK in a multicenter randomized controlled trial. Chapter 4 reports the uptake and clinical outcomes of DMEK in the Netherlands using data from the Netherlands Organ Transplant Registry (NOTR) Cornea.

Introduction

Chapter 5 identifies risk factors for rebubbling and graft failure after DMEK using data provided by the NOTR Cornea. Chapters 6 presents a first bird’s-eye view of corneal transplantation practice pattern across ten European countries, the United Kingdom and Switzerland using data from the European Cornea and Cell Transplantation Registry (ECCTR). Chapter 7 evaluates real-world graft survival and visual acuity outcomes of corneal transplantations performed in ten European countries, the United Kingdom and Switzerland using data from the ECCTR.

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Introduction

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24. Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009;4(1):7. 25. Fuchs E. Dystrophia epithelialis corneae. Albrecht von Græfe’s Archiv für Ophthalmologie. 1910;76(3):478-508. 26. Koeppe L. Klinische Beobachtungen MIT Der Nernstspaltlampeund dem Hornhautmikroskop. Graefes Arch Klin Exp Ophthalmol. 1916;91363–79. 27. Krachmer JH, Purcell JJ, Jr., Young CW, Bucher KD. Corneal endothelial dystrophy. A study of 64 families. Archives of ophthalmology (Chicago, Ill : 1960). 1978;96(11):2036-2039. 28. lhalis H, Azizi B, Jurkunas UV. Fuchs endothelial corneal dystrophy. The ocular surface. 2010;8(4):173-184. 29. 2019 Eye Banking Statistical Report. Eye Bank Association of America;2020. 30. Dunker SL, Armitage WJ, Armitage M, et al. Practice patterns of corneal transplantation in Europe: first report by the European Cornea and Cell Transplantation Registry. Journal of cataract and refractive surgery. 2021;47(7):865-869. 31. Dunker SL, Veldman MHJ, Winkens B, et al. Real-World Outcomes of DMEK: A Prospective Dutch registry study. American journal of ophthalmology. 2021;222:218-225. 32. Afshari NA, Pittard AB, Siddiqui A, Klintworth GK. Clinical study of Fuchs

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corneal endothelial dystrophy leading to penetrating keratoplasty: a 30-year experience. Archives of ophthalmology (Chicago, Ill : 1960). 2006;124(6):777-780. 33. Hamill CE, Schmedt T, Jurkunas U. Fuchs endothelial cornea dystrophy: a review of the genetics behind disease development. Seminars in ophthalmology. 2013;28(5-6):281-286. 34. Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet. 2001;10(21):2415-2423. 35. Gottsch JD, Zhang C, Sundin OH, Bell WR, Stark WJ, Green WR. Fuchs corneal dystrophy: aberrant collagen distribution in an L450W mutant of the COL8A2 gene. Investigative ophthalmology & visual science. 2005;46(12):4504-4511. 36. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. The New England journal of medicine. 2010;363(11):1016-1024. 37. Wieben ED, Aleff RA, Tosakulwong N, et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. PloS one. 2012;7(11):e49083. 38. Du J, Aleff RA, Soragni E, et al. RNA toxicity and missplicing in the common eye disease fuchs endothelial corneal dystrophy. J Biol Chem.

Introduction

2015;290(10):5979-5990. 39. Zander DB, Bohringer D, Fritz M, et al. Hyperosmolar Eye Drops for Diurnal Corneal Edema in Fuchs’ Endothelial Dystrophy: A Double-Masked, Randomized Controlled Trial. Ophthalmology. 2021;128(11):1527-1533. 40. Zirm E. Eine erfolgreiche totale keratoplastik. Archives of ophthalmology (Chicago, Ill : 1960). 1906;64:580–593. 41. Darlington JK, Adrean SD, Schwab IR. Trends of penetrating keratoplasty in the United States from 1980 to 2004. Ophthalmology. 2006;113(12):21712175. 42. Silbiger JS, Cohen EJ, Laibson PR. The rate of visual recovery after penetrating keratoplasty for keratoconus. The CLAO journal : official publication of the Contact Lens Association of Ophthalmologists, Inc. 1996;22(4):266269. 43. Christo CG, van Rooij J, Geerards AJ, Remeijer L, Beekhuis WH. Suture-related complications following keratoplasty: a 5-year retrospective study. Cornea. 2001;20(8):816-819. 44. Muraine M, Sanchez C, Watt L, Retout A, Brasseur G. Long-term results of penetrating keratoplasty. A 10-year-plus retrospective study. Graefe’s archive for clinical and experimental ophthalmology=Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2003;241(7):571-576. 45. Cheng YY, Schouten JS, Tahzib NG, et

al. Efficacy and safety of femtosecond laser-assisted corneal endothelial keratoplasty: a randomized multicenter clinical trial. Transplantation. 2009;88(11):1294-1302. 46. Thompson RW, Jr., Price MO, Bowers PJ, Price FW, Jr. Long-term graft survival after penetrating keratoplasty. Ophthalmology. 2003;110(7):13961402. 47. Reinhart WJ, Musch DC, Jacobs DS, Lee WB, Kaufman SC, Shtein RM. Deep anterior lamellar keratoplasty as an alternative to penetrating keratoplasty a report by the american academy of ophthalmology. Ophthalmology. 2011;118(1):209-218. 48. Melles GR, Lander F, Rietveld FJ, Remeijer L, Beekhuis WH, Binder PS. A new surgical technique for deep stromal, anterior lamellar keratoplasty. The British journal of ophthalmology. 1999;83(3):327-333. 49. Arenas E, Esquenazi S, Anwar M, Terry M. Lamellar corneal transplantation. Survey of ophthalmology. 2012;57(6):510-529. 50. Tan DT, Dart JK, Holland EJ, Kinoshita S. Corneal transplantation. Lancet (London, England). 2012;379(9827):17491761. 51. 2019 Eye banking statistical report. 52. Flockerzi E, Maier P, Bohringer D, et al. Trends in Corneal Transplantation from 2001 to 2016 in Germany: A Report of the DOG-Section Cornea and its Keratoplasty Registry.

American journal of ophthalmology. 2018;188:91-98. 53. Dickman MM, Peeters JM, van den Biggelaar FJ, et al. Changing Practice Patterns and Long-term Outcomes of Endothelial Versus Penetrating Keratoplasty: A Prospective Dutch Registry Study. American journal of ophthalmology. 2016;170:133-142. 54. Barraquer JI. Lamellar keratoplasty. (Special techniques). Annals of ophthalmology. 1972;4(6):437-469. 55. Tillett CW. Posterior lamellar keratoplasty. American journal of ophthalmology. 1956;41(3):530-533. 56. Melles GR, Eggink FA, Lander F, et al. A surgical technique for posterior lamellar keratoplasty. Cornea. 1998;17(6):618-626. 57. Gorovoy MS. Descemet-stripping automated endothelial keratoplasty. Cornea. 2006;25(8):886-889. 58. Terry MA, Shamie N, Chen ES, Phillips PM, Hoar KL, Friend DJ. Precut tissue for Descemet’s stripping automated endothelial keratoplasty: vision, astigmatism, and endothelial survival. Ophthalmology. 2009;116(2):248256. 59. Terry MA. Endothelial keratoplasty: a comparison of complication rates and endothelial survival between precut tissue and surgeon-cut tissue by a single DSAEK surgeon. Trans Am Ophthalmol Soc. 2009;107:184-191. 60. Price MO, Gorovoy M, Benetz BA, et

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al. Descemet’s stripping automated endothelial keratoplasty outcomes compared with penetrating keratoplasty from the Cornea Donor Study. Ophthalmology. 2010;117(3):438-444. 61. Tourtas T, Laaser K, Bachmann BO, Cursiefen C, Kruse FE. Descemet membrane endothelial keratoplasty versus descemet stripping automated endothelial keratoplasty. American journal of ophthalmology. 2012;153(6):1082-1090 e1082. 62. Busin M, Patel AK, Scorcia V, Ponzin D. Microkeratome-assisted preparation of ultrathin grafts for descemet stripping automated endothelial keratoplasty. Investigative ophthalmology & visual science. 2012;53(1):521-524. 63. Wacker K, Bourne WM, Patel SV. Effect of Graft Thickness on Visual Acuity After Descemet Stripping Endothelial Keratoplasty: A Systematic Review and Meta-Analysis. American journal of ophthalmology. 2016;163:18-28. 64. Dickman MM, Cheng YY, Berendschot TT, van den Biggelaar FJ, Nuijts RM. Effects of graft thickness and asymmetry on visual gain and aberrations after descemet stripping automated endothelial keratoplasty. JAMA ophthalmology. 2013;131(6):737744. 65. Dickman MM, Kruit PJ, Remeijer L, et al. A Randomized Multicenter Clinical Trial of Ultrathin Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) versus DSAEK. Ophthalmology. 2016;123(11):2276-2284.

Introduction

66. Dickman MM, Dunker SL, Kruit PJ, et al. Quality of vision after ultrathin descemet stripping automated endothelial keratoplasty: a multicentre randomized clinical trial. Acta ophthalmologica. 2019;97(4):e671-e672.

72. Studeny P, Farkas A, Vokrojova M, Liskova P, Jirsova K. Descemet membrane endothelial keratoplasty with a stromal rim (DMEK-S). The British journal of ophthalmology. 2010;94(7):909-914.

78. Dunker SL, Dickman MM, Wisse RPL, et al. Quality of vision and vision-related quality of life after Descemet membrane endothelial keratoplasty: a randomized clinical trial. Acta ophthalmologica. 2021;99(7):e1127-e1134.

67. Cheung AY, Hou JH, Bedard P, et al. Technique for Preparing Ultrathin and Nanothin Descemet Stripping Automated Endothelial Keratoplasty Tissue. Cornea. 2018;37(5):661-666.

73. Cost B, Goshe JM, Srivastava S, Ehlers JP. Intraoperative optical coherence tomography-assisted descemet membrane endothelial keratoplasty in the DISCOVER study. American journal of ophthalmology. 2015;160(3):430-437.

79. Schrittenlocher S, Schaub F, Hos D, Siebelmann S, Cursiefen C, Bachmann B. Evolution of Consecutive Descemet Membrane Endothelial Keratoplasty Outcomes Throughout a 5-Year Period Performed by Two Experienced Surgeons. American journal of ophthalmology. 2018;190:171178.

68. Kurji KH, Cheung AY, Eslani M, et al. Comparison of Visual Acuity Outcomes Between Nanothin Descemet Stripping Automated Endothelial Keratoplasty and Descemet Membrane Endothelial Keratoplasty. Cornea. 2018;37(10):1226-1231. 69. zam L, Dapena I, van Luijk C, van der Wees J, Melles GR. Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy: review of the first 50 consecutive cases. Eye (London, England). 2009;23(10):1990-1998.

74. Siebelmann S, Matthaei M, Horster R, Cursiefen C, Bachmann B. Lutein and Brilliant Blue-Based Dye for Donor Preparation and Transplantation in Descemet Membrane Endothelial Keratoplasty. Cornea. 2017;36(4):440444. 75. Marques RE, Guerra PS, Sousa DC, et al. Sulfur Hexafluoride 20% Versus Air 100% for Anterior Chamber Tamponade in DMEK: A Meta-Analysis. Cornea. 2018;37(6):691-697.

70. Baydoun L, Müller T, Lavy I, et al. TenYear Clinical Outcome of the First Patient Undergoing Descemet Membrane Endothelial Keratoplasty. Cornea. 2017;36(3):379-381.

76. Catala P, Vermeulen W, Rademakers T, et al. Transport and Preservation Comparison of Preloaded and Prestripped-Only DMEK Grafts. Cornea. 2020;39(11):1407-1414.

71. Dapena I, Moutsouris K, Droutsas K, Ham L, van Dijk K, Melles GR. Standardized “no-touch” technique for descemet membrane endothelial keratoplasty. Archives of ophthalmology (Chicago, Ill : 1960). 2011;129(1):8894.

77. Dunker SL, Dickman MM, Wisse RPL, et al. Descemet Membrane Endothelial Keratoplasty versus Ultrathin Descemet Stripping Automated Endothelial Keratoplasty: A Multicenter Randomized Controlled Clinical Trial. Ophthalmology. 2020;127(9):11521159.

80. Deng SX, Lee WB, Hammersmith KM, et al. Descemet Membrane Endothelial Keratoplasty: Safety and Outcomes: A Report by the American Academy of Ophthalmology. Ophthalmology. 2018;125(2):295-310. 81. Fernandez Lopez E, Baydoun L, Gerber-Hollbach N, et al. Rebubbling Techniques for Graft Detachment After Descemet Membrane Endothelial Keratoplasty. Cornea. 2016;35(6):759764. 82. Sales CS, Straiko MD, Terry MA. Novel Technique for Rebubbling DMEK Grafts at the Slit Lamp Using Intravenous Extension Tubing. Cornea. 2016;35(4):582-585. 83. Rodriguez-Calvo de Mora M, Groeneveld-van Beek EA, Frank LE, et al. Association Between Graft Storage Time and Donor Age With Endothelial Cell Density and Graft Adherence After Descemet Membrane

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Endothelial Keratoplasty. JAMA ophthalmology. 2016;134(1):91-94. 84. Mechels KB, Greenwood MD, Sudhagoni RG, Berdahl JP. Influences on rebubble rate in Descemet’s membrane endothelial keratoplasty. Clin Ophthalmol. 2017;11:2139-2144. 85. Leon P, Parekh M, Nahum Y, et al. Factors Associated With Early Graft Detachment in Primary Descemet Membrane Endothelial Keratoplasty. American journal of ophthalmology. 2018;187:117-124. 86. Maier AK, Gundlach E, Pilger D, et al. Rate and Localization of Graft Detachment in Descemet Membrane Endothelial Keratoplasty. Cornea. 2016;35(3):308-312. 87. Siebelmann S, Ramos SL, Matthaei M, et al. Factors Associated With Early Graft Detachment in Primary Descemet Membrane Endothelial Keratoplasty. American journal of ophthalmology. 2018;192:249-250. 88. Tourtas T, Schlomberg J, Wessel JM, Bachmann BO, Schlotzer-Schrehardt U, Kruse FE. Graft adhesion in descemet membrane endothelial keratoplasty dependent on size of removal of host’s descemet membrane. JAMA ophthalmology. 2014;132(2):155-161. 89. Dirisamer M, van Dijk K, Dapena I, et al. Prevention and management of graft detachment in descemet membrane endothelial keratoplasty. Archives of ophthalmology (Chicago, Ill

Introduction

: 1960). 2012;130(3):280-291. 90. Yuda K, Kato N, Takahashi H, et al. Effect of Graft Shift Direction on Graft Detachment and Endothelial Cell Survival After Descemet Membrane Endothelial Keratoplasty. Cornea. 2019;38(8):970-975. 91. Pilger D, Wilkemeyer I, Schroeter J, Maier AB, Torun N. Rebubbling in Descemet Membrane Endothelial Keratoplasty: Influence of Pressure and Duration of the Intracameral Air Tamponade. American journal of ophthalmology. 2017;178:122-128. 92. Dunker S, Winkens B, van den Biggelaar F, et al. Rebubbling and graft failure in Descemet membrane endothelial keratoplasty: a prospective Dutch registry study. The British journal of ophthalmology. 2021:bjophthalmol-2020-317041. 93. Gain P, Jullienne R, He Z, et al. Global Survey of Corneal Transplantation and Eye Banking. JAMA ophthalmology. 2016;134(2):167-173. 94. Cohen E, Mimouni M, Sorkin N, et al. Risk Factors for Repeat Descemet Membrane Endothelial Keratoplasty Graft Failure. American journal of ophthalmology. 2021;226:165-171. 95. Patel SV. Towards Clinical Trials in Fuchs Endothelial Corneal Dystrophy: Classification and Outcome Measures-The Bowman Club Lecture 2019. BMJ Open Ophthalmol. 2019;4(1):e000321. 96. van

der

Meulen

IJ,

Patel

SV,

Lapid-Gortzak R, Nieuwendaal CP, McLaren JW, van den Berg TJ. Quality of vision in patients with fuchs endothelial dystrophy and after descemet stripping endothelial keratoplasty. Archives of ophthalmology (Chicago, Ill : 1960). 2011;129(12):1537-1542. 97. Damman OC, Jani A, de Jong BA, et al. The use of PROMs and shared decision-making in medical encounters with patients: An opportunity to deliver value-based health care to patients. J Eval Clin Pract. 2020;26(2):524-540. 98. Ahern S, Ruseckaite R, Ackerman IN. Collecting patient-reported outcome measures. Intern Med J. 2017;47(12):1454-1457. 99. Ehrenstein V, Nielsen H, Pedersen AB, Johnsen SP, Pedersen L. Clinical epidemiology in the era of big data: new opportunities, familiar challenges. Clin Epidemiol. 2017;9:245-250. 100. Dunker SL, Armitage WJ, Armitage M, et al. Outcomes of corneal transplantation in Europe: report by the European Cornea and Cell Transplantation Registry. Journal of cataract and refractive surgery. 2021;47(6):780785.

CHAPTER 2

DMEK versus ultrathin UDSAEK

CHAPTER 2

Descemet Membrane Endothelial Keratoplasty versus Ultrathin Descemet Stripping Automated Endothelial Keratoplasty: A Multicenter Randomized Controlled Clinical Trial

Authors Suryan L. Dunker, Mor M. Dickman, Robert P.L. Wisse, Siamak Nobacht, Robert H.J. Wijdh, Marjolijn C. Bartels, Mei L. Tang, Frank J.H.M. van den Biggelaar, Pieter J. Kruit, and Rudy M.M.A. Nuijts OPHTHALMOLOGY. 2020 SEP;127(9):1152-1159

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Abstract 46

PURPOSE: To compare best spectacle-corrected visual acuity (BSCVA), endothelial cell density (ECD), refractive astigmatism, and complications after Descemet membrane endothelial keratoplasty (DMEK) and ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK). DESIGN Prospective, multicenter randomized controlled trial. PARTICIPANTS: Fifty-four pseudophakic eyes of 54 patients with corneal endothelial dysfunction resulting from Fuchs endothelial corneal dystrophy were enrolled in 6 corneal centers in The Netherlands. METHODS: Participants were allocated to DMEK (n=29) or UT-DSAEK (n=25) using minimization randomization based on preoperative BSCVA, recipient central corneal thickness, gender, age, and institution. Donor corneas were prestripped and precut for DMEK and UT-DSAEK, respectively. Six corneal surgeons participated in this study. MAIN OUTCOME MEASURES: The primary outcome measure was BSCVA at 12 months after surgery. RESULTS: Central graft thickness of UT-DSAEK lamellae measured 101 mm (95% confidence interval [CI], 90-112 μm). Best spectacle-corrected visual acuity did not differ significantly between DMEK and UT-DSAEK groups at 3 months (0.15 logarithm of the minimum angle of resolution [logMAR] [95% CI 0.080.22 logMAR] vs. 0.22 logMAR [95% CI 0.16-0.27 logMAR]; P=0.15), 6 months (0.11 logMAR [95% CI 0.05-0.17 logMAR] vs. 0.16 logMAR [95% CI 0.12-0.21 logMAR]; P=0.20), and 12 months (0.08 logMAR [95% CI 0.03-0.14 logMAR]

DMEK versus ultrathin UDSAEK

vs. 0.15 logMAR [95% CI 0.10-0.19 logMAR]; P=0.06). Twelve months after surgery, the percentage of eyes reaching 20/25 Snellen BSCVA was higher in DMEK compared with UT-DSAEK (66% vs. 33%; P=0.02). Endothelial cell density did not differ significantly 12 months after DMEK and UT-DSAEK (1870 cells/mm2 [95% CI 1670-2069 cells/mm2] vs. 1612 cells/mm2 [95%CI 1326-1898 cells/mm2]; P=0.12). Both techniques induced a mild hyperopic shift (12 months: +0.22 diopter [D; 95% CI -0.23 to 0.68 D] for DMEK vs. +0.58 D [95% CI 0.13-1.03 D] for UT-DSAEK; P=0.34). Conclusions: Descemet membrane endothelial keratoplasty and UT-DSAEK did not differ significantly in mean BSCVA, but the percentage of eyes achieving 20/25 Snellen vision was significantly higher with DMEK. Endothelial cell loss did not differ significantly between the treatment groups, and both techniques induced a minimal hyperopic shift.

2.1 Introduction Descemet membrane endothelial keratoplasty (DMEK) is the latest iteration in endothelial keratoplasty. The primary advantage of DMEK over previous techniques has been suggested to be superior visual recovery.1 Consequently, corneal surgeons are increasingly adopting DMEK for the treatment of corneal endothelial dysfunction.2 Currently, a lack of consensus exists regarding the definition of Descemet stripping automated endothelial keratoplasty (DSAEK) at various thicknesses. In line with our previous randomized controlled trial (RCT) comparing ultrathin DSAEK (UT-DSAEK) and DSAEK and a large prospective series of UT-DSAEK by Busin et al,3 we defined ultrathin as DSAEK grafts with intended central graft thickness of 100 μm.4 In 4 meta-analyses, DMEK showed superior best spectacle-corrected visual acuity (BSCVA) compared with DSAEK,5–8 but studies comparing DMEK with UT-DSAEK are scarce. A single RCT reported superior BSCVA after DMEK compared with UT-DSAEK.9 However, in that RCT, 70% of corneal

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transplantations were combined with cataract extraction and intraocular lens placement (triple procedure), which hinders attributing visual recovery to corneal transplantation only. Both eyes of 12 patients were enrolled in the study, leading to a dependency between eyes, and the visual recovery in the UT-DSAEK arm was reduced in the first 6 postoperative months compared with previous studies assessing UT-DSAEK.3,4,10 The purpose of the current RCT was to compare BSCVA, endothelial cell density (ECD), refraction, and complications of DMEK versus UT-DSAEK in pseudophakic eyes with Fuchs endothelial corneal dystrophy in a multicenter setting.

2.2 Methods This study was conducted at 6 corneal clinics in The Netherlands. The study received approval from the medical ethics committee of the Maastricht University Medical Center, Maastricht, The Netherlands and was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from all patients. Patients were recruited between November 2016 and November 2017. The trial was registered in the United States trial register as the DMEK versus DSAEK Study (Clinical-Trials.gov identifier, NCT02793310). Inclusion criteria were pseudophakic adult patients with corneal endothelial dysfunction resulting from Fuchs endothelial corneal dystrophy. Exclusion criteria were previous corneal transplantation in the study eye, vision-limiting comorbidities, the need for a human leukocyte antigen-typed corneal transplantation, or the inability to comply with study procedures or complete the followup. No triple procedures were performed, and only 1 eye per patient was enrolled. Each participant’s medical history was recorded, and all eligible patients underwent a comprehensive ophthalmic examination including slit-lamp examination, manifest refraction, BSCVA using an Early Treatment Diabetic Retinopathy Study letter chart (Vector Vision, Greenville, OH), Scheimpflug tomography (Pentacam HR; Oculus Optikgeräte GmbH, Wetzlar, Germany), specular microscopy (SP-3000; Topcon, Nagoya, Japan), posterior segment OCT (Spectralis; Heidelberg Engineering GmbH, Heidelberg, Germany), and anterior segment OCT (Casia SS-1000; Tomey, Nagoya, Japan).

DMEK versus ultrathin UDSAEK

DONOR PREPARATION Descemet membrane endothelial keratoplasty and UT-DSAEk grafts were prepared by a single eye bank (ETB-BISLIFE, Leiden, The Netherlands), except for 1 DMEK graft prepared by the surgeon during surgery. The selection criteria for donor corneas were identical between DMEK and UT-DSAEK. All donor tissues were preserved in organ culture.4 For DMEK, grafts were peeled manually by trained eye bank technicians, sparing a peripheral hinge of 10%.11 No grafts were prestamped. For UT-DSAEK, graft dissection was performed with the Gebauer SLc microkeratome system (Gebauer Medizintechnik GmbH, Neuhausen, Germany) using a single-pass technique,12 targeted at a central residual graft thickness of 10 ± 20 μm. Central corneal graft thickness was assessed by anterior segment OCT (Casia SS-1000) immediately after dissection. All grafts measured 8.5 mm in diameter except for 7 UT-DSAEK grafts with a diameter of 8 mm. Corneoscleral buttons were shipped to the medical center in transport medium supplemented with 6% dextran (Sigma Aldrich, St. Louis, MO) 1 day before surgery. SURGICAL PROCEDURE All surgical procedures were performed by experienced corneal surgeons (M.C.B., S.N., R.M.M.A.N., M.L.T., R.H.J.W., and R.P.L.W.) who completed hundreds of DSAEK and UT-DSAEK procedures and at least 25 DMEK procedures before inclusion began. The corneal surgeons were allowed to use their preferred surgical technique for DMEK and UT-DSAEK. Forty-three patients underwent neodymium:yttriume-aluminume-garnet laser iridotomy before surgery. The remaining 10 patients underwent preoperative surgical iridectomy. In DMEK and UT-DSAEK, 2.8-mm and 4.5-mm corneal incisions were made, respectively. Descemetorhexis was performed with a reversed Price-Sinskey hook (Moria, Antony, France) under air (DMEK, n=15; UTDSAEK, n=15) or viscoelastic substance (Healon; Abbott Medical, Uppsala, Sweden; DMEK, n=14; UT-DSAEK, n=10). Descemet membrane endothelial keratoplasty grafts were stained with trypan blue (Vision Blue; Dutch Ophthalmic USA, Exeter, NH) and injected into the anterior chamber of the recipient using a Geuder shooter (n=27) or DORC glass pipette (n=2). External corneal tapping was used to unfold and position the graft. UTDSAEK grafts were inserted using a Busin glide (n=12), Tan Endo glide (n=9), or Macaluso reusable injector (n=4). A full anterior chamber fill was performed between 8 and 15 minutes using air in UT-DSAEK cases and either 10% to 20% sulfur hexafluoride (SF6; n=17)

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or air (n=12) in DMEK. Afterward, the size of the gas bubble was reduced to 80%. An occlusive patch was applied, and the patients were asked to remain in a supine position for the first 24 hours after surgery. After surgery, both treatment arms received topical dexamethasone 0.1% eye drops (Ratiopharm, Zaandam, The Netherlands) and topical chloramphenicol 0.5% eye drops (Ratiopharm). Anterior chamber tamponade reinjections (rebubblings) were performed in cases of corneal edema caused by large, central, or complete graft detachments.13 OUTCOME MEASURES The primary outcome measure was high-contrast BSCVA. Secondary outcome measures were ECD, refraction, and complications. A certified optometrist determined manifest refractionusing a cross-cylinder technique for cylinder refinement. The BSCVA was recorded using the Early Treatment Diabetic Retinopathy Study letter chart at 4 m under mesopic ambient lighting conditions. The letter score was converted to the logarithm of the minimum angle of resolution (logMAR) units as follows: the log score of the last row where the patient identified all letters correctly was recorded, and 0.02 log units were subtracted for every letter that was identified correctly beyond the last row. Refractive shift was defined as the difference in postoperative spherical equivalent compared with baseline values. Donor ECD was determined at the eye bank by manual cell count using a light microscope after trypan blue staining to improve mosaic visualization. Postoperative ECD was assessed by specular microscopy. Using the corner method,14 technicians at each site defined manually, if possible, a minimum of 50 endothelial cells of the central cornea. To reduce sampling error, the ECDs of 3 photographs were averaged. SAMPLE SIZE The power calculation was based on the expected difference of 0.2 logMAR with a standard deviation of 0.2 logMAR between DMEK and UT-DSAEK. Assuming an a of 0.05 (2-sided), a power of 90%, and 15% loss to follow-up, at least 25 patients were required per treatment arm. Four to 5 patients were allocated per treatment arm per center. The number of inclusions per center was not limited, and inclusion was closed when the target was reached. RANDOMIZATION AND BLINDING

DMEK versus ultrathin UDSAEK

Minimization randomization was performed centrally by an investigator from the coordinating center using a random sequence generator (Trans European Network for Clinical Trials Services; (www.tenalea.net). Minimization was based on preoperative Early Treatment Diabetic Retinopathy Study BSCVA, recipient central corneal thickness, gender, age, and recruitment center. The randomization result was sent to the eye bank and the operating surgeon. Patients were blinded to treatment throughout the study period. Outcome assessors were unblinded to treatment because eyes that underwent DMEK and UT-DSAEK are distinguishable during postoperative assessment. STATYSTICAL ANALYSIS An intention-to-treat analysis was performed for all outcomes measures. Statistical analysis was performed using SPSS for Windows version 24.0 (SPSS, Inc., Chicago, IL). Data were described as mean ± standard deviation (95% confidence interval [CI]) for continuous variables and as individual counts and percentages for categorical variables. Continuous data were analyzed using the Student t test for differences between treatment arms. For sensitivity analysis of the primary outcome measure, a linear mixed model with BSCVA as the dependent variable, study group and time as factors, and an unstructured covariance matrix was used. In a post hoc analysis, total adverse events and the percentage of eyes reaching 20/20 or better and 20/25 or better Snellen BSCVA at 12 months were tested using the Fisher exact test or Pearson chi-square test as appropriate. Correction for multiple comparisons was performed using the Bonferroni correction. A 2-sided P value of less than 0.05 was considered statistically significant.

2.3 Results PARTICIPANT FLOW Participant flow based on the Consolidated Standards of Reporting Trials (CONSORT) guidelines is displayed in Figure 1.15 Fifty-four eyes of 54 patients were randomized to DMEK (n=29) or UT-DSAEK (n=25). A minimum of 6 patients was included per site, and every surgeon performed between 2 and 6 UT-DSAEK surgeries and between 2 and 8 DMEK surgeries. Before surgery,

CHAPTER 2

DMEK versus ultrathin UDSAEK

TABLE 1.. Baseline Patient and Donor Characteristics

Ultrathin descement stripping automated endothelial keratoplasty (n=25)

Descemet Membrane Endothelial Keratoplasty (n=29)

Baseline patient characteristics

Age (yrs)

71 ± 7 (68–74)

72 ± 7 (69–74)

ETDRS BSCVA (logMAR)

0.31 ± 0.13 (0.26–0.37)

0.37 ± 0.18 (0.30–0.44)

Spherical equivalent

–0.83 ± 1.54 (–1.46 to –0.19)

–0.09 ± 1.39 (–0.63 to –0.44)

72 ± 8 (69–75)*

73 ± 5 (72-75)*

Baseline donor characteristics Age, yrs

FIGURE 1. Participant flow chart. DMEK=Descemet membrane endothelial keratoplasty; UT-DSAEK=ultrathin Descemet stripping automated endothelial keratoplasty.

1 patient in the UT-DSAEK arm chose to postpone treatment for an indefinite period. All remaining patients in both groups received the allocated treatment. Two patients in the DMEK arm underwent re-transplantation because of graft detachment. No patients were lost to follow-up. BASELINE PATIENT AND DONOR CHARACTERISTICS Baseline patient and donor characteristics are displayed in Table 1. Following the 2012 CONSORT guidelines, baseline characteristics were not tested for statistical differences.15 Central graft thickness of UT-DSAEK lamellae measured 101±25 μm (range, 90-112 μm). VISUAL OUTCOMES Visual outcomes are shown in Figure 2. Recently published visual outcomes

Death to enucleation (hrs) 12 ± 6 (9–14)*

12 ± 6 (9–14)*

Death to preservation (hrs)

28 ± 7 (24–31)*

24 ± 11 (20–24)*

Organ culture preservation (days) asdfasdf

11 ± 4 (10–13)*

14 ± 6 (12–16)*

Transport medium (days)

3.5 ± 1 (3.1–39.9)*

3.1 ± 0.8 (3.1–3.7)*

ECD (cells/mm2)

2633 ± 158 (2567–2700)*

2679 ± 157 (2620–2739)

Central graft thickness (μm)

101 ± 25 (90–112)*

not applicable

BSCVA=best spectacle-corrected visual acuity D=diopter ECD=endothelial cell density ETDRS=Early Treatment Diabetic Retinopathy Study logMAR=logarithm of the minimum angle of

resolution Data are mean ± standard deviation (95% confidence interval) *One missing value

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DMEK versus ultrathin UDSAEK

FIGURE 2. Graph showing best spectacle-corrected visual acuity (in logarithm of the minimum angle of resolution [logMAR] units) of Descemet membrane endothelial keratoplasty (DMEK; blue circles) and ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK; green squares) at baseline and 3, 6, and 12 months after surgery. DETECT=Descemet Endothelial Thickness Comparison Trial. *Best spectacle-corrected visual acuities from the DETECT study are shown for comparison (purple diamonds and orange triangles for DMEK and UT-DSAEK, respectively).9

FIGURE 3. Bar graph showing the cumulative percentage of eyes achieving 20/32 or better, 20/25 or better, and 20/20 or better Snellen best-spectacle corrected visual acuity before surgery and 3, 6, and 12 months after Descemet membrane endothelial keratoplasty (DMEK) versus ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK). *P=0.02.

of the Descemet Endothelial Thickness Comparison Trial (DETECT) are shown for comparison.9 Baseline BSCVA measured 0.37±0.18 logMAR (95% CI 0.300.44 logMAR; n=29) in the DMEK arm and 0.31 ± 0.13 logMAR (95% CI 0.260.37 logMAR; n=25) in the UT-DSAEK arm. After surgery, BSCVA improved in both treatment arms to a similar extent. Postoperative BSCVA did not differ significantly between DMEK and UT-DSAEK at 3 months (0.15 ± 0.18 logMAR [95% CI, 0.08-0.22 logMAR; n=29] vs. 0.22 ± 0.13 logMAR [95% CI, 0.16-0.27 logMAR; n=24; P=0.15]), 6 months (0.1±10.16 logMAR [95% CI, 0.05-0.17 logMAR; n=29] vs. 0.16 ± 0.10 logMAR [95% CI, 0.12-0.21 logMAR; n=24]; P=0.20), and 12 months (0.08±0.14 logMAR [95% CI, 0.03-0.14 logMAR; n=29] vs. 0.15±0.11 logMAR [95% CI, 0.10-0.19 logMAR; n=24]; P=0.06). Linear mixed model sensitivity analysis showed better visual acuity in DMEK patients, but this was not statistically significant after adjusting for multiple testing (3 months: –0.09 logMAR [95% CI, –0.17 to –0.01 logMAR; adjusted P=0.08]; 6 months: –0.07 logMAR [95% CI, –0.14 to 0.00 logMAR; adjusted P=0.16]; and 12 months: –0.08 logMAR [95% CI, –0.15 to –0.014 logMAR; adjusted P=0.05). Figure 3 shows the percentage of eyes seeing 20/32 or better, 20/25 or better, and 20/20 or better Snellen after surgery. The percentage of eyes seeing 20/25 or

better Snellen BSCVA was higher in DMEK compared with UTDSAEK patients (19/29 [66%] vs. 8/24 [33%]; P=0.02). No statistically significant difference was observed in eyes seeing 20/20 or better Snellen BSCVA (DMEK: 7/29 [24%] vs. UTDSAEK: 1/24 [4%]; P=0.06). ENDOTHELIAL CELL DENSITY AND REFRACTIVE OUTCOMES Endothelial cell density and refractive outcomes are shown in Table 2. After adjusting for multiple comparisons, ECD did not differ significantly between DMEK and UT-DSAEK patients at all postoperative follow-up visits. Neither inserter, type of tamponade, nor graft size of UT-DSAEK significantly influenced ECD. The spherical equivalent did not differ significantly between DMEK and UT-DSAEK patients at all postoperative time points. Both techniques induced a comparable hyperopic shift of approximately 0.5 diopter (D). ADVERSE EVENTS Adverse events are shown in Table 2. The total number of complications

CHAPTER 2

DMEK versus ultrathin UDSAEK

TABLE 2. Baseline, donor, and surgery characteristics of all corneal transplants in the ECCR registry (N=12,913, unless otherwise specified).

Ultrathin Descemet Stripping Automated Endothelial Keratoplasty (n=24)

Descemet Membrane Endothelial Keratoplasty (n=29)

3 mos

0.22 ± 0.13 (0.16–0.27)

0.15 ± 0.18 (0.08–0.22)

0.15

6 mos

0.16 ± 0.10 (0.12–0.21)

0.11 ± 0.16 (0.05–0.17)

0.20

12 mos

0.15 ± 0.11 (0.10–0.19)

0.08 ± 0.14 (0.03–0.14)

0.06

P Value

ETDRS BSCBA (logMAR)

Spherical equivalent 3 mos

–0.33 ± 1.42 (–0.93 to 0.28) 0.31 ± 1.43 (–0,23 to 0.85)

0.11

6 mos

–0.08 ± 167 (–0.79 to 0.62)

0.74

12 mos

–0.29 ± 1.49 (–0,92 to 0.34) 0.13 ± 1.63 (–0.49 to 0.75)

0.34

3 mos

0.53 ± 1.09 (0.07–0.99)

0.41 ± 1.25 (–0.08 to 0.88)

0.42

6 mos

0.78 ± 1.01 (0.35–1.21)

0.16 ± 1.28 (–0.32 to 0.65)

0.06

12 mos

0.58 ± 1.07 (0.13–1.03)

0.22 ± 1.19 (–0.23 to 0.68)

0.27

3 mos

1564 ± 726 (1257–1870)

1924 ± 446 (1754–2094)

0.04*

6 mos

1642 ± 662 (1356–1929)†

1944 ± 492 (1753–2135)†

0.07

12 mos

1612 ± 645 (1326–1898)‡

1870 ± 504 (1670–2069)‡

0.012

Donor prepara1 tion failure

–

Rebubbling

7§

–

Re-transplantation

–

3§

–

Elevated IOP

–

Cystoid macular – edema

–

Graft rejection

–

Total

0.01

0.07 ± 11.58 (–0.53 to 0.67)

Hypertropic shift (D)

ECD (cells/mm2)

Adverse events

BSCVA=best spectacle-corrected visual acuity; D=diopter; ECD=endothelial cell density; ETDRS=Early Treatment Diabetic Retinopathy Study;IOP=intraocular pressure; logMAR=logarithm of the minimum angle of resolution.

Data are mean ± standard deviation (95% confidence interval). * Not significant after adjusting for multiple testing. † One missing value. ‡ Two missing values.

during the 1-year follow-up was higher after DMEK compared with UT-DSAEK (17/29 vs. 6/24; P=0.01). More dislocations requiring rebubbling occurred in the DMEK arm (n=7, including 1 patient with 2 rebubblings) compared with the UT-DSAEK arm (n=1). In the DMEK arm, 3 rebubblings were performed after primary SF6 tamponade and 4 rebubblings after primary air tamponade. Only 1 rebubbling was performed after UT-DSAEK (air tamponade). All graft detachments were partial, and rebubbling was performed only for graft detachments of more than one third of the graft surface area. Review of postoperative OCT images excluded reverse graft positioning. In the DMEK arm, 2 eyes underwent rebubbling that failed and was subsequently followed by repeated transplantation. One eye underwent a second repeat transplantation for partial graft detachment. No graft rejection occurred in either treatment arm during the first year after surgery. Four patients in the UT-DSAEK arm and 5 patients in the DMEK arm demonstrated elevated intraocular pressure (defined as >25 mmHg or an increase of 10 mmHg compared with baseline).

5.4 Discussion This multicenter RCT compared BSCVA, ECD, refractive astigmatism, and complications of DMEK versus UT-DSAEK during a follow-up period of 1 year. We found neither statistically significant nor clinically relevant differences in mean BSCVA, ECD, spherical equivalent, and hyperopic shift between the treatment arms. The percentage of eyes reaching 20/25 or better Snellen BSCVA at 12 months was significantly higher in DMEK patients compared with UT-DSAEK patients. However, significantly more adverse events occurred after DMEK. The primary outcome measure of our study was highcontrast BSCVA. We found no statistically significant differences in mean BSCVA between both techniques 3, 6, and 12 months after surgery. In this regard, our findings differ from those of the DETECT study. Average graft thickness in the UT-DSAEK arm of the DETECT trial was thinner compared with that in our study (73 mm vs. 101 mm). However, this did not translate to better BSCVA compared with the UT-DSAEK arm in our study. Nonetheless, comparing graft thickness between trials is made difficult because of the heterogeneity in measurement timing and techniques and graft storage methods. The DMEK arm of the DETECT study showed better postoperative VA compared with our DMEK arm (Figure

CHAPTER 2

2).9 Consequently, the DETECT study reported better BSCVA after DMEK compared with UT-DSAEK. Although the primary outcome, BSCVA 1 year after surgery, did not differ significantly between UT-DSAEK and DMEK groups, we consider the significant difference in the percentage of eyes achieving 20/25 or better Snellen vision clinically relevant and indicative of a real effect. Minor differences in design between the DETECT study and current RCT may explain the differences in mean visual acuity. Compared with the DETECT study, eligibility criteria in the current trial were limited to patients with corneal endothelial dysfunction resulting from Fuchs endothelial corneal dystrophy. No surgeries were combined with cataract extraction and intraocular lens placement, and to avoid dependency between 2 eyes, only the first eye was included in patients fulfilling the eligibility criteria for both eyes. Moreover, in the United States, donor corneas are preserved in cold storage media, whereas in Europe, preservation in organ culture medium is the standard. Endothelial cell density is a major determinant for longterm graft survival.16 The loss of endothelial cells after corneal transplantation is multifactorial and includes donor characteristics,17,18 recipient characteristics,19,20 and postoperative complications.19 In our study, postoperative ECD was lower after UT-DSAEK compared with DMEK, albeit not statistically significant. In contrast to our findings, the DETECT study reported a trend of lower ECD after DMEK compared with UT-DSAEK.9 The combined results of both RCTs may suggest that endothelial cell loss is comparable between DMEK and UT-DSAEK. The postoperative refractive change in our study was comparable between DMEK and UT-DSAEK groups. The meniscus-shaped profile of dissected lamellae has been suggested to contribute to a hyperopic shift. Yet, a comparable hyperopic shift in DMEK and UT-DSAEK points to corneal deswelling as the potential driver for refractive change. The small hyperopic shift observed with both techniques is in line with previous studies reporting an average refractive shift of +0.3 D.1,4 Consequently, both techniques have been used effectively in triple procedures.21 In our study, the most common complication was graft detachment necessitating rebubbling. Compared with 1 rebubbling in the UT-DSAEK arm (4%), 7 rebubblings occurred in the DMEK arm (24%), of which 2 were in the same eye. The rate of rebubbling in DMEK differs significantly between reports, averaging 29% but ranging from 2% to 82%.22,23 In line with our results,

DMEK versus ultrathin UDSAEK

the DETECT study reported rebubbling rates in DMEK and UT-DSAEK of 24% and 4%, respectively.9 In the current study, DMEK grafts were nonstamped. Use of prestamped DMEK tissue is reported to reduce graft detachment rate.24 Some reports suggest that an anterior chamber tamponade using SF6 gas reduces the rate of graft detachment by facilitating cellular wound healing at the graftehost interface.25–27 In our cohort, SF6 gas was not associated with statistically significant lower rebubbling rates compared with air, but our study was not powered to analyze these differences Similarly, the current study is not powered to assess the relationship between complication rates and type of study center. Larger, multicenter prospective studies are needed to answer this question. We believe that graft dislocation has a multifactorial origin and cannot be attributed solely to the learning curve of an individual surgeon. This is outlined by the current multicenter study, in which the participation of 6 surgeons led to similar rebubbling rates as compared with the DETECT trial (2 participating surgeons). Currently, no consensus exists regarding the definition of UT-DSAEK. In the current study, we aimed at a central graft thickness of 100 μm. This is in line with our previous RCT comparing UT-DSAEK and DSAEK4 and with a large prospective study by Busin et al.3 The current study has a number of limitations. The assessors of the primary outcome measure, BSCVA, were not masked. Corneal surgeons were allowed to practice their own surgical technique. This heterogeneity may influence complication rates. Larger multicenter studies are needed to address the impact of surgical variables on clinical outcomes. All surgical procedures were performed by experienced lamellar corneal surgeons, who completed hundreds of DSAEK and UT-DSAEK procedures and at least 25 DMEK procedures before operating on study patients. The corneal surgeons completed their training in The Netherlands, where the guidelines of the Dutch Cornea Workgroup determine the qualifications required to perform lamellar keratoplasty. Multiple studies report an inverse relationship between graft detachment and surgical experience for DMEK.28–30 However, no consensus exists regarding a cutoff point. For example, analysis of 2485 cases by Oellerich et al30 reported a graft detachment rate of 34% for novice DMEK surgeons (<25 cases) and 22% for experienced DMEK surgeons (>100 cases). The detachment rate in our study (24%) is in line with that reported for experienced surgeons in this large multicenter study. Visual recovery and endothelial cell loss do not seem to be dependent on a surgeon’s

CHAPTER 2

DMEK versus ultrathin UDSAEK

experience.28,30

References

In this study, a larger sample size might have yielded statistically significant differences. However, the observed effect size was 0.08 logMAR at 12 months, which is less than half of what can be considered a clinically relevant improvement.31 Moreover, the loss to follow-up rate was much smaller than anticipated, which increases the power. Similar to our study, the DETECT study also included 50 eyes. Six corneal clinics participated in this study to increase generalizability. These were academic and nonacademic centers, as requested by The Netherlands Association for Health Research and Development, which provided financial support for this study.

1. Deng SX, Lee WB, Hammersmith KM, et al. Descemet Membrane Endothelial Keratoplasty: Safety and Outcomes: A Report by the American Academy of Ophthalmology. Ophthalmology. 2018;125(2):295-310.

Modern lamellar keratoplasty techniques have evolved into procedures with a predictable outcome. However, a standard for reporting outcomes is lacking. Currently, the literature on endothelial keratoplasty reports the mean visual acuity or the percentage of eyes reaching certain threshold visual acuity. This creates a set of problems when outcomes are compared across trials. It would be helpful to set standards on reporting the most important outcome measure, that is, visual acuity, as has been done in the past in refractive surgery. In summary, DMEK and UT-DSAEK did not differ significantly in mean BSCVA, endothelial cell loss, or hyperopic shift. The percentage of eyes reaching 20/25 Snellen vision or better was higher in DMEK compared with UT-DSAEK patients, but the DMEK group also showed higher adverse event rates.

2. Eye Bank Association of America. 2018 Eye Banking Statistical Report. Available at: https://restoresight.org/ wp-content/uploads/2019/03/2018_ Statistical_Report-Complete-1.pdf. Accessed February 12th, 2020. 3. Dickman MM, Kruit PJ, Remeijer L, et al. A Randomized Multicenter Clinical Trial of Ultrathin Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) versus DSAEK. Ophthalmology. 2016;123(11):2276-2284. 4. Busin M, Madi S, Santorum P, Scorcia V, Beltz J. Ultrathin descemet’s stripping automated endothelial keratoplasty with the microkeratome double-pass technique: twoyear outcomes. Ophthalmology. 2013;120(6):1186-1194. 5. Pavlovic I, Shajari M, Herrmann E, Schmack I, Lencova A, Kohnen T. Meta-Analysis of Postoperative Outcome Parameters Comparing Descemet Membrane Endothelial Keratoplasty Versus Descemet Stripping Automated Endothelial Keratoplasty. Cornea. 2017;36(12):1445-1451. 6. Li S, Liu L, Wang W, et al. Efficacy and safety of Descemet’s membrane endothelial keratoplasty

versus Descemet’s stripping endothelial keratoplasty: A systematic review and meta-analysis. PloS one. 2017;12(12):e0182275. 7. Zhu L, Zha Y, Cai J, Zhang Y. Descemet stripping automated endothelial keratoplasty versus descemet membrane endothelial keratoplasty: a meta-analysis. International ophthalmology. 2018;38(2):897-905. 8. Singh A, Zarei-Ghanavati M, Avadhanam V, Liu C. Systematic Review and Meta-Analysis of Clinical Outcomes of Descemet Membrane Endothelial Keratoplasty Versus Descemet Stripping Endothelial Keratoplasty/Descemet Stripping Automated Endothelial Keratoplasty. Cornea. 2017;36(11):1437-1443. 9. Chamberlain W, Lin CC, Austin A, et al. Descemet Endothelial Thickness Comparison Trial: A Randomized Trial Comparing Ultrathin Descemet Stripping Automated Endothelial Keratoplasty with Descemet Membrane Endothelial Keratoplasty. Ophthalmology. 2019;126(1):19-26. 10. Droutsas K, Petrelli M, Miltsakakis D, et al. Visual Outcomes of Ultrathin-Descemet Stripping Endothelial Keratoplasty versus Descemet Stripping Endothelial Keratoplasty. Journal of ophthalmology. 2018;2018:5924058. 11. Hamzaoglu EC, Straiko MD, Mayko ZM, Sales CS, Terry MA. The First 100 Eyes of Standardized Descem-

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et Stripping Automated Endothelial Keratoplasty versus Standardized Descemet Membrane Endothelial Keratoplasty. Ophthalmology. 2015;122(11):2193-2199. 62

12. Dickman MM, Kruit PJ, van den Biggelaar FJ, Berendschot TT, Nuijts RM. Single-Pass Dissection of Ultrathin Organ-Cultured Endothelial Lamellae Using an Innovative Microkeratome System. Cornea. 2016;35(1):100-104. 13. Yeh RY, Quilendrino R, Musa FU, Liarakos VS, Dapena I, Melles GR. Predictive value of optical coherence tomography in graft attachment after Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2013;120(2):240-245.

DMEK versus ultrathin UDSAEK

17. Brockmann T, Pilger D, Brockmann C, Maier AB, Bertelmann E, Torun N. Predictive Factors for Clinical Outcomes after Primary Descemet’s Membrane Endothelial Keratoplasty for Fuchs’ Endothelial Dystrophy. Current eye research. 2019;44(2):147-153. 18. Musch DC, Meyer RF, Sugar A. Predictive factors for endothelial cell loss after penetrating keratoplasty. Archives of ophthalmology (Chicago, Ill : 1960). 1993;111(1):80-83. 19. Baydoun L, Ham L, Borderie V, et al. Endothelial Survival After Descemet Membrane Endothelial Keratoplasty: Effect of Surgical Indication and Graft Adherence Status. JAMA ophthalmology. 2015;133(11):1277-1285.

14. McCarey BE, Edelhauser HF, Lynn MJ. Review of corneal endothelial specular microscopy for FDA clinical trials of refractive procedures, surgical devices, and new intraocular drugs and solutions. Cornea. 2008;27(1):1-16.

20. Ishii N, Yamaguchi T, Yazu H, Satake Y, Yoshida A, Shimazaki J. Factors associated with graft survival and endothelial cell density after Descemet’s stripping automated endothelial keratoplasty. Sci Rep. 2016;6:25276.

15. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. International journal of surgery (London, England). 2012;10(1):28-55.

21. Schoenberg ED, Price FW, Jr., Miller J, McKee Y, Price MO. Refractive outcomes of Descemet membrane endothelial keratoplasty triple procedures (combined with cataract surgery). Journal of cataract and refractive surgery. 2015;41(6):1182-1189.

16. Patel SV, Lass JH, Benetz BA, et al. Postoperative Endothelial Cell Density Is Associated with Late Endothelial Graft Failure after Descemet Stripping Automated Endothelial Keratoplasty. Ophthalmology. 2019;126(8):10761083.

22. Phillips PM, Phillips LJ, Muthappan V, Maloney CM, Carver CN. Experienced DSAEK Surgeon’s Transition to DMEK: Outcomes Comparing the Last 100 DSAEK Surgeries With the First 100 DMEK Surgeries Exclusively Using Previously Published Tech-

niques. Cornea. 2017;36(3):275-279. 23. Tourtas T, Laaser K, Bachmann BO, Cursiefen C, Kruse FE. Descemet membrane endothelial keratoplasty versus descemet stripping automated endothelial keratoplasty. American journal of ophthalmology. 2012;153(6):1082-1090 e1082. 24. Veldman PB, Dye PK, Holiman JD, et al. The S-stamp in Descemet Membrane Endothelial Keratoplasty Safely Eliminates Upside-down Graft Implantation. Ophthalmology. 2016;123(1):161-164. 25. Guell JL, Morral M, Gris O, Elies D, Manero F. Comparison of Sulfur Hexafluoride 20% versus Air Tamponade in Descemet Membrane Endothelial Keratoplasty. Ophthalmology. 2015;122(9):1757-1764. 26. von Marchtaler PV, Weller JM, Kruse FE, Tourtas T. Air Versus Sulfur Hexafluoride Gas Tamponade in Descemet Membrane Endothelial Keratoplasty: A Fellow Eye Comparison. Cornea. 2018;37(1):15-19. 27. Siebelmann S, Lopez Ramos S, Scholz P, et al. Graft Detachment Pattern After Descemet Membrane Endothelial Keratoplasty Comparing Air Versus 20% SF6 Tamponade. Cornea. 2018;37(7):834-839. 28. Schrittenlocher S, Schaub F, Hos D, Siebelmann S, Cursiefen C, Bachmann B. Evolution of Consecutive Descemet Membrane Endothelial Keratoplasty Outcomes Throughout a

5-Year Period Performed by Two Experienced Surgeons. American journal of ophthalmology. 2018;190:171178. 29. Dapena I, Ham L, Droutsas K, van Dijk K, Moutsouris K, Melles GR. Learning Curve in Descemet’s Membrane Endothelial Keratoplasty: First Series of 135 Consecutive Cases. Ophthalmology. 2011;118(11):2147-2154. 30. Oellerich S, Baydoun L, Peraza-Nieves J, et al. Multicenter Study of 6-Month Clinical Outcomes After Descemet Membrane Endothelial Keratoplasty. Cornea. 2017;36(12):14671476. 31. Rosser DA, Cousens SN, Murdoch IE, Fitzke FW, Laidlaw DA. How sensitive to clinical change are ETDRS logMAR visual acuity measurements? Investigative ophthalmology & visual science. 2003;44(8):3278-3281.

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Quality of vision and vision-related quality of life after DMEK

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Quality of vision and visionrelated quality of life after Descemet membrane endothelial keratoplasty: a randomized clinical trial

Authors Suryan L. Dunker, Mor M. Dickman, Robert P.L. Wisse, Siamak Nobacht, Robert H.J. Wijdh, Marjolijn C. Bartels, N.E. Mei-Lie Tang, Frank J.H.M. van den Biggelaar, Pieter J. Kruit, Bjorn Winkens and Rudy M.M.A. Nuijts ACTA OPHTHALMOL. 2021 NOV;99(7):E1127-E1134

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Quality of vision and vision-related quality of life after DMEK

3.1 Introduction Abstract

AIMS: To compare quality of vision and vision-related quality of life (QOL) in patients undergoing Descemet membrane endothelial keratoplasty (DMEK) or ultrathin Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: Fifty-four eyes of 54 patients with Fuchs’ dystrophy from six corneal clinics in the Netherlands were randomized to DMEK or ultrathin DSAEK and examined preoperatively, and 3, 6 and 12 months postoperatively. Main outcome measures were corneal higher-order aberrations (HOAs), contrast sensitivity, straylight and vision-related QOL. RESULTS: Posterior corneal HOAs decreased after DMEK and increased after ultrathin DSAEK (p≤0.001) 3 months after surgery and correlated positively with best spectacle-corrected visual acuity (12 months: r=0.29, P=0.04). Anterior and total corneal HOAs did not differ significantly between both techniques at any time point. Contrast sensitivity was better (P=0.01), and straylight was lower (P=0.01) 3 months after DMEK compared with ultrathin DSAEK; 95% confidence interval [CI] of log(cs) 1.10–1.35 versus 95% CI: 0.84 to 1.12, and 95% CI: log(s) 1.18 to 1.43 versus 95% CI: 1.41 to 1.66, respectively. Both were comparable at later time points. Vision-related QOL (scale 0–100) did not differ significantly between both groups at any time point and improved significantly at 3 months (β=12 [95% CI: 7 to 16]; P<0.001), and subsequently between 3 and 12 months (β=5 [95% CI: 0 to 9]; P=0.06). CONCLUSION: Descemet membrane endothelial keratoplasty (DMEK) results in lower posterior corneal HOAs compared with ultrathin DSAEK. Contrast sensitivity and straylight recover faster after DMEK but reach similar levels with both techniques at 1 year. Vision-related QOL improved significantly after surgery, but did not differ between both techniques.

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation (Gain et al. 2016). Two transplantation techniques to treat corneal endothelial failure are ultrathin Descemet stripping automated endothelial keratoplasty (ultrathin DSAEK) and Descemet membrane endothelial keratoplasty (DMEK). We recently reported the results of a multicentre randomized controlled trial (RCT) showing mean best spectacle-corrected visual acuity (BSCVA) does not differ between DMEK and ultrathin DSAEK, although a signiﬁcantly higher proportion of patients achieved 0.8 Snellen or better after DMEK (Dunker et al. 2020). Nonetheless, there is more to vision than visual acuity. Patients routinely seek treatment for symptoms related to glare and reduced contrast sensitivity. In the era of modern endothelial keratoplasty, such complaints may even be the main indication for corneal transplantation in selected cases. The current study provides the most comprehensive evaluation to date of quality of vision and vision-related quality (QOL) of life after DMEK. In this prespeciﬁed analysis, we compare corneal higher-order aberrations (HOAs), contrast sensitivity, straylight (forward scatter) and vision-related QOL in patients with symptomatic FECD randomized to either DMEK or ultrathin DSAEK.

3.2 Methods The full methods of this study were previously reported in detail (Dunker et al. 2020). The current study is a prespecified analysis of a RCT comparing secondary clinical outcomes of DMEK and ultrathin DSAEK over 12 months follow-up. Patients with corneal dysfunction due to FECD were included in six corneal clinics in the Netherlands. The primary outcome measure was BSCVA in logarithm of minimum angle of resolution (logMAR) using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart twelve months after surgery. The study received approval from the institutional review boards of all participating clinics and complied with the tenets of the Declaration of Helsinki. All participants provided written informed consent. Patients were recruited between November 2016 and November 2017. The trial was

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registered in the US trial register as the DMEK Versus DSAEK Study (www. clinicaltrials.gov, no. NCT02793310, accessed October 15th, 2020). Inclusion criteria were pseudophakic adult patients with corneal endothelial dysfunction due to FECD. Exclusion criteria were previous corneal transplantation in the study eye, vision-limiting comorbidities, the need for a human leukocyte antigen-typed (HLA) corneal transplantation, or inability to comply with study procedures or complete follow-up. No triple procedures were performed, and only one eye per patient was enrolled. 68

OUTCOME MEASURES Patients were evaluated preoperatively, and three, six, and twelve months postoperatively. At each visit, corneal higher-order aberrations (HOAs), contrast sensitivity, and straylight were measured, and subjects completed the NEI VFQ-25 questionnaire. Scheimpflug tomography (Pentacam HR, Oculus Optikgeräte GmbH, Wetzlar, Germany) was used to measure corneal HOAs. Measurements were conducted under mesopic conditions using the 50 pictures, 3-dimensional scan mode with automatic release. All scans were checked for data acquisition errors and repeated if necessary. Corneal aberrations were measured using ray-tracing over a 6-mm diameter zone centered at the corneal apex. Using Zernike polynomials, the root-mean-square (RMS) of the corneal HOAs (3rd– 6th order) was calculated. Contrast sensitivity was measured at three, six, eight, and twelve cycles per degree using the CSV-1000 chart (Vector vision Inc., Greenville, OH, USA). The system’s internal light source was calibrated at 85 candelas (cd)/m2 and adjusts automatically for ambient light, providing standardized testing. Patients were tested monocularly in undilated eyes at 2.5 m distance with manifest refraction in place. Individual values were converted into the area under the log contrast sensitivity function (log(cs)). Intraocular forward light scatter (straylight) was measured using the compensation-comparison based C-Quant straylight meter (Oculus Optikgeräte GmbH, Wetzlar, Germany). Refractive error was corrected in the tested undilated eye, while the fellow eye remained occluded. Measurements

Quality of vision and vision-related quality of life after DMEK

took place in a dark room. Examinations were considered reliable when estimated standard deviation and quality factor were ≤0.08 and ≥1.00, respectively. Forward light scatter was expressed as the logarithm of the straylight parameter (log(s)). Vision-related QOL was assessed using the National Eye Institute visual function questionnaire 25 items (NEI VFQ-25) questionnaire. This instrument consists of eleven vision-related subscales and one scale addressing general health. Each scale ranges from zero to 100, i.e. from worst to best possible outcome, respectively. A composite score was calculated by averaging all unweighted item scores except general health. SAMPLE SIZE Sample size calculation was based on the primary outcome measure, BSCVA twelve months after surgery. We expected a difference of 0.2 logMAR with a standard deviation of 0.2 logMAR between DMEK and ultrathin DSAEK. Choosing a two-sided alpha at 5%, a power of 90%, and expecting 15% loss to follow-up, at least 25 subjects were required per treatment arm. Four to five patients were allocated per treatment arm per center. RANDOMIZATION AND BLINDING Randomization with minimization was performed centrally by an investigator from the coordinating center using a random sequence generator (Trans European Network for Clinical Trials Services, TENALEA, available at www.tenalea.net). Patients were randomized based on the following stratification factors: preoperative ETDRS logMAR BSCVA, recipient central corneal thickness, recipient sex, recipient age, and recruitment center. The cornea bank (ETB-BISLIFE, Leiden, the Netherlands) received the assigned treatment plan and distributed the grafts to surgeons. Patients were blinded throughout the study period. Outcome assessors were unblinded because eyes that underwent DMEK and ultrathin DSAEK are distinguishable during postoperative assessment. STATISTICAL ANALYSIS Data were analyzed using an intention-to-treat analysis. Analyses were

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performed using SPSS for Windows (version 24.0, SPSS Inc., Chicago, IL). Categorical data were described as individual counts and percentages and continuous data as mean ± standard deviation. A linear mixed model (LMM) with the respective mean outcome variable as the dependent variable, study group, time, and study group*time as factors, and an unstructured covariance matrix was used. Bivariate relationships were calculated using Pearson correlation analysis. Sensitivity analysis was performed for the outcome measure vision-related quality of life. Data of patients that underwent corneal transplantation in the fellow eye during the study were excluded at the followup time points six months and twelve months to eliminate the effect of the

Quality of vision and vision-related quality of life after DMEK

fellow eye surgery. A two-sided P≤0.05 was considered statistically significant.

3.3 RESULTS A study flow diagram is presented in Figure 1. Briefly, fifty-four eyes of 54 patients were randomized to DMEK (n=29) or UT-DSAEK (n=25). All patients in both groups received the allocated treatment, except for one patient in the UTDSAEK arm who postponed treatment indefinitely. Two patients in the DMEK arm underwent repeated transplantation due to persistant graft detachment. No patients were lost to follow-up. In the DMEK arm, patients were 72 [69 – 74] years old and endothelial cell density of the donor graft measured 2679 [2620 – 2739] cells/mm2. In the ultrathin DSAEK arm, patients were 71 [68 – 74] years old, endothelial cell density of the donor graft measured 2633 [2567 – 2700] cells/mm2, and preoperative central graft thickness measured 101 ± 25 µm [90 – 112]. In the DMEK arm, 24% (n=7) underwent cornea transplantation in the other eye before the study, and 31% (n=9) underwent cornea transplantation in the other eye during the study. In the ultrathin DSAEK arm, 21% (n=5) underwent cornea transplantation in the other eye before the study, and 38% (n=9) underwent cornea transplantation in the other eye during the study. CORNEAL HIGHER-ORDER ABERRATIONS Anterior corneal HOAs did not differ between DMEK and ultrathin DSAEK at all time points, Table 1. Anterior corneal HOAs increased by β=0.18 [95% CI 0.01 – 0.34], P=0.039, and subsequently stabilized between 3 and 12 months (β=-0.04 [95% CI -0.2 – 0.13], P=0.7), Figure 2A. At 6 months, anterior corneal HOAs significantly correlated with BSCVA (r=0.3, P=0.033), but not at other time points. BSCVA values are given in Table 1.

FIGURE 1. Randomized controlled trial of DMEK versus ultrathin DSAEK: Participant flow diagram. Twentynine eyes of 29 patients were randomized to DMEK, and 25 eyes of 25 patients were randomized to ultrathin DSAEK. One patient in the ultrathin DSAEK arm did not undergo corneal transplantation. DMEK=Descemet membrane endothelial keratoplasty, UT-DSAEK=ultrathin Descemet stripping automated endothelial keratoplasty.

Posterior corneal HOAs did not differ between both groups before surgery. After surgery, posterior corneal HOAs were significantly lower after DMEK compared with ultrathin DSAEK at all time points, Figure 2A. In DMEK, posterior corneal HOAs decreased at three months compared to baseline (β=-0.2 [95% CI -0.36 – -0.4], P=0.015), and subsequently stabilized between three and twelve months (β=-0.02 [95% CI -0.18 – 0.14], P=0.8). In ultrathin DSAEK, posterior corneal HOAs increased at three months (β=0.24 [95% CI 0.14 – 0.33], P<0.001), and significantly decreased between three and twelve months (β=-0.21 [95% CI -0.31 – -0.11], P<0.001). At 3 and 12 months, in both

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Quality of vision and vision-related quality of life after DMEK

TABLE 1. Randomized controlled trial of DMEK versus ultrathin DSAEK: Contrast sensitivity, straylight, corneal higher-order aberrations and vision-related quality of life outcomes. UT-DSAEK, EMM [95% CI] (n)

HOAs CF, rms Preoperative 3 mos 6 mos 12 mos HOAs CF, rms Preoperative 3 mos 6 mos 12 mos HOAs TC, rms Preoperative 3 mos 6 mos 12 mos Contrast sensitivity, log Preoperative 3 mos 6 mos 12 mos Straylight, log Preoperative 3 mos 6 mos 12 mos VFQ-25, composite score Preoperative 3 mos 6 mos

DMEK, EMM [95% CI] (n)

0.83 [0.70–0.96] (24) 0.98 [0.80–1.17] (24) 0.93 [0.72–1.14] (23) 0.90 [0.73–1.08] (24)

0.77 [0.65–0.89] (28) 0.99 [0.82–1.16] (27) 0.96 [0.77–1.16] (27) 0.97 [0.81–1.13] (28)

0.5 1 0.8 0.6

0.47 [0.31–0.63] (24) 0.71 [0.62–0.79] (24) 0.59 [0.52–0.66] (23) 0.50 [0.43–0.56] (24)

0.57 [0.43–0.72] (28) 0.38 [0.30–0.46] (27) 0.37 [0.31–0.43] (27) 0.36 [0.30–0.41] (28)

0.3 <0.001 <0.001 0.002

0.92 [0.71–1.13] (24) 1.13 [0.93–1.33] (24) 1.04 [0.81–1.27] (23) 1.02 [0.84–1.21] (24)

0.95 [0.76–1.15] (28) 1.04 [0.86–1.23] (27) 1.00 [0.79–1.22] (27) 1.02 [0.85–1.19] (28)

0.8 0.5 0.8 1

0.66 [0.56–0.76] (24) 0.98 [0.84–1.12] (22) 1.13 [1.03–1.24] (23) 1.15 [1.03–1.28] (24)

0.71 [0.61–0.80] (28) 1.22 [1.10–1.35] (26) 1.23 [1.13–1.33] (28) 27 [1.15–1.39] (28)

0.5 0.01 0.2 0.2

1.55 [1.44–1.66] (17) 1.54 [1.41–1.66] (18) 1.40 [1.30–1.50] (15) 1.33 [1.23–1.43] (18)

1.58 [1.47–1.68] (17) 1.30 [1.18–1.43] (19) 1.35 [1.26–1.45] (18) 1.34 [1.24–1.45] (15)

0.7 0.01 0.5 0.9

69 [63–75] (23) 77 [72–83] (23) 82 [78–86] (24)

67 [62–72] (27) 80 [75–85] (29) 84 [80–88] (28)

0.6 0.4 0.5

84 [80–89] (29)

0.9

0.37 [0.30–0.44] (29)

–*

12 mos

84 [79–89] (23) ETDRS BSCVA, logMAR (Dunker et al. 2020) 0.31 [0.26–0.37] (25) Preoperative 3 mos

0.22 [0.16–0.27] (24)

0.15 [0.08–0.22] (29)

0.2

6 mos

0.16 [0.12–0.21] (24)

0.11 [0.05–0.17] (29)

0.2

12 mos

0.15 [0.10–0.19] (24)

0.08 [0.03–0.14] (29)

0.1

BSCVA=Best spectacle-corrected visual acuity, CB=cornea back, CF=cornea front, CI=confidence interval, DMEK=Descemet membrane endothelial keratoplasty, EMM=estimated marginal mean, ETDRS=Early Treatment Diabetic Retinopathy Study, HOAs=higher order aberrations,

logMAR=Logarithm of the Minimum Angle of Resolution, rms=root mean square, TC=total cornea, UT-DSAEK=ultrathin Descemet stripping automated endothelial keratoplasty, VFQ-25=National Eye Institute Visual Function Questionnaire 25 items. * Not tested.

FIGURE 2. Randomized controlled trial of DMEK versus ultrathin DSAEK: Corneal higher-order aberrations (HOAs, 3rd to 6th order) over a 6.0-mm optical zone in both treatment groups. (A) Left: Anterior corneal HOAs did not differ between DMEK and ultrathin DSAEK at all time points. Anterior corneal HOAs increased by β=0.18 [95% CI: 0.01 to 0.34], P=0.039, and subsequently stabilized between 3 and 12 months. (B) Right: Posterior corneal HOAs were significantly lower after DMEK compared with ultrathin DSAEK at 3 months (rms=0.38 [95% CI: 0.30 to 0.46] versus rms=0.71 [95% CI: 0.62 to 0.79]; P<0.001), 6 months (rms=0.37 [95% CI: 0.31 to 0.43] versus rms=0.59 [95% CI: 0.52 to 0.66], P<0.001) and 12 months (rms=0.36 [95% CI: 0.30 to 0.41] versus rms=0.50 [95% CI: 0.43 to 0.56], P=0.002). Total corneal HOAs (not shown) did not differ significantly between DMEK and ultrathin DSAEK at all time points and did not change significantly over time (all β≤0.13, all P≥0.2). DMEK=Descemet membrane endothelial keratoplasty, UT-DSAEK=ultrathin Descemet stripping automated endothelial keratoplasty. **P≤0.01; ***P≤0.001.

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Quality of vision and vision-related quality of life after DMEK

FIGURE 3. Randomized controlled trial of DMEK versus ultrathin DSAEK: Contrast sensitivity in both treatment groups. Three months after surgery, contrast sensitivity was significantly higher after DMEK compared with ultrathin DSAEK (log(cs)=1.22 [95% CI: 1.10 to 1.35] versus log(cs)=0.98 [95% CI: 0.84 to 1.12]; respectively, P=0.01). Contrast sensitivity correlated negatively with best spectacle-corrected visual acuity (logarithm of the minimum angle of resolution) at all time points (preoperative: r= 0.4, P=0.003; 3 months: r= 0.43, P=0.003; 6 months: r= 0.52, P<0.001; 12 months: r= 0.53, P<0.001). CS=contrast sensitivity value, DMEK=Descemet membrane endothelial keratoplasty, UT-DSAEK=ultrathin Descemet stripping automated endothelial keratoplasty. **P≤0.01.

groups, posterior corneal HOAs were significantly correlated with BSCVA, albeit weakly (r=0.29, P=0.04, and r=0.29, P=0.04; respectively), but not at baseline and 6 months (r=0.22, P=0.1, and r=0.21, P=0.2; respectively). Total corneal HOAs did not differ significantly between DMEK and ultrathin DSAEK at all time points, Table 1, and did not change significantly over time (all β ≤0.13, all P≥0.2). Total corneal HOAs significantly correlated with BSCVA at 6 months (r=0.32, P=0.023), but not at other time points.

FIGURE 4. Randomized controlled trial of DMEK versus ultrathin DSAEK. Intraocular straylight in both treatment groups. Three months after surgery, straylight was lower in DMEK compared to ultrathin DSAEK (log(s)=1.30 [95% CI: 1.18 to 1.43] versus log(s)=1.54 [95% CI: 1.41 to 1.66], respectively, P=0.01). In DMEK, straylight improved significantly at 3 months by β=0.27 [95% CI: 0.13 to 0.41], P<0.001, and stabilized thereafter. In ultrathin DSAEK, straylight improved significantly at 12 months compared to baseline (β=0.23 [95% CI: 0.06 to 0.39, P=0.007). DMEK=Descemet membrane endothelial keratoplasty, S=straylight value, UT-DSAEK=ultrathin Descemet stripping automated endothelial keratoplasty. **P≤0.01.

differ at other time points, Figure 3. In DMEK, contrast sensitivity improved significantly at three months (β=0.52 [95% CI 0.37 – 0.68], P<0.001) and stabilized thereafter (three to twelve months: β=0.04 [95% CI -0.12 – 0.20], P=0.6). In ultrathin DSAEK, contrast sensitivity improved significantly at three months (β=0.30 [95% CI 0.14 – 0.46], P<0.001), and subsequently significantly improved between 3and 12 months (β=0.20 [95% CI 0.04 – 0.36], P=0.016). Contrast sensitivity correlated significantly with BSCVA (logMAR) at all time points (preoperative: r=-0.4, P=0.003; 3 months: r=-0.43, P=0.003; 6 months: r=-0.52, P<0.001; 12 months: r=-0.53, P<0.001). STRAYLIGHT

CONTRAST SENSITIVITY Preoperative contrast sensitivity did not differ significantly between DMEK and ultrathin DSAEK. Three months after surgery, contrast sensitivity was significantly better after DMEK compared with ultrathin DSAEK but did not

Preoperative straylight did not differ significantly between DMEK and ultrathin DSAEK. Three months after surgery, straylight was lower in DMEK compared to ultrathin DSAEK but did not differ significantly at other time points, Figure 4. In DMEK, straylight improved significantly at three months by β=0.27 [95%

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CI 0.13 – 0.41], P<0.001 and stabilized thereafter (3-12 months: β=0.07 [95% CI -0.07 – 0.22], P=0.3). In ultrathin DSAEK, straylight did not change significantly at 3 and 6 months compared to baseline (P=0.8 and P=0.1, respectively), but improved significantly at 12 months compared to baseline (β=0.23 [95% CI 0.06 – 0.39, P=0.007). Straylight did not correlate significantly with BSCVA at baseline (r=0.06, P=0.7), but correlated significantly at 3 and 6 months and was marginally significant at 12 months (r=0.47, P=0.003; and r=0.50, P=0.003; and r=0.3, P=0.09; respectively). 76

VISION-RELATED QUALITY OF LIFE NEI VFQ-25 composite score and the eleven vision-related subscales did not differ significantly between both groups at all time points, Table 1. Three months after surgery, the composite score increased significantly compared with preoperative values in both groups (β=12 [95% CI 7 – 16]; P<0.001). Between 3 and 12 months after surgery, a subsequent marginally significant improvement in composite score was observed in both groups (β=5 [95% CI 0 – 9]; P=0.06). In sensitivity analysis (excluding data at 6 and 12 months of patients that underwent corneal transplantation in the fellow eye during the study), mean vision-related quality of life did not differ significantly between DMEK and ultrathin DSAEK at 6 months (83 [95% CI 79 – 87] vs. 82 [95% CI 78 – 86], P=0.9), and 12 months (82 [95% CI 77 – 87] vs. 81 [95% CI 76 – 87], P=1.0).

Quality of vision and vision-related quality of life after DMEK

shown that subjective experience of vision depends also on factors related to the large-angle domain of the point spread function, such as contrast sensitivity and straylight (van der Meulen et al. 2012). The majority (about 80%) of ocular aberrations occur on the corneal surface (Hamam 2003). Both anterior and posterior corneal HOAs have been suggested to impact visual acuity after EK, but reports are inconsistent (Nielsen et al. 2016; Duggan et al. 2019). In the current study, anterior corneal HOAs increased postoperatively in both treatment arms, stabilizing after three months. The increase in anterior corneal HOAs is likely related to surgical incisions, wound healing, and subepithelial fibrosis (Patel et al. 2012). Anterior corneal HOAs did not differ significantly between ultrathin DSAEK and DMEK. Posterior corneal HOAs decreased after DMEK and increased 3 months after ultrathin DSAEK, decreasing subsequently at 6 and 12 months.

3.4 DISCUSSION In this prespecified secondary analysis of a multicenter RCT, we report quality of vision and vision-related quality of life in DMEK versus ultrathin DSAEK. Three months after surgery, posterior corneal HOAs and straylight were lower, and contrast sensitivity was higher in DMEK compared to UT-DSAEK. Visionrelated QOL increased to a similar extend in both treatment arms. Light entering the eye and reaching the retina can be described in terms of spatial distribution and intensity. When plotted, the resulting graph is termed point spread function (see Figure 5). High intensity is found at the very center of the point spread function, while intensity rapidly decreases towards the periphery (van den Berg et al. 2009). When visual acuity is tested, only the very center, an area of a few minutes of arc, is assessed. Earlier reports have

FIGURE 5. Randomized controlled trial of DMEK versus ultrathin DSAEK: Schematic retinal point spread function showing visual domains of visual acuity, higher-order aberrations, contrast sensitivity and straylight in the human eye. The visual angle is exaggerated for clarity. Cpd=cycles per degree, DMEK=Descemet membrane endothelial keratoplasty, DSAEK=Descemet stripping automated endothelial keratoplasty, HOAs=higher-order aberrations.

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Graft asymmetry (Dickman et al. 2013), graft folds (Seery et al. 2011), and a donor-recipient curvature mismatch (Yamaguchi et al. 2015) may be responsible for the increase in posterior corneal HOAs after ultrathin DSAEK. Interestingly, compared to anterior and total corneal HOAs, posterior corneal HOAs showed the strongest correlation with BSCVA. Nevertheless, the correlation was only weak to modest (r≤0.29). This is likely owing to the smaller change in refractive index at the posterior cornea compared with that at the anterior cornea. 78

To the best of our knowledge, this is the first study to directly compare contrast sensitivity and straylight in DMEK versus ultrathin DSAEK. In both treatment arms, preoperative contrast sensitivity and straylight values were worse compared to healthy age-matched eyes (Hashemi et al. 2012; Labuz et al. 2015). This may be attributed to structural changes in the recipient’s Descemet membrane and corneal edema (Watanabe et al. 2015). After surgery, patients in both treatment arms achieved near-normative values of contrast sensitivity and straylight 3 months after DMEK and 12 months after ultrathin DSAEK. In straylight, a decrease of 0.1 log(s) has approximately the same impact as a gain of 0.1 logMAR, and may therefore be considered clinically relevant (Labuz et al. 2015). Three months after surgery, a clinically relevant mean difference of 0.24 log(s) was observed in favor of DMEK. One year after surgery, straylight improved by approximately 70% with both techniques compared with baseline. A doubling in contrast sensitivity may be considered clinically relevant (Legge et al. 1987). Three months after surgery, a mean difference of 0.24 log(CS) was observed in favor of DMEK, nearly equivalent to twice better contrast sensitivity. One year after surgery, contrast sensitivity tripled with both techniques compared to baseline. In ultrathin DSAEK, slower recovery may be due to light scattering at the stroma-to-stroma interface, or from the added tissue itself, as even normally hydrated corneal stroma scatters light (Olsen 1982). In clinical research, identifying outcomes relevant to patients is vital (Seligman et al. 2019). Benefit, as perceived by patients, is not necessarily revealed by clinical outcome measures and may vary between individuals with similar objective outcomes. This subjective dimension can be captured by patient reported outcome measures (PROMs). Vision-related QOL did not differ between DMEK and ultrathin DSAEK at all time points. Preoperatively, visionrelated QOL was lower in both groups compared to age-matched controls

Quality of vision and vision-related quality of life after DMEK

(Mangione et al. 2001). Three months after surgery, the composite score of the VFQ-25 increased by twelve points, followed by a small and marginally significant improvement at twelve months. This overall improvement is considered clinically relevant based on a study suggesting a cut-off value of ten points (Lindblad & Clemons 2005). Although a higher percentage of DMEK eyes reached 0.8 Snellen BSCVA (Dunker et al. 2020), and recovery of contrast sensitivity and straylight was faster, this did not translate to better vision-related QOL. The DETEC trial made a similar observation comparing DMEK to ultrathin DSAEK using the same questionnaire (Ang et al. 2019). Twelve months after surgery, the composite scores of both groups remained lower compared to healthy eyes (Mangione et al. 2001), indicating incomplete recovery. However, corneal remodeling is a continuous process and visionrelated QOL has been reported to improve up to three years after surgery (Trousdale et al. 2014). Corneal transplantation of the fellow eye may impact outcomes of vision-related quality of life. To reduce bias from fellow eye surgery on vision-related quality of life we performed a sensitivity analysis excluding data at six and twelve months of patients that underwent corneal transplantation in the fellow eye during the study. Importantly, our findings remain unchanged. As the difference in visual acuity between the latest iterations of EK grows smaller, comprehensive evaluation of visual function and vision-related QOL becomes increasingly important. This RCT provides the most comprehensive evaluation of visual function to date after DMEK and ultrathin DSAEK. Interestingly, better objective outcomes after DMEK did not translate to higher vision-related QOL in the current study. One possible explanation may be that the NEI VFQ-25 lacks sensitivity to capture relevant domains after corneal transplantation. Two questionnaires have recently been validated to measure subjective visual function in corneal transplantation, Catquest-9SF (Claesson et al. 2017), and specifically for FECD, V-Fuchs (Wacker et al. 2018). V-Fuchs incorporates disease-specific domains, such as glare disability and diurnal shift, but is also more extensive and only validated in English. For future clinical research on treatments for corneal disease, both questionnaires are promising. Another limitation of this secondary analysis pertains to the statistical power. Sample size was based on the expected difference in primary outcome, i.e., BSCVA (Dunker et al. 2020). Therefore, statistical power may be insufficient for the parameters assessed in the current study. However, this study did not identify clinically relevant differences that merely failed to reach statistical

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significance, suggesting that a bigger sample size would lead to smaller confidence intervals without materially altering our conclusions.

In our cohort, we observed no rejection episodes in both treatment arms (Dunker et al. 2020). Although encouraging, our study was insufficiently powered to assess this adverse event. The reported risk of immune rejection is approximately 10% after DS(A)EK and 2% after DMEK (Deng et al. 2018). Taken together, the results of both RCTs comparing DMEK and ultrathin DSAEK and the prospective study by Busin et al. suggest the one-year rate of immune rejection after ultrathin DSAEK (0% - 3.4%) is closer to DMEK than DSAEK (Madi et al. 2019). In the primary report of this RCT, we showed that BSCVA did not differ significantly between DMEK and UT-DSAEK but a significantly higher percentage of eyes reached 20/25 Snellen after DMEK (Dunker et al. 2020). In this prespecified sub-analysis of the same cohort, DMEK showed faster recovery of straylight and contrast sensitivity and lower posterior corneal HOAs compared to ultrathin DSAEK. Posterior corneal HOAs correlated weakly to moderately with BSCVA. Vision-related quality of life improved significantly in both groups to a similar extend. Acknowledgments: The authors thank the eye bank technicians of ETB-BISLIFE for their support and assistance with this project. Special thanks also go to Wessel Vermeulen, Petra Steijger-Vermaat, Liberata Uwantege, BSc, Chantal Jumelet van Ast, BSc, Maartje Fleuren, BSc, Nienke Soeters, PhD, Mark Willems, BSc, Kim Westra, BSc, and Anne Brucker, for their valuable contribution and dedication. Finally, the authors thank the Dutch Cornea Patient Organization (Hoornvlies Patiënten Vereniging) for their support during all stages of the study and Rogier Trompert (http://www.medical-art.nl) for the illustration of the point spread function of the human eye. Funding: The Netherlands Association for Health Research and Development (ZonMw), The Hague, The Netherlands; Algemene Nederlandse Vereniging Ter Voorkoming Van Blindheid, Doorn, The Netherlands; Dutch Eyefund, Utrecht,

Quality of vision and vision-related quality of life after DMEK

The Netherlands; Dr. F.P. Fischer-Stichting, Utrecht, The Netherlands; and Landelijke Stichting Blinden en Slechtzienden (LSBS), Ede, The Netherlands. The sponsor or funding organization had no role in the design or conduct of this research. No conflicting relationship exists for any author.

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Quality of vision and vision-related quality of life after DMEK

References

1. Ang MJ, W Chamberlain, CC Lin, J Pickel, A Austin & J Rose-Nussbaumer (2019): Effect of Unilateral Endothelial Keratoplasty on Vision-Related Quality-of-Life Outcomes in the Descemet Endothelial Thickness Comparison Trial (DETECT): A Secondary Analysis of a Randomized Clinical Trial. JAMA ophthalmology 137: 747-754. 2. Claesson M, WJ Armitage, B Bystrom, P Montan, B Samolov, U Stenvi & M Lundstrom (2017): Validation of Catquest-9SF-A Visual Disability Instrument to Evaluate Patient Function After Corneal Transplantation. Cornea 36: 1083-1088. 3. Deng SX, WB Lee, KM Hammersmith, AN Kuo, JY Li, JF Shen, MP Weikert & RM Shtein (2018): Descemet Membrane Endothelial Keratoplasty: Safety and Outcomes: A Report by the American Academy of Ophthalmology. Ophthalmology 125: 295-310. 4. Dickman MM, YY Cheng, TT Berendschot, FJ van den Biggelaar & RM Nuijts (2013): Effects of graft thickness and asymmetry on visual gain and aberrations after descemet stripping automated endothelial keratoplasty. JAMA ophthalmology 131: 737-744. 5. Duggan MJ, J Rose-Nussbaumer, CC Lin, A Austin, PC Labadzinzki & WD Chamberlain (2019): Corneal Higher-Order Aberrations in Descemet Membrane Endothelial Keratoplasty versus Ultrathin DSAEK in the De-

scemet Endothelial Thickness Comparison Trial: A Randomized Clinical Trial. Ophthalmology 126: 946-957.

(1987): Psychophysics of reading—V. The role of contrast in normal vision. Vision research 27: 1165-1177.

6. Dunker SL, MM Dickman, RPL Wisse, S Nobacht, RHJ Wijdh, MC Bartels, ML Tang, F van den Biggelaar, PJ Kruit & R Nuijts (2020): Descemet Membrane Endothelial Keratoplasty versus Ultrathin Descemet Stripping Automated Endothelial Keratoplasty: A Multicenter Randomized Controlled Clinical Trial. Ophthalmology 127: 1152-1159.

12. Lindblad AS & TE Clemons (2005): Responsiveness of the National Eye Institute Visual Function Questionnaire to progression to advanced age-related macular degeneration, vision loss, and lens opacity: AREDS Report no. 14. Archives of ophthalmology (Chicago, Ill. : 1960) 123: 12071214.

7. Gain P, R Jullienne, Z He, M Aldossary, S Acquart, F Cognasse & G Thuret (2016): Global Survey of Corneal Transplantation and Eye Banking. JAMA ophthalmology 134: 167-173. 8. Hamam H (2003): A new measure for optical performance. Optometry and vision science : official publication of the American Academy of Optometry 80: 175-184. 9. Hashemi H, M Khabazkhoob, E Jafarzadehpur, MH Emamian, M Shariati & A Fotouhi (2012): Contrast sensitivity evaluation in a population-based study in Shahroud, Iran. Ophthalmology 119: 541-546. 10. Labuz G, NJ Reus & TJ van den Berg (2015): Ocular straylight in the normal pseudophakic eye. Journal of cataract and refractive surgery 41: 14061415. 11. Legge GE, GS Rubin & A Luebker

13. Madi S, P Leon, Y Nahum, S D’Angelo, G Giannaccare, J Beltz & M Busin (2019): Five-Year Outcomes of Ultrathin Descemet Stripping Automated Endothelial Keratoplasty. Cornea 38: 1192-1197. 14. Mangione CM, PP Lee, PR Gutierrez, K Spritzer, S Berry, RD Hays & I National Eye Institute Visual Function Questionnaire Field Test (2001): Development of the 25-item National Eye Institute Visual Function Questionnaire. Archives of ophthalmology (Chicago, Ill. : 1960) 119: 1050-1058. 15. Nielsen E, A Ivarsen, S Kristensen & J Hjortdal (2016): Fuchs’ endothelial corneal dystrophy: a controlled prospective study on visual recovery after endothelial keratoplasty. Acta ophthalmologica 94: 780-787. 16. Olsen T (1982): Light scattering from the human cornea. Investigative ophthalmology & visual science 23: 81-86.

17. Patel SV, KH Baratz, LJ Maguire, DO Hodge & JW McLaren (2012): Anterior corneal aberrations after Descemet’s stripping endothelial keratoplasty for Fuchs’ endothelial dystrophy. Ophthalmology 119: 1522-1529. 18. Seery LS, CB Nau, JW McLaren, KH Baratz & SV Patel (2011): Graft thickness, graft folds, and aberrations after descemet stripping endothelial keratoplasty for fuchs dystrophy. American journal of ophthalmology 152: 910-916. 19. Seligman WH, M Salt, A la Torre Rosas & Z Das-Gupta (2019): Unlocking the potential of value-based health care by defining global standard sets of outcome measures that matter to patients with cardiovascular diseases. Eur Heart J Qual Care Clin Outcomes 5: 92-95. 20. Trousdale ER, DO Hodge, KH Baratz, LJ Maguire, WM Bourne & SV Patel (2014): Vision-related quality of life before and after keratoplasty for Fuchs’ endothelial dystrophy. Ophthalmology 121: 2147-2152. 21. van den Berg TJ, L Franssen & JE Coppens (2009): Straylight in the human eye: testing objectivity and optical character of the psychophysical measurement. Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists) 29: 345-350. 22. van der Meulen IJ, J Gjertsen, B Kruijt,

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Quality of vision and vision-related quality of life after DMEK

JP Witmer, A Rulo, RO Schlingemann & TJ van den Berg (2012): Straylight measurements as an indication for cataract surgery. Journal of cataract and refractive surgery 38: 840-848.

23. Wacker K, KH Baratz, WM Bourne & SV Patel (2018): Patient-Reported Visual Disability in Fuchs’ Endothelial Corneal Dystrophy Measured by the Visual Function and Corneal Health Status Instrument. Ophthalmology 125: 1854-1861. 24. Watanabe S, Y Oie, H Fujimoto, T Soma, S Koh, M Tsujikawa, N Maeda & K Nishida (2015): Relationship between Corneal Guttae and Quality of Vision in Patients with Mild Fuchs’ Endothelial Corneal Dystrophy. Ophthalmology 122: 2103-2109. 25. Yamaguchi T, Y Satake, M Dogru, K Ohnuma, K Negishi & J Shimazaki (2015): Visual Function and Higher-Order Aberrations in Eyes After Corneal Transplantation: How to Improve Postoperative Quality of Vision. Cornea 34 Suppl 11: S128-135.

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Real-World Outcoms of DMEK

CHAPTER 4

Real-World Outcomes of DMEK: A Prospective Dutch registry study

Authors Suryan L. Dunker, Manon H.J. Veldman, Bjorn Winkens, Frank J.H.M. Van Den Biggerlaar, Rudy M.M.A Nuijts, Pieter Jan Kruit, and Mor M. Dickman on behalf of the Dutch Cornea Consortium AM J OPHTHALMOL. 2021 FEB;222:218-225

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Abstract PURPOSE: This study analyzed real-world practice patterns, graft survival, and outcomes of Descemet membrane endothelial keratoplasty (DMEK) in the Netherlands. DESIGN: Population-based interventional clinical study.

METHODS: In this prospective registry study, all consecutive primary DMEK procedures registered in the Netherlands Organ Transplant Registry were identified. Shortterm graft survival and outcomes of primary transplants for Fuchs’ endothelial dystrophy (FED) were analyzed using Kaplan-Meier survival curves with logrank test and Cox regression. Linear mixed model analyses were used for best spectacle-corrected visual acuity (BSCVA), spherical equivalent, hyperopic shift, and endothelial cell density. RESULTS: 752 DMEKs were identified between 2011 and 2018. In 90% of cases, the indication for DMEK was FED. Graft survival measured 87% at 3 months, 85% at 6 months, 85% at 1 year, and 78% at 2 years. DMEK procedures after 2015 showed better survival compared to previous years (Hazard ratio=0.4; P <.001). Baseline BSCVA in primary transplants with FED measured on average 0.45 logarithm of the minimum angle of resolution (logMAR) (95% confidence interval [CI], 0.41-0.49), and significantly improved (overall P<.001) to 0.17 logMAR (95% CI, 0.14-0.21) at 3 months, 0.15 logMAR (95% CI, 0.11-0.18) at 6 months, 0.12 logMAR (95% CI, 0.08-0.16) at 1 year, and 0.08 (95% CI, 0.050.12) at 2 years. At 3 months, a hyperopic shift of +0.36 diopters (P<.001) was observed and endothelial cell loss measured 33%. CONCLUSION: Our findings provide real-world support that DMEK is an effective treatment for FED with respect to vision restoration, inducing a small hyperopic shift with an acceptable endothelial cell loss. Graft survival improved over time, suggesting a learning curve on a national level.

Real-World Outcoms of DMEK

4.1 Introduction National quality registries are increasingly recognized in recent years as a valuable tool for improving healthcare via the use of real-world data.1 The primary attribute that distinguishes “real-world” evidence is related to the context in which the evidence is gathered – in other words, in clinical care settings. Key to understanding the usefulness of real-world evidence is an appreciation of its potential for complementing the knowledge gained from traditional clinical trials, whose well-known limitations make it difficult to generalize findings to larger, more inclusive populations of patients and settings that reflect actual use in practice.2 Much of our knowledge on the outcomes of corneal transplantation originates from such registries. Using the Netherlands Organ Transplant Registry (NOTR), our group previously reported on the long-term real-world outcomes of penetrating keratoplasty (PK) and Descemet stripping automated endothelial keratoplasty (DSAEK).3,4 Descemet membrane endothelial keratoplasty (DMEK), the latest iteration in endothelial keratoplasty (EK), is reported to achieve excellent visual outcomes with relatively low complication rates in specialized centers.5 However, little is known about the real-world outcomes of DMEK. In the current study, we retrospectively analyze prospectively collected NOTR data and report the real-world outcomes of DMEK in the Netherlands in terms of graft survival, longitudinal trends in visual acuity, refraction, endothelial cell density (ECD), and complications.

4.2 Methods GRAFT REGISTRY AND DATA COLLECTION Data for this multicenter prospective registry study was obtained from the NOTR, a prospective national database founded by the Netherlands Transplantation Foundation (Nederlandse Transplantatie Stichting [NTS], https://www.transplantatiestichting.nl/over-de-nts). In the Netherlands, donor corneas are centrally allocated and registered in NOTR. Therefore, data

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regarding graft survival is complete and independent of center/surgeon reporting. Using NOTR, the NTS prospectively captures data related to the recipient, donor, eye bank processing, and surgical procedure of all corneal transplantations performed in the Netherlands except for one clinic. Corneal surgeons prospectively complete relevant follow-up data at predefined time points using a standardized electronic data capture system. The evaluating factors defined in the prospective study protocol include donor characteristics: age, gender, and ECD; recipient characteristics: age, gender, and indication for transplantation; surgery characteristics: date of surgery, transplant type, previous corneal transplants, baseline visual acuity and refraction, complications, and lens status; and postoperative data: date of follow-up, graft status, visual acuity, refraction, ECD, adverse events, interventions, graft failure specification and date, last known follow-up date, lost to follow up status. Data collection continues until graft failure or loss to follow-up. For this study, the NOTR steering group provided institutional review board approval for data extraction and analysis. Informed consent was obtained from all patients to participate in the registry and for the use of data for research. The study adhered to the tenants of the declaration of Helsinki and Dutch legislation. POPULATION DMEK tissue was provided by two eye banks. Ten corneal clinics registered DMEK in NOTR. In line with institutional review board approval, information on center and surgeons was not made available. The first DMEK surgery registered in NOTR was performed on October 5th, 2011. The study cohort included all consecutive DMEK procedures until May 31st, 2018. All patients received a tapered topical corticosteroid regimen during the first six months after surgery, followed by low dose maintenance thereafter. OUTCOME MEASURES The primary outcome measure was graft survival. Graft failure was reported by the corneal surgeon as defined by the coding guidelines provided by NOTR, or identified in case of a subsequent corneal transplantation in the same eye. Graft failure occurring within three months of transplantation was defined as early graft failure (EGF). Secondary outcomes were: best spectacle-corrected visual acuity (BSCVA), ECD, spherical equivalent (SE), hyperopic shift, and

Real-World Outcoms of DMEK

rebubbling. Snellen acuity was converted to the logarithm of the minimum angle of resolution (logMAR) for statistical analyses. Spherical equivalent was defined as the sum of the spherical value and half of the cylindrical value. Refractive shift was defined as the difference in postoperative SE and preoperative SE. Refractive shift was calculated for single DMEK as data on target refraction was not available in triple DMEK. STATISTICAL ANALYSIS Statistical analyses were performed using IBM SPSS Statistics for Windows, version 24.0 (IBM Corp., Armonk, N.Y., USA). Baseline characteristics were reported as frequencies with percentages or mean ± standard deviation (SD). The number of transplants over time was tested using the X2 goodness-of-fit test. Graft survival and longitudinal trends in BSCVA, ECD, and SE were calculated for all DMEK procedures that had Fuchs endothelial dystrophy (FED) as indication excluding cases with anterior chamber intraocular lenses, and unknown lens status. Outcomes are reported over two years after surgery, due to a very low number of events (i.e. failed grafts), and limited number of cases with longer follow-up. In case both eyes of the same patient were operated or repeat transplant was performed, only the first transplant per patient was included in the primary analyses. This was done to prevent bias related to correlated measurements within the same patient or eye. Deathcensored graft survival was assessed using Kaplan-Meier survival curves with log-rank test and univariable Cox regression analysis with transplant year (five categories: before 2015, 2015, 2016, 2017, 2018) as an explanatory factor. Cox regression analysis was performed over the first six months postoperatively, since the vast majority of events (i.e. graft failure) occurred during the period. Proportional hazard assumption was checked using the log(-log) survival function plot. Sensitivity analyses including all transplants were also performed. Linear mixed models (LMM) were fitted to investigate the longitudinal trend in BSCVA, ECD, SE, and hyperopic shift, where time, transplant year, ocular comorbidity, and lens status were included as fixed factors and an unstructured covariance structure was used for the repeated measures (preoperative recipient or donor, 3, 6, and 12 months). LMM assume missing at random (MAR), i.e. missingness may depend on observed variables, which should then be incorporated in the model. The

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Real-World Outcoms of DMEK

TABLE 1. Real-world

outcomes of DMEKa

PARAM TER Recipient Primary disease, % FED; PBK; graft failure Central corneal thickness, μm Age, yrs % MAles % Right eyes undergoing surgery Donor Age, yrs % Males Surgery % Surgeries in the pseudophakic eye % Surgeries in the phakic eye % Triple procedures % Surgeries in eyes with PAC or other

FIGURE 1. Real-world outcomes of Descemet membrane endothelial keratoplasty (DMEK), a prospective Dutch registry study. The figure shows all consecutively performed DMEK procedures (blue diamonds) in the Netherlands until 2017. Descemet stripping automated endothelial keratoplasty (DSAEK, red circles) and penetrating keratoplasty (PK, green triangles) are shown for comparison. The proportion of DMEK procedures increased significantly over time (P<0.001). The year 2016 marks a major turning point, showing a 395% increase in the number of procedures performed compared to 2015.

differences in characteristics in patients with missing data were compared to patients without missing data (no significant differences found). Cases that developed graft failure were excluded from the analysis of BSCVA, ECD, and SE. Estimated marginal means (EMM) were reported, and changes between different time-points were tested. P-values ≤0.05 were considered statistically significant.

4.3 RESULTS PRACTICE PATTERNS In total, 752 DMEK procedures were registered in NOTR between January 1st, 2011 until May 31st, 2018. The proportion of DMEK procedures increased significantly over time (P<0.001)(Figure 1). Until 2015, 104 DMEK procedures

DMEK=Descemet membrane endothelial keratoplasty FED=Fuchs’ endothelial dystrophy PAC=pseudophakic, anterior chamber PBK=pseudophakic bullous keratopathy SD=standard deviation

MEAN ± SD OR % 90; 3; 5 647 ± 82 71 ± 9 47 51 72 ± 8 63 77 6 7 10

Table shows baseline patient, donor, and surgery characteristics of all consecutive DMEK surgeries registered in Netherlands Organ Transplant Registry until May 31st, 2018. a

were performed. The greatest increase occurred between 2015 and 2016 (n=43 vs. n=213, respectively, P<0.001). In contrast, the proportion of Descemet stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK) procedures decreased since 2015 (2015 vs. 2017: n=735 vs. n=527, respectively, P<0.001, DSAEK; and n=360 vs. n=248, respectively, P<0.001, PK). In 2017, the number of DMEK procedures surpassed PK for the first time. In the first half of 2018, slightly more DMEK procedures were performed compared to DSAEK (171 vs. 166, respectively). Recipient and donor demographics, indication for surgery, and surgical procedure are given in Table 1. The leading indication was FED (90%), followed by graft failure (5%), and pseudophakic bullous keratopathy (3%). 77% of DMEK procedures were performed in pseudophakic eyes, 6% in phakic eyes, and

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Real-World Outcoms of DMEK

FIGURE 2. Real-world outcomes of Descemet membrane endothelial keratoplasty (DMEK). The figure shows the overall graft survival of primary DMEK grafts for Fuchs’ endothelial dystrophy throughout 2 years of follow-up (n=468 at time 0). Graft survival measured 85% after 1 year (censored cases, n=244) and 78% after 2 years (censored cases, n=369).

FIGURE 3. Real-world outcomes of Descemet membrane endothelial keratoplasty (DMEK). Evolution of graft survival over time of primary DMEK for Fuchs’ endothelial dystrophy. Graft survival was significantly better in procedures performed since 2016 compared to earlier procedures (hazard ratio=0.4; P<0.001). Procedures performed <2015, n=41; 2015, n=34; 2016, n=179; 2017, n=175; and 2018, n=39 (excluding censoring).

7% were combined with cataract extraction and intraocular lens placement (triple DMEK).

2). A single graft failure was registered after two years. In <2015, 2015, 2016, 2017, and 2018, 41, 34, 179, 175, and 39 cases were available for analysis, respectively. Graft survival was similar for <2015 and 2015 (P=0.85), as well as for 2016, 2017 and 2018 (all P≥0.26). When combined, transplants performed between 2016 and 2018 showed higher survival probability compared to earlier transplants (Hazard ratio [HR]=0.4; 95% confidence interval [CI] 0.25– 0.63; P<0.001)(Figure 3). The database captured two graft rejection episodes. In both cases, patients did not have known risk factors for graft rejection and were treated according to standard protocol prior to graft rejection. Graft rejection was reversible in both cases.

GRAFT SURVIVAL A total of 468 DMEK procedures were available for graft survival analysis after excluding fellow eyes (n=125), indications other than FED including regrafts (n=58), anterior chamber intraocular lenses or unknown lens status (n=53), and missing data (n=48). At 3, 6, 12 and 24 months 30, 98, 244, and 369 cases were censored, respectively. Overall graft survival measured 87% at three months, 85% at six months, 85% at 1 year, and 78% at two years (Figure

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Real-World Outcoms of DMEK

FIGURE 4. Real-world outcomes of Descemet membrane endothelial keratoplasty (DMEK). Estimated marginal means best spectacle-corrected visual acuity during a follow-up period of 2 years for primary DMEK for Fuchs’ endothelial dystrophy (blue diamonds). best spectacle-corrected visual acuity improved signiﬁcantly after DMEK and was superior to DSAEK and PK. However, baseline differences among the techniques make a direct comparison difﬁcult. Baseline, n=442; 3 months, n=380; 6 months, n=306; 12 months, n=214; 24 months, n=45. *BSCVA in DSAEK (purple circles) and PK (green triangles) in eyes with Fuchs’ endothelial dystrophy of a previous NOTR study are shown for comparison.3 DMEK=Descemet membrane endothelial keratoplasty; DSAEK=Descemet stripping automated endothelial keratoplasty; LogMAR=logarithm of the minimum angle of resolu-tion; NOTR=the Netherlands Organ Transplantation Registry; PK=penetrating keratoplasty.

VISUAL AND REFRACTIVE OUTCOMES Mean BSCVA during a follow-up period of one year is shown in Figure 4. BSCVA measured 0.45 logMAR (95% CI, 41-0.49) (n=442) preoperatively and significantly improved (overall P<.001) to 0.17 logMAR (95% CI, 0.14-0.21) (n=380) at three months, 0.15 logMAR (95% CI, 0.11-0.18) (n=306) at six months, 0.12 logMAR (95% CI, 0.08-0.16) (n=214) at one year, and 0.08 logMAR (95% CI, 0.05-0.12) (n=45) at two years. The cumulative percentage of eyes reaching various best spectacle- corrected Snellen acuities is given in Figure 5. Twelve months after DMEK, 67% and 28% of eyes reached ≥20/ 25 and ≥20/20 Snellen BSCVA, respectively. A statistically significant hyperopic shift was observed three months after

FIGURE 5. Real-world outcomes of Descemet membrane endothelial keratoplasty (DMEK). Bar graph shows the best spectacle-corrected Snellen visual acuity in primary DMEK for Fuchs’ endothelial dystrophy before surgery (n=442), and 3 months (n=380), 6 months (n=306), 12 months (n=214), and 24 months (n=45) after surgery. Twelve months after DMEK, 67%and 28% of eyes reached ≥20/25 and ≥20/20 Snellen, respectively.

DMEK alone (0.36 D; 95% CI, [0.20- 0.51], P<.001), which stabilized thereafter. Spherical equivalents values for single DMEK are given in Table 2.

ENDOTHELIAL CELL DENSITY Donor and postoperative ECD are given in Table 2. Donor ECD measured 2706 cells/mm2 (95% CI, 2670-2741), decreasing to 1799 cells/ mm2 (95% CI, 1729-1869), P<.001 (33% cell loss) at three months and stabilizing thereafter. REBUBBLINGS Rebubbling was the most common complication. In the entire cohort, 144 rebubblings were registered, corresponding to a 19% rebubbling rate. Subsequent rebubbling was performed in 3%, and a single case underwent a third rebubbling. Rebubbling rate measured 11% before 2015, 14% in 2015, 25% in 2016, 20% in 2017, and 14% in 2018. In triple DMEK, rebubbling rate did

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Real-World Outcoms of DMEK

TABLE 2. Real-world outcomes of Descemet membrane endothelial keratoplasty (DMEK)a

Follow-Up

Baseline or donor 3 mos 6 mos 1 year 2 years 98

BSCVA

ECD

EMM LogMAR [95% EMM Diopter [95% CI] (n) CI] (n)b

EMM cells/mm2 [95% Cl] (n)

0.45 [0.41-0.49] (442)

2706 [2670-2741] (441)

-0.49 [ -0.75 to -0.23] (355) -0.13 [- 0.39 to 0.12] 0.17 [0.14-0.21] (380) (309) -0.20 [ -0.46 to 0.06] 0.15 [0.11-0.18] (306) (212) - 0.20 [ -0.46 to 0.07] 0.12 [0.08-0.16] (214) (149) -0.07 [ -0.44 to 0.30] 0.08 [0.05-0.12] (45) (34)

1799 [1729-1869] (182) 1762 [1689-1836] (168) 1744 [1668-1820] (138) 1670 [1495-1844] (23)

BSCVA=Best spectacle-corrected visual acuity; CI=confidence interval; DMEK=Descemet membrane endothelial keratoplasty; ECD=Endothelial cell density; EMM=Linear mixedmodel estimated marginal mean; LogMAR=logarithm of the minimum angle of resolution; SE=spherical equivalent. Table shows BSCVA, SE, and ECD in eyes with Fuchs’ endothelial dystrophy at 3, 6, 12, and 24 months after DMEK. a

DMEK combined with cataract extraction and intraocular lens implantation were excluded.

not differ significantly from single DMEK (odds ratio=0.87 [95% CI 0.41 – 1.85], P=0.72). Sensitivity analyses, including all transplants, did not appreciably change the outcomes. For the primary outcome measure, graft survival measured for sensitivity vs. primary analysis 87% vs. 87% at three months, 86% vs. 85% at six months, 86% vs. 85% at one year, and 77% vs. 78% two years after surgery, respectively.

4.4 DISCUSSION This registry study analyzed the practice patterns and outcomes of DMEK in the Netherlands. To the best of our knowledge, this is the first national registry study to report the real-world outcomes of DMEK.

DMEK was introduced in the Netherlands in 2002.6 Between 2002 and 2010, the procedure was performed in a single private clinic that does not register in NOTR. From 2011 until 2015, a total of 104 DMEK procedures were recorded in NOTR. In contrast, 213 DMEK procedures were registered in 2016 alone, marking a major turning point in the uptake of the technique. Concurrently, the number of DSAEK procedures decreased since 2016. In the first half of 2018, marginally more DMEK procedures were recorded compared to DSAEK. In our cohort, graft survival measured 85% twelve months after DMEK. Almost all failures occurred during the first three months after surgery. This figure is lower compared to the 92% - 100% graft survival rate reported in the Ophthalmic Technology Assessment (OTA) by the American Academy of Ophthalmology.7 While the current registry study captures data from a heterogeneous group of medical centers, including high- and low-volume as well as specialized and non-specialized centers, most of the data in the OTA arises from highly specialized centers, limiting generalizability. DMEK survival in this NOTR cohort was also lower compared to the 94% twoyear graft survival rate after DSAEK in NOTR.3 The short-term graft survival in DMEK improved significantly over time, which suggests a learning curve on a national level for a technically challenging procedure. Indeed, the time frame in our study includes the learning curve of multiple surgeons. Another explanation for improving graft survival over time is standardization of the surgical technique during the study period. We recently reported that the survival and functional outcomes of repeat-DSAEK grafts are significantly worse compared to primary DSAEK.4 This is important as the current study found higher DMEK graft failure rate during the early years (<2016). If repeatDMEK is also significantly worse compared to primary DMEK, it would underscore the impact of introducing DMEK on a national level. With the introduction of DMEK, anatomic restoration of the cornea became possible, avoiding interface irregularities and potentially improving vision. In our study, BSCVA improved from 0.45 logMAR before surgery to 0.12 logMAR one year after surgery. The postoperative BSCVA in DMEK is better compared to PK and DSAEK for FED in NOTR (0.39 logMAR and 0.29 logMAR at one year, respectively).3 However, PK and DSAEK show worse BSCVA at baseline compared to DMEK (0.9 logMAR and 0.68 logMAR, respectively). The reason for this difference in baseline BSCVA may be two-fold. First, an allocation bias

CHAPTER 4

of eyes with better prognosis to novel techniques. Second, a lower threshold for surgical intervention at earlier stages of visual disability.8

Real-World Outcoms of DMEK

months postoperatively, mean cell loss measured 33%, stabilizing thereafter. The cell loss is in line with previous reports on DMEK,7,14,15 and comparable to the NOTR DSAEK cohort for FED.3

Historically, the core outcome parameter for corneal transplantation shifted from graft survival in the era of PK to visual acuity with EK. However, differences in VA in modern EK procedures are small, and patients routinely undergo surgery for symptoms such as reduced contrast sensitivity or glare disability irrespectively of VA.9-11 Patient-reported outcome measures have been developed to capture this information.12,13 However, these are currently not part of the standard evaluation in many centers, and as such are not yet recorded in NOTR.

100

Randomized controlled trials offer a less biased comparison between treatment modalities under controlled circumstances. However, they are costly and under certain circumstances no longer ethical to perform. In contrast, registries provide a low-cost window into routine clinical care (realworld). The strong internal validity of RCTs goes inevitably at the expense of generalizability, while registries suffer from low internal validity. Both study designs can complement each other. Registries can provide external validity to RCTs with restrictive eligibility criteria. In the current study, BSCVA is comparable to two recent RCTs comparing DMEK and ultrathin DSAEK.14,15 A novel study design, the randomized registry study, combines the strength of randomization with the advantages of registries and may provide a costeffective solution for increasingly more expensive health care systems.1 The hyperopic shift after DSAEK is primarily thought to result from the meniscusshaped profile of the donor lenticule.16 In DMEK, the hyperopic shift is likely due to curvature changes in response to corneal hydration status.17 In the current cohort, a hyperopic shift of +0.36 D after DMEK was observed three months after surgery, which is in line with the mean astigmatism change of +0.31 D reported in the OTA.7 Consequently, DMEK can be considered a predictable and relatively refractive neutral procedure that allows safe combination with cataract surgery and intraocular lens placement.17,18 Target refraction in triple DMEK was not captured by the registry. Cases that underwent triple DMEK were therefore excluded in the analysis of spherical equivalent and refractive shift. In EK, most endothelial cell loss is registered early after transplantation. Three

Graft detachment necessitating rebubbling is the Achilles heel of DMEK. In the literature, the percentage of eyes requiring rebubbling ranges from 2% to 84%,7 with most studies reporting percentages between 10% and 30%.14,15,19 In the current cohort, 19% of eyes required underwent rebubbling. The rebubbling protocols were not standardized across medical centers. NOTR does not capture details on the degree of graft detachment. However, most surgeons in the Netherlands perform rebubbling for graft detachments that are centrally located or affect more than 1/3 of the graft surface area. There is controversy in the literature regarding complication rates with triple procedure compared with DMEK alone.20-22 In our cohort, there was no significant or clinically relevant difference in rebubbling rate between triple and single procedures. Sulfur hexafluoride (SF6) at various concentrations can be used instead of 100% air to decrease graft detachment rate, because SF6 has a longer tamponade time than 100% air. A recent meta-analysis reported that SF6 20% was associated with 58% fewer rebubblings compared to 100% air.23 However, this information was not captured prospectively by NOTR. Future registry studies could shed light on the effect of SF6 in routine clinical practice. Previous studies reported complication rates decrease over time as surgical experience increases.19,23,24 While overall graft survival improved over the study period, the incidence of rebubbling procedures increased. This may be due to consecutive learning curves of multiple surgeons and/or more aggressive approach towards graft dislocation. However, in accordance with the institutional review board of NOTR, data for the current study was not stratified by surgeon or center. The risk of an immunological rejection after DMEK is lower compared to previous keratoplasty techniques and often does not lead to graft failure.25-27 Moreover, the clinical picture of graft rejection after DMEK can be very subtle.28 For prophylaxis, local corticosteroid therapy is recommended until at least the end of the second postoperative year.26 In our cohort, patients received a tapered topical corticosteroid regimen during the first six months, followed by low dose maintenance and two patients developed graft rejection that was reversible following local steroid injection. From six months postoperatively

101

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onwards, only six cases of graft failure occurred. The follow-up of the current cohort is insufficient to determine long-term rates of graft failure and rejection. Every cohort study has to cope with missing data and loss to follow-up. With respect to our primary outcome, i.e. graft survival, centralized donor allocation by the Dutch Transplant Society (NTS) ensured registration of all primaryand repeated transplantations. With regard to secondary outcomes, LMM analysis uses all available data (no list-wise deletion that would only allow completers in the analyses). Almost all graft failures occurred prior to the first follow-up visit registered in NOTR, i.e. three months postoperatively, therefore, to increase the robustness of the data, graft failures were excluded from analyses of VA, ECD, and SE.

102

Real-World Outcoms of DMEK

References 1. Lauer MS, D’Agostino RB, Sr. The randomized registry trial-the next disruptive technology in clinical research? N Engl J Med 2013;369(17):1579-1581. 2. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence - what is it and what can it tell us? N Engl J Med. 2016;375(23):2293-2297. 3. Dickman MM, Peeters JM, van den Biggelaar FJ, et al. Changing practice patterns and long-term outcomes of endothelial versus penetrating keratoplasty: a prospective dutch registry study. Am J Ophthalmol. 2016;170:133142. 4. Dickman MM, Spekreijse LS, Dunker SL, et al. Long-term outcomes of repeated corneal transplantations: a prospective dutch registry study. Am J Ophthalmol. 2018;193:156-165. 5. Peraza-Nieves J, Baydoun L, Dapena I, et al. Two-year clinical outcome of 500 consecutive cases undergoing descemet membrane endothelial keratoplasty. Cornea. 2017;36(6):655660. 6. Melles GR, Lander F, Rietveld FJ. Transplantation of descemet’s membrane carrying viable endothelium through a small scleral incision. Cornea. 2002;21(4):415-418. 7. Deng SX, Lee WB, Hammersmith KM, et al. Descemet membrane endothelial keratoplasty: safety and outcomes: a report by the American

Academy of Ophthalmology. Ophthalmology. 2018;125(2):295-310. 8. van Rooij J, Lucas EH, Geerards AJ, Remeijer L, Wubbels R. Corneal transplantation for fuchs endothelial dystrophy: a comparison of three surgical techniques concerning 10 year graft survival and visual function. PloS one. 2018;13(10):e0203993. 9. van den Berg TJ, Franssen L, Coppens JE. Straylight in the human eye: testing objectivity and optical character of the psychophysical measurement. Ophthalmic Physiol Opt. 2009;29(3):345-350. 10. van der Meulen IJ, van Riet TC, Lapid-Gortzak R, Nieuwendaal CP, van den Berg TJ. Correlation of straylight and visual acuity in long-term follow-up of manual descemet stripping endothelial keratoplasty. Cornea. 2012;31(4):380-386. 11. van der Meulen IJ, Patel SV, Lapid-Gortzak R, Nieuwendaal CP, McLaren JW, van den Berg TJ. Quality of vision in patients with fuchs endothelial dystrophy and after descemet stripping endothelial keratoplasty. Arch Ophthalmol. 2011;129(12):15371542. 12. Wacker K, Baratz KH, Bourne WM, Patel SV. Patient-reported visual disability in Fuchs’ endothelial corneal dystrophy measured by the visual function and corneal health status instrument. Ophthalmology.

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2018;125(12):1854-1861. 13. Claesson M, Armitage WJ, Bystrom B, et al. Validation of catquest-9SF-a visual disability instrument to evaluate patient function after corneal transplantation. Cornea. 2017;36(9):10831088.

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14. Chamberlain W, Lin CC, Austin A, et al. Descemet endothelial thickness comparison trial: a randomized trial comparing ultrathin descemet stripping automated endothelial keratoplasty with sescemet membrane endothelial keratoplasty. Ophthalmology. 2019;126(1):19-26. 15. Dunker SL, Dickman MM, Wisse RPL, et al. DMEK versus ultrathin DSAEK: a multicenter randomized controlled clinical trial. Ophthalmology. In press. 16. Scorcia V, Matteoni S, Scorcia GB, Scorcia G, Busin M. Pentacam assessment of posterior lamellar grafts to explain hyperopization after descemet’s stripping automated endothelial keratoplasty. Ophthalmology. 2009;116(9):1651-1655. 17. Schoenberg ED, Price FW, Jr., Miller J, McKee Y, Price MO. Refractive outcomes of descemet membrane endothelial keratoplasty triple procedures (combined with cataract surgery). J Cataract Refract Surg. 2015;41(6):1182-1189. 18. Chaurasia S, Price FW, Jr., Gunderson L, Price MO. Descemet’s membrane endothelial keratoplasty: clinical results of single versus triple procedures

Real-World Outcoms of DMEK

(combined with cataract surgery). Ophthalmology. 2014;121(2):454-458. 19. Oellerich S, Baydoun L, Peraza-Nieves J, et al. Multicenter study of 6-month clinical outcomes after descemet membrane endothelial keratoplasty. Cornea. 2017;36(12):1467-147. 20. Leon P, Parekh M, Nahum Y, et al. Factors associated with early graft detachment in primary descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2018;187:117-124. 21. Siebelmann S, Ramos SL, Matthaei M, et al. Factors associated with early graft detachment in primary descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2018;192:249-250. 22. Godin MR, Boehlke CS, Kim T, Gupta PK. Influence of lens status on putcomes of descemet membrane endothelial keratoplasty. Cornea. 2019;38(4):409-412. 23. Schrittenlocher S, Schaub F, Hos D, Siebelmann S, Cursiefen C, Bachmann B. Evolution of consecutive descemet membrane endothelial keratoplasty outcomes throughout a 5-year period performed by two experienced surgeons. Am J Ophthalmol. 2018;190:171-178. 24. Dapena I, Ham L, Droutsas K, van Dijk K, Moutsouris K, Melles GR. Learning curve in descemet’s membrane endothelial leratoplasty: first series of 135 consecutive cases. Ophthalmology. 2011;118(11):2147-2154.

25. Hos D, Tuac O, Schaub F, et al. Incidence and clinical course of immune reactions after descemet membrane endothelial Keratoplasty: retrospective analysis of 1000 consecutive eyes. Ophthalmology. 2017;124(4):512-518. 26. Price MO, Scanameo A, Feng MT, Price FW, Jr. Descemet’s membrane endothelial keratoplasty: risk of immunologic rejection episodes after discontinuing topical corticosteroids. Ophthalmology. 2016;123(6):12321236. 27. Price MO, Price FW, Jr., Kruse FE, Bachmann BO, Tourtas T. Randomized comparison of topical prednisolone acetate 1% versus fluorometholone 0.1% in the first year after descemet membrane endothelial keratoplasty. Cornea. 2014;33(9):880-886. 28. 28. Hos D, Matthaei M, Bock F, et al. Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation. Prog Retin Eye Res. 2019;73:100768.

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Rebubbling and graft failure in Descement membrane endothelial keratoplasty

CHAPTER 5

Rebubbling and graft failure in Descement membrane endothelial keratoplasty: a prospective Dutch registry study

106

107

Authors Suryan L. Dunker, Bjorn Winkens, Frank J.H.M. van den Biggelaar, Rudy M.M.A. Nuijts, Pieter Jan Kruit, and Mor M. Dickman on behalf of the Dutch Cornea Consortium

BR J OPHTHALMOL. 2021 FEB;0:1–7

CHAPTER 5

Rebubbling and graft failure in Descement membrane endothelial keratoplasty

5.1 Introduction Abstract AIMS: To identify risk factors for rebubbling, and early graft failure after Descemet membrane endothelial keratoplasty (DMEK). METHODS: In this prospective registry study, all consecutive DMEK procedures registered in the Netherlands Organ Transplant Registry were assessed (n=752). Univariable and multivariable analysis was performed using logistic regression. The effect of rebubbling on endothelial cell density was analysed using a linear mixed model.

108

RESULTS: 144 of 752 (19%) eyes underwent rebubbling. Rebubbling was successful in 101 eyes (70%). In eyes that underwent rebubbling, the graft failure rate was significantly higher than eyes that did not undergo rebubbling (30% vs 9%, respectively; OR: 4.28, 95% CI 2.72 to 6.73, P<0.001). In multivariable analysis, independent risk factors for rebubbling were surgical complication (OR: 2.28, 95% CI 1.20 to 4.33, P=0.012) and older recipient age (OR: 1.04 (per increase of 1 year), 95% CI 1.01 to 1.07, P=0.003). Risk factors for developing graft failure within 3 months were transplant before 2016 (OR: 3.32, 95% CI 1.87 to 5.90, P<0.001), and surgical complication (OR: 2.93, 95% CI 1.42 to 6.04, P=0.004). Throughout the study period, rebubbling and early graft failure were inversely related. Eyes that underwent rebubbling showed significantly lower endothelial cell densities at 3, 6 and 12 months compared with eyes that did not undergo rebubbling (all P<0.001). CONCLUSION: This Dutch registry study identified independent risk factors for DMEK graft detachment leading to rebubbling, namely recipient age and surgical complication, and early graft failure, namely transplantation before 2016 and surgical complication. Rebubbling was associated with significantly higher endothelial cell loss in the first year after surgery.

In the last decade, Descemet membrane endothelial keratoplasty (DMEK) gradually gained popularity as the technique of choice for treating corneal endothelial disease.1 2 While DMEK provides excellent visual and refractive outcomes, early postoperative graft detachment requiring intracameral gas reinjection (rebubbling), and graft failure remain the Achilles heel of this procedure. The incidence of graft detachment and graft failure in the literature ranges considerably after DMEK. According to the American Academy of Ophthalmology Ophthalmic Technology Assessment the incidence of graft detachment ranges between 2% and 82% (averaging 28%), and the incidence of primary graft failure ranges between 0% and 12.5%.3 Previous studies identified risk factors for graft detachment related to donor,4 5 recipient6–8 and surgery.5,6 8–20 These mostly originate from single-centre retrospective studies. Registries capture prospective data from multiple centres and are therefore poised to assess incidence and risk factors for complications. In the current study, we analyse prospectively collected data from the Netherlands Organ Transplant Registry (NOTR) to identify donor, recipient and surgery-related risk factors for graft detachment leading to rebubbling, and graft failure after DMEK.

5.2 Methods GRAFT REGISTRY AND DATA COLLECTION This prospective multicentre registry study obtained data from the NOTR, a Dutch national database founded by the Netherlands Transplantation Foundation (Nederlandse Transplantatie Stichting (NTS), https://www.tran splantatiestichting.nl/overdents). In the Netherlands, donor corneas are centrally allocated by the NTS. Using NOTR, the NTS prospectively captures data on donor, recipient, eye bank processing and surgical procedure of all corneal transplantations in the Netherlands except for one clinic. Using a standardised electronic data capture system, corneal surgeons complete

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CHAPTER 5

relevant follow-up data at predefined time points. Data collection continues until graft failure or loss to follow-up. Except for a few cases, DMEK grafts were prepeeled by the eye bank. All donor corneas were stored in organ culture, and transplantation took place within 3 days after graft preparation. Early graft failure was defined as any graft failure occurring within 3 months after surgery. In the Netherlands, information on repeated transplantation is complete, since donor corneas are allocated centrally by NTS. The date of repeated transplantation served as a surrogate for graft failure date unless otherwise indicated in the registry. POPULATION The first DMEK surgery registered in NOTR was performed on October 5th, 2011. The study cohort included all consecutive DMEK procedures until May 31st, 2018. OUTCOME MEASURES

Rebubbling and graft failure in Descement membrane endothelial keratoplasty

age, donor graft preparation complication, surgical complication, graft diameter, and peroperative lens status (pseudophakic, phakic, and triple procedure). Variables with a two-sided p-value≤0.05 in multivariable analysis were considered independent risk factors. Multicollinearity, i.e., intercorrelation between risk factors, was checked for the multivariable models, where a variance inflation factor (VIF) > 10 indicates a (multi)collinearity problem. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) and p-values were reported. The effect of rebubbling on ECD was assessed using linear mixed model, where rebubbling (yes/no), time (donor, 3, 6 and 12 months after surgery), the interaction rebubbling*time and potential confounders (indication, year of transplantation, lens status, surgical complication, and recipient age) were included as fixed factors, and an unstructured covariance structure was used for repeated measures. Estimates means with corresponding 95%CI and p-values for the difference in estimated means between rebubbling and no rebubbling were reported for each time point. Two-sided p-values ≤0.05 were considered statistically significant.

110

111

The cohort was categorized into eyes that underwent rebubbling versus eyes that did not undergo rebubbling, and eyes developed early graft failure versus eyes that did not develop early graft failure. Parameters related to the recipient, donor, and surgery were analyzed and outcomes compared. STATISTICAL ANALYSIS Statistical analyses were performed using SPSS Statistics for Windows, version 24.0 (IBM Corp., Armonk, N.Y., USA). A chi-square goodness-of-fit test was used to check whether the number of transplantations changed over time. The difference in mean time to rebubbling over years (≤2015, 2016, 2017 and 2018) was tested using a one-way analysis of variance. The percentages of eyes undergoing rebubbling, unsuccessful rebubbling, and developing early graft failure were analyzed using Pearson chi-square test for categorical risk factors and using univariable logistic regression for numerical risk factors. To be included in the multivariable model, covariates were either selected based on a 0.1 significance threshold in univariable analysis or in case they were considered clinically relevant based on literature, i.e., surgery indication, transplant date, recipient age, recipient and donor gender mismatch, donor

As sensitivity analyses, all logistic regression and linear mixed model (LMM) analyses were repeated on primary transplants with FED as indication.

5.3 RESULTS The current study comprises of 752 DMEK procedures performed by 15 corneal surgeons in seven corneal clinics. The number of DMEK surgeries per year are 2011: n=2; 2012, n=4; 2013, n=24; 2014, n=31; 2015, n=43; 2016, n=213; 2017, n=213; and 2018 until May 31st, n=171. The percentage of eyes that underwent a single rebubbling was 19% (144 of 752), 2% (15 of 752) received a second rebubbling, and a single eye received a third rebubbling. The percentage of eyes that underwent rebubbling changed significantly over time (P=0.022). Rebubbling rate measured 11% before 2015, 14% in 2015, 25% in 2016, 20% in 2017, and 14% 2018, Figure 1. The percentage of eyes that developed early graft failure measured overall 11% and changed significantly over time (P<0.001). Early graft failure rate measured 23% before 2015, 26% in 2015, 5% in 2016, 9% in 2017, and 4% in 2018, Figure 1.

CHAPTER 5

Rebubbling and graft failure in Descement membrane endothelial keratoplasty

TABLE 1. Recipient, donor and surgery characteristics All consecutive performed DMEK (n=752) Mean ± SD or %

% or range

Recipient parameters Age, years Sex, male/female Baseline IOP, mm HG Baseline CCT, μm

112

FIGURE 1. Rebubbling and early graft failure in Descemet membrane endothelial keratoplasty (DMEK). The percentage of eyes that underwent rebubbling (red circles) and early graft failure (blue diamonds) of all registered DMEKs in the Netherlands Organ Transplant Registry. The percentage of eyes undergoing rebubbling and developing early graft failure changed significantly over time (P=0.022 and P<0.001, respectively).

Table 1 shows the recipient, donor, and surgery characteristics of the entire cohort.

71 ± 10

27-91

352/400

47%/53%

13 ± 3

6-29

657 ± 82

456-1140

Indication, FED

687

90%

Indication, PBK

2.5%

Indication, graft failure

Indication, other

2.5%

Lens status, PPC

579

77%

Lens status, phakic

13%

Lens status, PAC or other

10%

Ocular comorbidities, except cataract

104

14%

72 ± 8

45-85

478/274

63%/36%

109/589/54

15%/78%/7%

2681 ± 173

2300-3200

2.5%

138/280/334

18%/37%/44%

Recipient donor sex mismatch

368

49%

Surgery date after 2015

648

86%

Phakic DMEK

Triple procedure

383/369

51%/49%

Donor parameters Age, years Sex, male/female Graft diameter, mm <8.5/8.5/>8.5 Endothelial cell density, cells/ mm2 Complicated gract preparation Surgery parameters

Of eyes that underwent rebubbling, 30% (43 of 144) developed graft failure. Rebubbling was successful in 101 eyes (70%). In eyes that did not undergo rebubbling, graft failure rate was significantly lower (9%, 55 of 608; OR: 4.28, 95% CI, 2.72 – 6.73, P<0.001). In patients that received a DMEK in one eye and a subsequent DMEK in the fellow eye, the percentage of eyes that underwent rebubbling was 13% (14 of 111) in the first eye and 18% (20 of 111) in the fellow eye. Eyes that underwent rebubbling in one eye did not have significantly higher risk of undergoing rebubbling in the fellow eye compared to eyes that did not undergo rebubbling in the first eye. The time to rebubbling averaged 15 days (95% CI, 13 – 17), and did not differ significantly over the study period (≤2015: 19 days, 95% CI, 10 – 27; 2016: 16 days, 95% CI, 11 – 20; 2017: 15 days, 95% CI, 12 – 18; and 2018: 11 days, 95% CI, 8 – 14; P=0.27). There was no statistically significant

Surgical complication Descemetorhexis diameter, mm <8.5/8.5/>8.5

Eye undergoing surgery, right/ left

BCVA, best-corrected visual acuity; CCT, central cornea thickness; DMEK, Descemet membrane endothelial keratoplasty; ECD, Endothelial cell density; FED, Fuchs endothelial dystrophy; IOP, intraocular pressure; PAC, pseudophakic, anterior chamber; PBK, Pseudophakic bullous keratopathy; PPC, pseudophakic, posterior chamber.

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relationship between the timing of rebubbling (i.e. within one week or longer) and incidence of graft failure. REBUBBLING In univariable analysis, significant risk factors for undergoing rebubbling were recipient age, and surgical complication, Table 2. The most frequently registered complications were related to graft insertion (10%), unfolding (16%), or centration (8%), intraocular hemorrhage (10%), and graft folds (10%). In 37% of complications, no specific details were recorded. No donor demographics were significantly related to rebubbling, Table 2. In multivariable analysis, significant risk factors for undergoing rebubbling were surgical complication (OR: 2.28, 95% CI, 1.20 – 4.33, P=0.012), and recipient age (OR: 1.04 [per increase in 1 year], 95% CI, 1.01 – 1.07, P=0.003). There were no (multi)collinearity issues (all VIFs≤1.05). UNSUCCESFUL REBUBBLING 114

In univariable analysis, significant risk factors for unsuccessful rebubbling were recipient age (OR 1.051 95% CI 1.001 – 1.102, P=0.045) and grafts smaller than 8.5mm (OR 2.9 95% CI 1.02 – 8.06, P=0.046). Grafts bigger than 8.5mm showed a higher odds ratio but did not reach statistical significance (OR=2.15 95% CI 0.71 – 6.52, P=0.18). In multivariable analysis, no parameter reached statistical significance (all P≥0.27). EARLY GRAFT FAILURE

Rebubbling and graft failure in Descement membrane endothelial keratoplasty

rebubbling did not differ significantly compared to grafts in eyes that did not undergo rebubbling (estimated mean=2738 cells/mm2, 95% CI, 2565 – 2911, n=607 vs. 2722 cells/mm2, 95% CI, 2559 – 2884, n=144; P=0.62). After surgery, eyes that underwent rebubbling showed statistically significant lower ECD compared to eyes that did not undergo rebubbling at three months (1564 cells/mm2, 95% CI, 1360 – 1769, n=209 vs. 1851 cells/mm2, 95% CI, 1680 – 2022, n=38; P<0.001), six months (1433 cells/mm2, 95% CI, 1232 – 1635, n=190 vs. 1827 cells/mm2, 95% CI, 1656 – 1998, n=44; P<0.001), and twelve months (1295 cells/ mm2, 95% CI, 1080 – 1510, n=152 vs. 1764 cells/mm2, 95% CI, 1590 – 1937, n=29; P<0.001). Sensitivity analyses (only primary transplants with FED as indication) showed similar results.

5.4 DISCUSSION Graft detachment and graft failure are two of the most common adverse events after DMEK.3 In the literature, numerous risk factors for graft detachment have been identified, but agreement across reports is weak. These include donor characteristics, such as donor age,4 low ECD and poor morphology;5,19 recipient factors, such as primary disease,6 recipient age,7 and lens status;6,20 and surgical parameters, such as descemetorhexis diameter,8 use of viscoelastic,9 graft folding and orientation,19 use of plastic instruments,19 synechiae,19 irregularity of the main incision,19 graft decentration,5,10,11 anterior chamber tamponade agent and dimensions,6,12,13,19 Descemet remnants,14,15 postoperative intraocular pressure,13,16 and surgeon experience.17,18

In univariable analysis, significant risk factors for developing early graft failure were older recipient age, graft diameter smaller or larger than standard, surgical complication, and transplant date before 2016, Table 3. 124 grafts (16%) were larger and 334 grafts (44%) were smaller than the rhexis diameter. Neither were significant risk factors for early graft failure (all P≥0.1). In multivariable analysis, significant risk factors were transplant date before 2016 (OR: 3.32, 95% CI, 1.87 – 5.90, P<0.001), and surgical complication (OR: 2.93, 95% CI, 1.42 – 6.04, P=0.004). There were no (multi)collinearity issues (all VIFs≤1.05).

This prospective multicenter registry study captured all DMEK procedures in the Netherlands from the first procedure registered in October 2011 until mid-2018. While most reports on risk factors originate from single-center retrospective studies, data of the current study were prospectively collected in multiple corneal clinics. In our cohort, independent risk factors for rebubbling after DMEK were surgical complications and older recipient age. With regard to early graft failure, independent risk factors were surgical complication, and transplant date before 2016.

Preoperative donor endothelial cell density (ECD) of grafts that underwent

The risk of rebubbling increased with recipient age (odds ratio 1.04 per year). Maier et al. postulated that older patients may be unable to maintain a

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Rebubbling and graft failure in Descement membrane endothelial keratoplasty

TABLE 2. Univariable analysis of recipient, donor and surgery parameters for undergoing rebubbling after DMEK surgery

TABLE 2. continued

All consecutive performed DMEK (n=752) Rebubbling rate (n=144)(%)

All consecutive performed DMEK (n=752)

95% Cl

P value

1.03 (per 1 unit)

1.01 to 1.05

0.005

1.02

0.71 to 1.47

0.91

Recipient parameters Sex, male/female Female

19 19

Baseline IOP, mm HG

1.00 (per 1 unit)

0.96 to 1.06

0.97

Baseline CCT, μm

1.00 (per 1 unit)

0.99 to 1.00

0.62

Indication, FED

1.8

0.87 to 3.70

0.11

Yes

Indication, PBK 22

19 13

Lens status, PPC 20

Ocular comorbidities, except cataract

95% Cl

P value

1.13 to 3.54

0.016

0.39 to 3.74

0.74

0.25 to 1.70

034

0.75 to 1.82

0.49

0.40 to 1.3

0.29

Donor parameters Age, years Sex

Diameter deescemetorhexis, mm <8.5

–

8.5

0.73

0.44 to 1.19

0.2

>8.5

0.68

0.42 to 1.11

0.12

1.05

0.73 to 1.52

0.78

1.77

0.96 to 3.27

0.06

0.89

0.42 to 1.89

0.78

0.86

0.38 to 1.88

0.7

PPC vs phakic DMEK

1.19

0.52 to 2.63

0.66

PPC vs triple DMEK

1.14

0.54 to 2.42

0.72

1.18

0.54 to 2.59

0.68

0.72

0.49 to 1.03

0.07

Yes

Phakic DMEK 0.74

Yes

Triple procedure 1.12

Yes

Surgery date after 2015 0.64

Yes

Surgical complication

Recipient donor sex mismatch 1.21

Yes Indication, graft failure 116

Surgery parameters

Age, years Male

Rebubbling rate (n=144)(%)

Yes

1.00 (per 1 unit)

0.97 to 1.02

0.76

PPC and triple DMEK vs phakic DMEK

0.88

0.60 to 1.28

0.5

Eye undergoing surgery

Male

Left

Female

Right

Graft diameter, mm <8.5

–

8.5

1.16

0.67 to 2.01

0.59

>8.5

2.13

0.98 to 4.61

0.06

1.00 (per 1 unit)

0.99 to 1.00

0.61

1.53

0.54 to 4.31

0.42

Endothelial cell density, cells/mm2 Complicated graft preparation Yes

CCT, central cornea thickness; DMEK, Descemet membrane endothelial keratoplasty; ECD, endothelial cell density; FED, Fuchs endothelial dystrophy; IOP, intraocular pressure; PBK, pseudophakic bullous keratopathy; PPC, pseudophakic, posterior chamber.

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Rebubbling and graft failure in Descement membrane endothelial keratoplasty

TABLE 3. Univariable analysis of recipient, donor and surgery parameters for developing early graft failure after DMEK surgery

TABLE 3. continued

All consecutive performed DMEK (n=752) Rebubbling rate OR (n=144)(%)

All consecutive performed DMEK (n=752)

95% Cl

P value

1.03 (per 1 unit)

1.00 to 1.06

0.037

1.55

0.98 to 2.44

0.06

Recipient parameters Sex, male/female Female

14 9

Baseline IOP, mm HG

1.03 (per 1 unit)

0.96 to 1.10

0.43

Baseline CCT, μm

1.00 (per 1 unit)

1.00 to 1.01

0.43

Indication, FED

0.8

0.39 to 1.62

Yes

Indication, PBK

P value

11 14

Lens status, PPC 12

Ocular comorbidities, except cataract

2.83

1.50 to 5.32

0.001

0.45 to 5.61

0.47

0.47 to 3.27

0.66

0.87 to 2.89

0.13

0.41 to 1.63

0.56

Donor parameters Age, years Sex Male

Female

0.98 (per 1 unit)

0.95 to 1.01

0.15

1.12

0.70 to 1.80

0.64

Graft diameter, mm <8.5

–

8.5

0.37

0.21 to 0.64

<0.001

>8.5

1.25

0.58 to 2.74

0.57

1.00 (per 1 unit)

1.00 to 1.00

0.65

2.15

0.70 to 6.62

0.17

Endothelial cell density, cells/mm2 Complicated graft preparation Yes

Diameter deescemetorhexis, mm <8.5

–

8.5

0/67

0.33 to 1.33

0.25

>8.5

1.41

0.76 to 2.61

0.27

0.65 to 1.61

0.93

0.32

0.19 to 0.54

<0.001

0.84

0.33 to 2.19

0.73

0.33

0.08 to 1.40

0.08

PPC vs phakic DMEK

3.15

0.75 to 13.35

0.1

PPC vs triple DMEK

1.29

0.49 to 3.34

0.61

PPC and triple DMEK vs phakic DMEK

3.09

0.73 to 12.98

0.11

Eye undergoing surgery

0.78

0.49 to 1.23

0.28

Yes

Phakic DMEK 0.81

Yes

Triple procedure 1.59

Yes

Surgery date after 2015 1.24

Yes

Surgical complication

Recipient donor sex mismatch 1.59

Yes Indication, graft failure 118

95% Cl

Surgery parameters

Age, years Male

Rebubbling rate OR (n=144)(%)

Yes

Left

Right

CCT, central cornea thickness; DMEK, Descemet membrane endothelial keratoplasty; ECD, endothelial cell density;

FED, Fuchs endothelial dystrophy; IOP, intraocular pressure; PBK, pseudophakic bullous keratopathy; PPC, pseudophakic, posterior chamber.

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supine position postoperatively, leading to inadequate air bubble support for the graft.7 This hypothesis is supported by the fact that graft detachments develop most often inferiorly, coinciding with the least air bubble support in an upright head position. For early graft failure, surgery before 2016 was the most important independent risk factor. This is likely related to a learning curve on a national level, which is supported by the significant decrease in incidence of graft failures over time. This is in line with previous literature showing a relationship between surgeon experience and adverse event rate.17,18 The large majority of graft failures (93%) occurred in the first six months postoperatively, indicating graft detachment and primary graft failure are the leading causes. Interestingly, rebubbling was unsuccessful in 30% of cases, and surgeons mostly opted for repeated transplantation instead of subsequent rebubbling. Univariable analysis indicated elderly patients and grafts smaller than 8.5 mm were at higher risk for failed rebubbling. However, this did not reach statistical significance in multivariable analysis. It is encouraging that only a handful of graft failures were recorded beyond six months after surgery. 120

In our cohort, rebubbling was associated with statistically significant endothelial cell loss after correcting for recipient age, indication, lens status, and surgical complication. Similarly, one study found lower ECD in eyes that underwent a single rebubbling compared to eyes with complete postoperative graft attachment (1350 cells/mm2 vs. 1613 cells/mm2, P=0.033),21 while another study reported that two, but not one, rebubblings led to higher endothelial cell loss.22 The adverse effect of rebubbling should be weighed against the risk of complete graft detachment. In our cohort, eyes that underwent more than one rebubbling were rare. Whether an increased cell loss is due to rebubbling, graft detachment, or donor-related factors is currently unknown. Interestingly, we observed a concurrent decrease in graft failure rate and increased rebubbling rate over time. While correlation does not imply causation, we hypothesize that proactive rebubbling may have prevented some complete graft detachments. The indication and timing of rebubbling vary considerably in the literature. Some surgeons rebubble as early as possible to prevent graft fibrosis and corneal edema,6 while others await spontaneous reattachment for 1 – 2 weeks,22 or even longer.23 In our cohort, mean duration until rebubbling averaged 15 days, but decreased over time,

Rebubbling and graft failure in Descement membrane endothelial keratoplasty

albeit not significantly. Interestingly, a history of rebubbling in one eye did not increase the risk of rebubbling in the other eye. This information is of particular relevance for counseling patients. Air and SF6 gas were used in 57% and 43% of centers registering in NOTR. Few centers switched from air to SF6 after the initial 5-10 cases. Therefore, the increase in rebubbling rate in our study is not related to the type of tamponade used. In the Netherlands, grafts are prepeeled within three days before surgery. Subsequently, graft storage time was not a significant risk factor for rebubbling, unsuccessful rebubbling, or early graft failure. Two studies reported that phakic DMEK was protective against graft detachment requiring rebubbling and graft failure compared to eyes that were either preoperatively pseudophakic or underwent a triple procedure.6,20 We included this parameter in univariable and multivariable analysis, but it showed neither a statistically significant nor clinically relevant effect. The current study also has several limitations. Being a registry study, internal validity is low due to heterogeneity in surgical technique, postoperative medication, and measurement technique. On the other hand, the results are highly generalizable. The current NOTR does not capture all parameters which may be related to graft detachment, such as graft detachments that did not undergo rebubbling, location and extent of graft detachment, but also anterior chamber depth, use of intraoperative optical coherence tomography, presence of recipient Descemet remnants in the interface, and postoperative inpatient versus outpatient care. In line with institutional review board approval, data were not stratified based on individual surgeon or center level. In conclusion, this prospective registry study on DMEK found independent risk factors for developing graft detachment leading to rebubbling, namely recipient age and surgical complication. For developing early graft failure, independent risk factors were surgical complication and transplantation before 2016 which likely reflects a learning curve on a national level. Based on this data, we make the following recommendations. First, we recommend close postoperative monitoring in elderly patients or in case surgical complications occur. Second, our study excludes various risk factors such as triple procedure and donor-related parameters such as donor age (within the range of 45-85 years). Therefore, triple procedures may performed

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safely when indicated, and it is not necessary to select donors based on such criteria. Third, the inverse relationship between rebubbling and early graft failure rates suggests a proactive approach to graft detachment may be beneficial. Acknowledgements The authors would like to thank Mrs Cynthia Konijn of theDutch Transplant Foundation (NTS), Leiden, the Netherlands, for processing our dataapplication and the members of the Dutch Corneal Workgroup for their dedication and precise data registration. Contributors SLD: planning, conduct and reporting; BW: reporting; FvdB: reporting, conducting; RN: planning, conduct and reporting; PJK: planning, conductand reporting; MD: planning, conduct and reporting; Dutch Cornea Consortium: planning, conduct and reporting. 122

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared

Rebubbling and graft failure in Descement membrane endothelial keratoplasty

References 1. Gain P, Jullienne R, He Z, Aldossary M, Acquart S, Cognasse F, Thuret G. Global Survey of Corneal Transplantation and Eye Banking. JAMA ophthalmology. 2016;134(2):167-173. 2. Armitage WJ, Jones MNA, Zambrano I, Carley F, Tole DM. The Suitability of Corneas Stored by Organ Culture for Penetrating Keratoplasty and Influence of Donor and Recipient Factors on 5-Year Graft Survival. Invest Ophthalmol Vis Sci. 2014;55(2):784-791. 3. Sherman RE, Anderson SA, Dal Pan GJ, Gray GW, Gross T, Hunter NL, LaVange L, Marinac-Dabic D, Marks PW, Robb MA, Shuren J, Temple R, Woodcock J, Yue LQ, Califf RM. Real-World Evidence - What Is It and What Can It Tell Us? N Engl J Med. 2016;375(23):2293-2297. 4. Lundstrom M, Dickman M, Henry Y, Manning S, Rosen P, Tassignon MJ, Young D, Stenevi U. Femtosecond laser-assisted cataract surgeries reported to the European Registry of Quality Outcomes for Cataract and Refractive Surgery: Baseline characteristics, surgical procedure, and outcomes. J Cataract Refract Surg. 2017;43(12):1549-1556. 5. Keane M, Coster D, Ziaei M, Williams K. Deep anterior lamellar keratoplasty versus penetrating keratoplasty for treating keratoconus. Cochrane Database Syst Rev. 2014(7):Cd009700. 6. Price DA, Kelley M, Price FW, Jr., Price

MO. Five-Year Graft Survival of Descemet Membrane Endothelial Keratoplasty (EK) versus Descemet Stripping EK and the Effect of Donor Sex Matching. Ophthalmology. 2018;125(10):1508-1514. 7. Akanda ZZ, Naeem A, Russell E, Belrose J, Si FF, Hodge WG. Graft rejection rate and graft failure rate of penetrating keratoplasty (PKP) vs lamellar procedures: a systematic review. PloS one. 2015;10(3):e0119934. 8. Williams KM, Galettis R, Jones V, Mills R, Coster D. The Australian Corneal Graft Registry - 2015 Report. 9. Dickman MM, Spekreijse LS, Dunker SL, Winkens B, Berendschot TTJM, van den Biggelaar FHJM, Kruit PJ, Nuijts RMMA. Long-term Outcomes of Repeated Corneal Transplantations: A Prospective Dutch Registry Study. Am J Ophthalmol. 2018;193:156-165. 10. Deng SX, Lee WB, Hammersmith KM, Kuo AN, Li JY, Shen JF, Weikert MP, Shtein RM. Descemet Membrane Endothelial Keratoplasty: Safety and Outcomes: A Report by the American Academy of Ophthalmology. Ophthalmology. 2018;125(2):295-310. 11. Lee WB, Jacobs DS, Musch DC, Kaufman SC, Reinhart WJ, Shtein RM. Descemet’s stripping endothelial keratoplasty: safety and outcomes: a report by the American Academy of Ophthalmology. Ophthalmology. 2009;116(9):1818-1830.

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124

14. Claesson M, Armitage WJ, Bystrom B, Montan P, Samolov B, Stenvi U, LundstromM. Validation of Catquest9SF-A Visual Disability Instrument to Evaluate Patient Function After Corneal Transplantation. Cornea. 2017;36(9):1083-1088. 15. Mandeville KL, Valentic M, Ivankovic D, Pristas I, Long J, Patrick HE. Quality Assurance of Registries for Health Technology Assessment. Int J Technol Assess Health Care. 2018;34(4):360367.

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Practice patterns of corneal transplantion in Europe

CHAPTER 6

Practice patterns of corneal transplantion in Europe: First report by the European Cornea and Cell Transplantation Registry (ECCTR)

126

127

Authors Suryan L. Dunker, W. John Armitage, Margareta Armitage, Lucia Brocato, Francisco C. Figueiredo, Martin B.A. Heemskerk, Jesper Hjortdal, Gary L.A. Jones, Cynthia Konijn, Rudy M.M.A. Nuijts, Mats Lundström, and Mor M. Dickman J CATARACT REFRACT SURG. 2021 JUL 1;47(7):865-869.

CHAPTER 6

Abstract Purpose: To report practice patterns of corneal transplantation in Europe.

Practice patterns of corneal transplantion in Europe

Conclusions: This report provides the most comprehensive overview of corneal transplantation practice patterns in Europe to date. Fuchs endothelial dystrophy is the most common indication, vision improvement the leading reason, and DS(A)EK the predominant technique for corneal transplantation.

Setting: Corneal clinics in ten European member states, the United Kingdom, and Switzerland. Design: Multinational registry study. Methods: Corneal transplant procedures registered in the European Cornea and Cell Transplantation Registry (ECCTR) were identified. We analyzed preoperative donor and recipient characteristics, indication and reason for transplantation, and surgical techniques.

128

Results: 12,913 corneal transplants were identified from ten European Union member states, the United Kingdom (UK) and Switzerland. Most countries were self-sufficient with regard to donor tissue. Fuchs’ endothelial corneal dystrophy (FED) was the most common indication (41%, n=5,325), followed by regraft (16%, n=2,108), Pseudophakic bullous keratopathy (PBK, 12%, n=1,594), and keratoconus (12%, n=1,506). Descemet stripping (automated) endothelial keratoplasty (DS[A]EK, 46%, n=5,918) was the most commonly performed technique, followed by Penetrating keratoplasty (PK, 30%, n=3,886), and Descemet membrane endothelial keratoplasty (DMEK, 9%, n=1,838). Vision improvement was the main reason for corneal transplantation (90%, n=11,591). Surgical technique and reason for transplantation differed between indications.

6.1 Introduction Quality of care registries collect real-world data about patients that is used to measure, report and improve quality of care. In addition to their primary function in quality of healthcare improvement, registries inform policy and research efforts, and improve cost-effectiveness of patient care, therefore should be facilitated and encouraged.1 The European Cornea and Cell Transplantation Registry (ECCTR) was established by a consortium of seven partners, including three national registries and professional societies, to develop a common assessment methodology and European web-based registry in the field of corneal transplantation. The aim of ECCTR is to provide academics, health professionals and authorities a framework to assess and verify safety, quality and efficacy of corneal transplantation. The ECCTR received co-funding from the Third Health Programme of the European Union and the European Society of Cataract and Refractive Surgeons (ESCRS). The web-based system implemented for the registry allows for the uploading of data directly from affiliated eye clinics and corneal transplant surgeons lacking such registries, as well as integration of existing national registries. The last decade witnessed a revolution in corneal transplantation with the implementation of lamellar corneal transplantation techniques on a broad scale.2-7 It is currently unknown how this development impacted practice pattern in Europe, such as indication for transplantation, recipient age and

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reason for transplantation. In this first report by ECCTR, we aim to report practice pattern across Europe using a dataset of 12,913 transplants performed in ten European member states and the United Kingdom and Switzerland.

6.2 Methods GRAFT REGISTRY AND DATA COLLECTION

130

This is a multinational longitudinal registry study. The Steering Group (SG) provided approval for data extraction and analysis in accordance with European legislation and national regulations governing the collection and use of data for registries. The ECCTR conducted a Data Protection Impact Analysis (DPIA) ensuring data protection by design, compliance with the General Data Protection Regulation (GDPR) and supporting trust and engagement with users. All data reported to ECCTR are anonymized. The study adhered to the tenants of the declaration of Helsinki. The SG consists of representatives from seven partners, i.e., the European Society of Cataract and Refractive Surgeons (ESCRS), European Society of Cornea and Ocular Surface Disease Specialists (EuCornea), the Veneto Eye Bank Foundation (Fondazione Banca degli Occhi del Veneto Onlus, FBOV)/European Eye Bank Association (EEBA), UK NHS Blood and Transplant (NHSBT), University of Maastricht (UM), Dutch Transplant Foundation (Nederlandse Transplantatie Stichting: NTS), and Blekinge Läns Landsting (LTBlekinge). Data extraction took place on February 20th, 2020. Data for the current study were either uploaded as a cohort by national registries or manually registered via the ECCTR web-based platform by affiliated eye clinics. The registry collects data on surgery and donor country, indication, surgical techniques, reason for transplantation, and patient and donor characteristics. Mandatory preoperative characteristics include year of birth, sex, eye, refraction and corrected distance visual acuity, indication and reason for transplant, co-existing eye diseases, and previous ophthalmic surgeries. Donor characteristics include country of cornea retrieval, year of birth, sex, endothelial cell density, graft storage type, and time in storage. Surgical data include date of surgery, keratoplasty type, indication and reason for surgery, risk factors, surgical complication, surgeon experience, and date of decision to treat. In accordance with protocol, consecutive cases are reported

Practice patterns of corneal transplantion in Europe

to the database by participating units, and follow-up is captured at two years (± three months) after surgery. Follow-up data include date of examination, postoperative refraction and corrected distance visual acuity, endothelial cell density, and postoperative complications. Graft failure specification during the first two years after surgery is reported separately. OUTCOME MEASURES The primary outcome measure of this study is corneal transplantation practice patterns, including preoperative recipient and donor characteristics, indication and surgical technique. STATISTICAL ANALYSIS Statistical analyses were performed using IBM SPSS Statistics for Windows, version 24.0 (IBM Corp., Armonk, N.Y., USA). Baseline characteristics were reported as frequencies with percentages or mean (SD). The distribution of sex, age, keratoplasty technique and indications was tested using the X2 goodness of fit test. Two-sided P-values ≤0.05 were considered statistically significant.

6.3 Results PRACTICE PATTERNS Pre-operative recipient, donor, and surgery characteristics are shown in Table 1. In total, 12,913 corneal transplants were registered in ECCTR from ten European Union member states (MS): Belgium, Czech Republic, Denmark, Finland, France, Ireland, Italy, Latvia, the Netherlands, Spain, and from Switzerland and the United Kingdom (UK). Most of the participating MS were self-sufficient regarding donor tissue. The total number of transnational shipments of donor tissue amounted to 5% (n=619). Most tissues were exported by the Netherlands (45%, n=280), followed by Germany (6%, n=37), France (4%, n=25), and Italy (3%, n=18). Two percent (n=257) of donor corneal tissue were imported from the United States. The most common indication for corneal transplantation was Fuchs’

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Practice patterns of corneal transplantion in Europe

TABLE 1. Baseline, donor, and surgery characteristics of all corneal transplants in the ECCR registry (N=12,913, unless otherwise specified). Recipient

MEAN ± SD OR N (%)

Indication Fuchs endothelial dystrophy

5,325 (41%)

Regraft

2,108 (16%)

Pseudophakic bullous keratopathy

1,594 (12%)

Keratoconus

1,506 (12%)

Infection

892 (7%)

Other corneal dystrophy

303 (2%)

Trauma

217 (2%)

Other

968 (8%)

Age (years)

65 ± 18

Male sex (n=12,433)

6,493 (52%)

Donor Age (years, n=12,655)

66 ± 13

Male sex (n=12,152)

7,154 (59%)

Transplant days in storage (n=4,668)

16 ± 5.4

Endothelial cell density, cells/mm (n=9,349)

2,656 ± 257

Surgery Surgery type 132

DS(A)EK

5,918 (46%)

Penetrating keratoplasty

3,886 (30%)

DMEK

1,838 (14%)

DALK

1,051 (9%)

ALK

138 (1%)

Other

81 (<1%)

Combined surgery (n=11,767) No combined surgery

9,116 (77%)

CEIOL

1,641 (14%)

Peripheral iredectomy

535 (5%)

ECLE

194 (2%)

Other

281 (2%)

ALK=Anterior lamellar keratoplasty; CEIOL=Cataract extraction with intraocular lens implantation; DALK=Deep anterior lamellar keratoplasty; DMEK=Descemet membrane endothelial keratoplasty; DS(A)EK=Descemet stripping (automated) endothelial keratoplasty; ECLE=Extracapsular cataract extraction; FED=Fuchs endothelial dystrophy; PBK= Pseudophakic bullous keratopathy; PI=Peripheral iridectomy.

DALK=Deep anterior lamellar keratoplasty; DMEK=Descemet membrane endothelial keratoplasty; DS(A)EK=Descemet stripping (automated)

endothelial keratoplasty; FED=Fuchs endothelial dystrophy; PBK=Pseudophakic bullous keratopathy; PK=Penetrating keratoplasty.

FIGURE 1. Surgical technique per indication for corneal transplantation in the ECCTR. DS(A)EK and DMEK were primarily performed for FED, PBK, and regraft. DALK was mainly performed for Keratoconus. PK was performed for all indications, but was the main technique for trauma, infection, keratoconus, and regraft.

endothelial corneal dystrophy (41%, n=5,325), followed by regraft (16%, n=2,108), Pseudophakic bullous keratopathy (PBK, 12%, n=1,594), and keratoconus (12%, n=1,506) (Table 1). The three most common surgical techniques were Descemet stripping (automated) endothelial keratoplasty (DS[A]EK, 46%, n=5,918), Penetrating keratoplasty (PK, 30%, n=3,886), and Descemet membrane endothelial keratoplasty (DMEK, 9%, n=1,838) (Table 1). In FED, DS(A)EK was the technique of choice followed by DMEK (70%, n=3,721 vs. 25%, n=1,357; P<0.001, respectively). Similarly, in PBK, DS(A)EK was the primary technique followed by DMEK (64%, n=1,013 vs. 17%, n=273; P<0.001, respectively). In regraft, PK was the most common technique, followed by DS(A)EK, and DMEK (52%, n=1,095 vs. 39%, n=822 vs. 6%, n=137; P<0.001, respectively). In keratoconus, PK and DALK were the predominant techniques (51%, n=765 vs. 47%, n=701; P=0.1, respectively). In infectious keratitis, PK was the technique of choice followed by DALK (77%, n=690 vs. 15%, n=136; P<0.001, respectively)

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(Figure 1). In 77% of cases (n=9,116), corneal transplantation was a standalone procedure and in 14% of cases (n=1,641), corneal transplantation was combined with lens extraction and intraocular lens implantation. However, this differed between techniques: 22% (n=365) of DMEK, 22% (n=903) of DS(A) EK, and 10% (n=337) of PK procedures were combined with lens extraction and intraocular lens implantation. The reason for transplantation is categorized as vision improvement, tectonic, pain reduction, and ‘other’, e.g. debulking in infectious keratitis. Overall, vision improvement was the main reason for corneal transplantation (89.8%, n=11,591), followed by tectonic (1.4%, n=181), pain reduction (1.2%, n=150), and ‘other’ (7.7%, n=991). In ‘other’, n=868 cases were not further specified and few cases were reported as contact lens intolerance and for cosmetic improvement. The rationale differed between keratoplasty techniques. In D(S) AEK, DMEK, and DALK, vision improvement was the reason in 97% (n=4,259), 90% (n=1,751), and 92% (n=970) of cases, respectively. In PK, vision improvement was the motivation in only 78% (n=3,045) of cases, while 22% (n=841) were performed for other reasons.

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Recipient sex was male in 52% (n=6,493) of cases and female in 48% (n=5,940) of cases. The percentage of males (M) and females (F) differed significantly between indications: trauma, 83%M/17%F; keratoconus, 70%M/30%F; regraft, 56%M/44%F, infectious keratitis, 52%M/48%F; FED, 45%M/55%F; PBK 49%M/51%F; respectively, P<0.001. Patients of all ages received a corneal transplant. The youngest recipient was less than 1 year old (indication corneal dermoid), and the oldest recipient was 101 years old (indication regraft). Average patient age was 65 (SD 18) years. Patient age differed significantly between indications, P<0.001. In keratoconus, patients were the youngest and patients with PBK were the oldest (36 (SD 13) years and 75 (SD 11) years, respectively). The majority of cornea donors were males (59%, n=7,154 vs. 41%, n=4,998 females). Mean donor age was 66 (SD 13) years with a mean donor endothelial cell count of 2656 (SD 257) cells/mm2. Storage time measured 16 (SD 5) days.

6.4 Discussion This European registry study analyzed practice patterns, of 12,913 corneal

Practice patterns of corneal transplantion in Europe

transplants reported to the ECCTR between November 2017 and February 2020. The transplants were performed in ten European member states and the United Kingdom and Switzerland, providing the largest data on corneal transplant practice in Europe to date. A recent systematic review identified 97 clinical registries in Ophthalmology.8 In Europe, a variety of registries and institutes collect data on corneal transplantation, but substantial differences exist in frequency and scope of reporting. Outcomes are reported by national registries established in Scandinavia9, the Netherlands10, and the United Kingdom.11,12 Data is collected and trends have been reported to a varying degree in France13, Germany7, Italy, and Ireland.14 Outside Europe, Australia15, and Singapore16 frequently report outcomes on corneal transplants and the Asia Cornea Society established a consortium including China, India, Japan, New Zealand, Pakistan, Singapore, South Korea, Taiwan and Thailand (https://www.asiacorneasociety.org/). The value of such collaborations is well recognized internationally and clearly demonstrated by a recently published study on infectious keratitis in Asia.17 The Eye Bank Association of America (EBAA) also publishes an annual report chronicling trends in corneal transplantation in the United States.5 Registries play an important role in providing clinical evidence.18 The primary attribute that distinguishes “real-world” evidence is related to the context in which the evidence is gathered, i.e., routine clinical care. The key to understanding the usefulness of real-world evidence is an appreciation of its potential for complementing knowledge gained from traditional clinical trials,1 whose well known limitations make it difficult to generalize findings.19 Large prospective registries such as the ECCTR can drive and support quality improvement, auditing, and research.19 New techniques can be rapidly integrated, rare events can be monitored, and evidence can be collected. The ECCTR uniquely aggregates large data sets across Europe and therefore has enormous potential to analyze trends and outcomes, as well as to inform therapeutic development, resource planning, and policymaking in and beyond Europe. Importantly, time and money can be saved while yielding answers relevant to broader populations of patients than would be possible in a specialized research environment such as a randomized clinical trial. Based on survey data from 140 countries, the leading global indications for corneal transplants in 2012 were FED, followed by keratoconus, bullous

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keratopathy, and infectious keratitis.20 However, indications vary strongly between regions. In ECCTR, the most common indications for corneal transplantation were FED (41%), regraft (16%), keratoconus (12%), and PBK (12%). Interestingly, regraft was the second most common indication in our study. As more and more often patients receive corneal transplants at earlier stages of disease and life expectancy increases in Europe, the indication regraft will likely increase over time.21 This information is especially relevant since each consecutive graft has a shorter survival compared with its predecessors.6 In Asian countries, PBK (Philippines, Japan, Taiwan, Singapore, and Hong Kong) and infectious keratitis (China, India, the Philippines, Sri Lanka, and Thailand) are the most common indications.16 Keratoconus is a major indication in Australia, Italy, Russia, South Africa, and the Middle East ranging between 30% to 53%.16 However, in various countries, the number of corneal transplants for keratoconus decreased owing to the implementation of cross-linking.22,23

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The predominant procedures in ECCTR for the treatment of corneal endothelial pathology (e.g. FED, PBK) are DS(A)EK, followed by DMEK, and rarely PK. However, DMEK is on the rise, and it will be interesting to monitor this in the future. For keratoconus, PK remains the most common technique, with DALK having a niche activity, likely reflecting a discrepancy between technical difficulty and theoretical benefits. We hope this trend will change in the future and recommend that patients with keratoconus are referred to surgeons/centers with expertise in DALK. This is especially important as the number of transplants for keratoconus is expected to decrease due to broad scale implementation of timely collagen crosslinking. For infections keratitis, PK remains the most common procedure, and the role of DALK remains controversial and limited. Similarly to other parts of the world, corneal transplantations across Europe were performed for patients of all ages starting from the first year of life to patients over 100 years old. However, patient age differed significantly between indications: keratoconus patients were on average the youngest patients undergoing keratoplasty and patients with PBK were the oldest. This corresponds with the early disease progression seen in keratoconus, while PBK typically occurs after cataract extraction in mostly elderly patients. The European Union endorses the development of sustainable transplant systems to meet the challenge of self-sufficiency of tissues, such as cornea.24

Practice patterns of corneal transplantion in Europe

Most countries represented in ECCTR were self-sufficient as less than 5% of donor tissue was exchanged across borders. This may be increasingly important in times of global calamities such as the COVID-19 pandemic. Originally co-funded by the European Union, ECCTR is not restricted to member states only. Currently, Switzerland, and the UK contribute to ECCTR. In line with the ECCTR consortium agreement and institutional review board approval, data is not stratified by country, center, or surgeon. For individual surgeons who are registered in ECCTR, personal outcomes can be benchmarked against national and European outcomes. The main reason for missing data in ECCTR is non-response. Some items are more likely to generate a non-response compared to others, e.g., donor endothelial cell density was available in 72% of grafts, whereas information on recipient sex was available in 96% of cases. ECCTR is dedicating effort and resources to optimize data completeness. Additional limitations pertain to data accuracy. Data is not externally audited, including the diagnosis or surgical indications. As a result, coding or classification bias may influence outcomes. The ECCTR captures data from three national registries and individual clinics in nine countries without a national registry. In countries with a national registry, near complete coverage is achieved. In countries without a national registry it is not possible to determine the coverage of ECCTR. Interestingly, more donor tissue was provided by males compared to females in every country contributing to the ECCTR. In altruistic living donation, twothirds of all organs were donated by women,25 while data from the UK National Health Service on cadaver organ donation and transplant in 2015– 2016 indicates that 51% of organ donors after brain death and 61% of organ donors after circulatory death are men. The nature of how gender dynamics figure into the relationship of the deceased to family decision-making is underexplored in the scholarly literature.26 National differences across Europe are likely not responsible as this effect is seen in every member state. Likewise, while ethnicity is not captured in ECCTR, deceased donation in ethnic minority groups is low, and focused effort is needed to address this issue.27 Identifying reasons for this discrepancy could help combat shortage of donor tissue. The scope and infrastructure of ECCTR also provides a unique opportunity to analyze rare diseases, such as aniridia, that effect few but have important health implication for affected individuals and high societal costs.

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In summary, in this first report from the ECCTR, 12,913 corneal transplants from ten European member states and the United Kingdom and Switzerland were analyzed and practice patterns reported. The data in this manuscript may inform evidence-based decision making for policy changes, for example with regard to self-sufficiency of donor tissue and practice patterns. For example, with regard to organization of corneal transplant care in Europe to improve access to DALK for keratoconus patients, and addressing emerging challenges such as regrafts that constitute the second most common indication for transplantation. The ECCTR invites other European national registries, eye clinics, and individual corneal transplant surgeons to join this registry. Existing national registries can be incorporated in ECCTR and individual surgeons can easily upload data using a secure web- based form (for more information visit https://www.ecctr.org).

6.5 Value Statement WHAT WAS KNOWN • 138

In cohort studies and from some registry data it has been reported about corneal transplantation practice patterns. WHAT THIS PAPER ADDS

•

This paper provides comprehensive information on corneal transplantation practice patterns in Europe from a large multinational database of 12,913 corneal transplants. Fuchs dystrophy is the predominant indication, vision improvement is the most common reason, and DS(A)EK is the most frequent technique for corneal transplantation in Europe.

Practice patterns of corneal transplantion in Europe

References 1. Larsson S, Lawyer P, Garellick G, Lindahl B, Lundstrom M. Use of 13 disease registries in 5 countries demonstrates the potential to use outcome data to improve health care's value. Health Aff (Millwood). 2012;31(1):220227. 2. Deng SX, Lee WB, Hammersmith KM, Kuo AN, Li JY, Shen JF, Weikert MP, Shtein RM. Descemet Membrane Endothelial Keratoplasty: Safety and Outcomes: A Report by the American Academy of Ophthalmology. Ophthalmology. 2018;125(2):295-310. 3. Lee WB, Jacobs DS, Musch DC, Kaufman SC, Reinhart WJ, Shtein RM. Descemet's stripping endothelial keratoplasty: safety and outcomes: a report by the American Academy of Ophthalmology. Ophthalmology. 2009;116(9):1818-1830. 4. Reinhart WJ, Musch DC, Jacobs DS, Lee WB, Kaufman SC, Shtein RM. Deep anterior lamellar keratoplasty as an alternative to penetrating keratoplasty a report by the american academy of ophthalmology. Ophthalmology. 2011;118(1):209-218. 5. Eye Bank Association of America. 2018 Eye Banking Statistical Report. Available at: https://restoresight.org/ wp-content/uploads/2019/03/2018_ Statistical_Report- Complete-1.pdf. Accessed November 18th, 2020. 6. Williams K KM, Galettis R, Jones V, Mills R, Coster D. The Australian Cor-

neal Graft Registry - 2015 Report. 7. Flockerzi E, Maier P, Bohringer D, Reinshagen H, Kruse F, Cursiefen C, Reinhard T, Geerling G, Torun N, Seitz B. Trends in Corneal Transplantation from 2001 to 2016 in Germany: A Report of the DOG-Section Cornea and its Keratoplasty Registry. Am J Ophthalmol. 2018;188:91-98. 8. Tan JCK, Ferdi AC, Gillies MC, Watson SL. Clinical Registries in Ophthalmology. Ophthalmology. 2019;126(5):655662. 9. Claesson M, Armitage WJ, Fagerholm P, Stenevi U. Visual outcome in corneal grafts: a preliminary analysis of the Swedish Corneal Transplant Register. Br J Ophthalmol. 2002;86(2):174-180. 10. Dickman MM, Peeters JM, van den Biggelaar FJ, Ambergen T A, van Dongen MC, Kruit PJ, Nuijts RM. Changing Practice Patterns and Long-term Outcomes of Endothelial Versus Penetrating Keratoplasty: A Prospective Dutch Registry Study. Am J Ophthalmol. 2016;170:133-142. 11. Keenan TD, Jones MN, Rushton S, Carley, FM. Trends in the indications for corneal graft surgery in the United Kingdom: 1999 through 2009. Arch Ophthalmol. 2012;130(5):621-628. 12. Armitage WJ, Jones MNA, Zambrano I, Carley F, Tole DM. The Suitability of Corneas Stored by Organ Culture for Penetrating Keratoplasty and Influ-

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ence of Donor and Recipient Factors on 5-Year Graft Survival. Invest Ophthalmol Vis Sci. 2014;55(2):784-791.

titis Study: A Prospective Multicenter Study of Infectious Keratitis in Asia. Am J Ophthalmol. 2018;195:161- 170.

13. Bigan G, Puyraveau M, Saleh M, Gain P, Martinache I, Delbosc B, Gauthier AS. Corneal transplantation trends in France from 2004 to 2015: A 12-year review. Eur J Ophthalmol. 2018;28(5):535-540.

18. Hoque DME, Kumari V, Ruseckaite R, Romero L, Evans SM. Impact of clinical registries on quality of patient care and health outcomes: protocol for a systematic review. BMJ Open. 2016;6(4):e010654.

14. Quigley C, McElnea E, Fahy G. Trends in corneal transplant surgery in Ireland: indications and outcomes of corneal transplant surgery and intraocular lens opacification following Descemet's stripping automated endothelial keratoplasty. Ir J Med Sci. 2018;187(1):231-236.

19. Sherman RE, Anderson SA, Dal Pan GJ, Gray GW, Gross T, Hunter NL, LaVange L, Marinac-Dabic D, Marks PW, Robb MA, Shuren J, Temple R, Woodcock J, Yue LQ, Califf RM. Real-World Evidence - What Is It and What Can It Tell Us? N Engl J Med. 2016;375(23):2293-2297.

15. Coster DJ, Lowe MT, Keane MC, Williams KA. A comparison of lamellar and penetrating keratoplasty outcomes: a registry study. Ophthalmology. 2014;121(5):979- 987.

20. Gain P, Jullienne R, He Z, Aldossary M, Acquart S, Cognasse F, Thuret G. Global Survey of Corneal Transplantation and Eye Banking. JAMA ophthalmology. 2016;134(2):167-173.

16. Tan D, Ang M, Arundhati A, Khor W-B. Development of Selective Lamellar Keratoplasty within an Asian Corneal Transplant Program: The Singapore Corneal Transplant Study (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc. 2015;113:T10.

21. Dickman MM, Spekreijse LS, Dunker SL, Winkens B, Berendschot TTJM, van den Biggelaar FHJM, Kruit PJ, Nuijts RMMA. Long-term Outcomes of Repeated Corneal Transplantations: A Prospective Dutch Registry Study. Am J Ophthalmol. 2018;193:156-165.

17. Khor WB, Prajna VN, Garg P, Mehta, JS, Xie L, Liu Z, Padilla MDB, Joo CK, Inoue Y, Goseyarakwong P, Hu FR, Nishida K, Kinoshita S, Puangsricharern V, Tan AL, Beuerman R, Young A, Sharma N, Haaland B, Mah FS, Tu EY, Stapleton FJ, Abbott RL, Tan DT. The Asia Cornea Society Infectious Kera-

22. Godefrooij DA, Gans R, Imhof SM, Wisse RP. Nationwide reduction in the number of corneal transplantations for keratoconus following the implementation of crosslinking. Acta ophthalmologica. 2016;94(7):675-678. 23. Sandvik GF, Thorsrud A, Råen M, Østern AE, Sæthre M, Drolsum L.

Does Corneal Collagen Cross-linking Reduce the Need for Keratoplasties in Patients With Keratoconus? Cornea. 2015;34(9):991-995. 24.

European Union 2004 Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage, and distribution of human tissues and cells. Official Journal of the European Union L102/48.

25. Steinman JL. Gender disparity in organ donation. Gend Med. 2006;3(4):246-252. 26. Martinez JM, López JS, Martín A, Martín MJ, Scandroglio B, Martín JM. Organ donation and family decision-making within the Spanish donation system. Soc Sci Med. 2001;53(4):405-421. 27. Morgan M, Kenten C, Deedat S, Farsides B, Newton T, Randhawa G, Sims J, Sque M. Programme Grants for Applied Research. In: Increasing the acceptability and rates of organ donation among minority ethnic groups: a programme of observational and evaluative research on Donation, Transplantation and Ethnicity (DonaTE). Southampton (UK): NIHR Journals Library.

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Outcomes of corneal transplantation in Europe: Report by the European Cornea and Cell Transplantation Registry (ECCTR)

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J CATARACT REFRACT SURG. 2021 JUN 1;47(6):780-785.

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Outcomes of corneal transplantation in Europe

7.1 Introduction Abstract Purpose: To analyze real-world graft survival and visual acuity outcomes of corneal transplantation in Europe. Setting: Corneal clinics in ten European Union member states, the United Kingdom, and Switzerland. Design: Multinational registry study. Methods: All corneal transplant procedures registered in the European Cornea and Cell Transplantation Registry (ECCTR) were identified. Graft survival of primary corneal transplants were analyzed using Kaplan-Meier survival curves with log-rank test and Cox regression. Corrected distance visual acuities (CDVA) are reported at baseline and two-years postoperatively using the Lundström distribution matrix.

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Results: 12,913 corneal transplants were identified. Overall two-year graft survival of corneal transplants is high (89%) but differed between indications, ranging from 98% in keratoconus and 80% for trauma. Overall, CDVA improved after surgery, but the risk of losing vision ranged from 7% (baseline vision ≤0.1 Snellen) to 58% (baseline vision ≥1.0 Snellen). Conclusions: This report provides a comprehensive overview of graft survival and visual outcomes of corneal transplantation in Europe. We provide real-world estimates of outcomes for a variety of indications and surgical techniques to support benchmarking, and demonstrate the relationship between baseline and postoperative vision.

Corneal transplantation is one of the most prevalent tissue transplant procedures worldwide.1 Although it is predominantly performed to improve vision, it may also be indicated to preserve the globe, for pain relief and to improve patient’s quality of life. Studies based on clinical registries improved our understanding of realworld outcomes of corneal transplantion.2 Registries provide outcomes that are translatable to wider patient populations, allow benchmarking, enhance quality improvement, policy and research efforts while improving costeffectiveness of patient care.3 The European Cornea and Cell Transplantation Registry (ECCTR) is a webbased European registry that developed a common assessment methodology in corneal transplantation. The ECCTR was established through co-funding by the Third Health Programme of the European Union (EU) and the European Society of Cataract and Refractive Surgeons (ESCRS) in collaboration with three national registries and professional societies. The web-based system enables integration of existing national registries, as well as uploading data directly from affiliated clinics and surgeons throughout Europe. As transplant techniques evolved, patients are increasingly operated at earlier stages of disease and lower levels of visual disability. In this paper, we provide real-world estimates of graft survival and visual outcomes to inform shared decision-making for a wide variety of indications and transplant techniques in a cohort of 12,913 corneal transplants from ten EU member states, the United Kingdom (UK) and Switzerland.

7.2 Methods GRAFT REGISTRY AND DATA COLLECTION Data for this multinational prospective study was obtained from the ECCTR registry. The ECCTR steering group provided approval for data extraction and analysis. The study adhered to the tenants of the declaration of Helsinki and national and European legislation governing the collection and use of data

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for registries. All data reported to ECCTR are anonymized. Data extraction took place on February 20th, 2020. Data were either manually registered by affiliated clinics or uploaded as a cohort by national registries. The registry collects data on pre-specified parameters pertaining to donor cornea, preoperative patient characteristics, surgery, complications, and follow-up. Follow-up was captured at two years (± three months) after surgery. Two years after surgery, follow-up data is collected on date of examination, refraction, corrected distance visual acuity (CDVA), and endothelial cell density. Graft failure specification during the first two years after surgery is reported separately. OUTCOME MEASURES The primary outcome measure was two-year graft survival, secondary outcomes were CDVA preoperatively, and two years postoperatively. Individual medical centers registered vision values as no light perception (NLP), light perception (LP), hand movement, (HM), counting fingers (CF), and different visual acuity notations, i.e. Snellen notation at 6 meters and 20 feet or decimal. All visual acuity values are reported in decimal and the Logarithm of the Minimum Angle of Resolution (LogMAR). STATISTICAL ANALYSIS

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Statistical analyses were performed using IBM SPSS Statistics for Windows, version 24.0 (IBM Corp., Armonk, N.Y., USA). Baseline characteristics were reported as frequencies with percentages or mean (SD). Death-censored graft survival was assessed using Kaplan-Meier curves with log-rank test and univariable Cox regression analysis. Cox regression analysis was performed over two years after keratoplasty. Proportional hazard assumption was checked using the log(-log) survival function plot. If both eyes of the same patient were operated or a repeat transplant was performed, only the first transplant for each patient was included in the analysis to prevent bias related to correlated measurements within the same patient or eye. Twosided P-values ≤0.05 were considered statistically significant.

7.3 Results Baseline, donor, and surgery characteristics are summarized in Table 1. 52% (n=6,493) of cases were male and 48% (n=5,940) were female. Average patient age was 65 (SD 18) years. At the time of data extraction, a total of 12,913 corneal transplants from ten EU member states and the United Kingdom and Switzerland were registered in ECCTR. We included one transplant per recipient (n=11,971) for analysis of graft survival and CDVA to avoid correlation generally present between observations made for the right and left eye of the same patient or within the same eye. Graft Survival Follow-up data regarding graft survival was available for 3,048 transplants (25%). Lost to follow-up was registered in 233 cases (2%). Overall graft survival was 96% (n=2,865) at three-months, 95% (n=2,784) at six-months, 93% (n= 2,636) at one-year, and 89% (n=1,520) at two-years postoperatively (Figure 1). In total, 433 (4%) cases developed graft failure and in 360 graft failure was specified: endothelial decompensation (n=124, 1%), primary graft failure (n=82, <1%), infection (n=34, <1%), endothelial rejection (n=30, <1%), recurrence of original disease (n=14, <1%), graft detachment (n=11, <1%), and other (n=65, <1%). Graft survival differed significantly between indications (P<0.001). Two years after surgery, graft survival was highest in keratoconus (98%, n=263), corneal dystrophies other than FED (94%, n=67), FED (92%, n=1,494), followed by infectious keratitis (82%, n=273), PBK (82%, n=337), regraft (82%, n=284), and trauma (80%, n=72) (Figure 2). For keratoconus, two-year graft survival did not differ significantly between PK and DALK (n=170, 98% vs. n=74, 99%, P=0.92). This was also the case for infectious keratitis (PK n=220, 74% vs. DALK n=37, 89%, P=0.12). For FED, two-year graft survival was better with PK (n=115, 97%) and DS(A)EK (n=1,244, 93%) compared to DMEK (n=130, 71%, HR=5.00, 95% CI 3.38 – 7.41, P<0.001, compared to DS(A)EK; and HR=5.40, 95% CI 2.41 – 12.20, P<0.001, compared to PK), Figure 3. For PBK, two-year graft survival was better for PK (n=118, 87%) and DS(A)EK (n=191, 81%) compared to DMEK (n=26, 58%, HR=3.41, 95% CI 1.71 – 6.80, P<0.001, compared to DS(A)EK; and HR=5.31, 95% CI 2.34 – 11.75, P<0.001, compared to PK). Two-year graft survival of transplants

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TABLE 1. Baseline, donor, and surgery characteristics of all corneal transplants in the ECCTR registry (N=12,913, unless otherwise specified).

MEAN ± SD OR N (%)

Recipient Indication Fuchs endothelial dystrophy

5,325 (41%)

Regraft

2,108 (16%)

Pseudophakic bullous keratopathy

1,594 (12%)

Keratoconus

1,506 (12%)

Infection

892 (7%)

Other corneal dystrophy

303 (2%)

Trauma

217 (2%)

Other

968 (8%)

Age (years)

65 ± 18

Male sex (n=12,433)

6,493 (52%)

Donor Age (years, n=12,655)

66 ± 13

Male sex (n=12,152)

7,154 (59%)

Transplant days in store (n=4,668)

16 ± 5.4

Endothelial cell density, cells/mm (n=9,349)

2,656 ± 257

Surgery Surgery type

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DS(A)EK

5,918 (46%)

Penetrating keratoplasty

3,886 (30%)

DMEK

1,838 (14%)

DALK

1,051 (9%)

ALK

138 (1%)

Other

81 (<1%)

Combined surgery (n=11,767) No combined surgery

9,116 (77%)

CEIOL

1,641 (14%)

535 (5%)

ECCE

194 (2%)

Other

281 (2%)

ALK=Anterior lamellar keratoplasty; CEIOL=Cataract extraction with intraocular lens implantation; DALK=Deep anterior lamellar keratoplasty; DMEK=Descemet membrane endothelial keratoplasty; DS(A) EK=Descemet stripping (automated) endothelial keratoplasty; ECLE=Extracapsular cataract extraction; FED=Fuchs endothelial dystrophy; PBK= Pseudophakic bullous keratopathy; PI=Peripheral iridectomy.

FIGURE 1. Kaplan-Meier curve of two-year graft survival for all corneal transplants in ECCTR with available follow-up data (n=3,048). Graft survival measured 96% at three-months, 95% at six-months, 93% at one-year, and 89% two-years postoperatively. 149

performed for endothelial failure did not differ significantly between PK (84%, n=272) and DS(A)EK (80%, n=70, P=0.6). For the indication trauma, PK was performed almost exclusively and two-year graft survival was 85%. Graft survival also differed based on reason for grafting. Transplants to improve vision showed the best two-year graft survival (90%, n=2,775), followed by pain relief (74%, n=60,, HR=2.90, 95% CI 1.72 , 4.88, P<0.001, compared with improving vision) and tectonic transplants (70%, n=71, HR=3.36, 95% CI 2.08 , 5.42, P<0.001, compared with improving vision).

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FIGURE 2. Kaplan-Meier curve of two-year graft survival per surgery indication in ECCTR. Graft survival differed significantly between indications (P<0.001). Two-year graft survival was best in keratoconus and lowest in trauma, graft failure, PBK, and infection, P<0.001. FED=Fuchs endothelial dystrophy; PBK=pseudophakic bullous keratopathy.

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Visual Acuity Table 2 shows the Lundström distribution matrix of preoperative versus twoyear CDVA (complete case analysis).4 Eyes with worse preoperative CDVA had a higher chance of improvement while eyes with better preoperative CDVA had higher risk of worse postoperative CDVA. Table 3 shows the distribution of visual acuity for various indications in eyes with available preoperative and two-year postoperative data. Pre-operative, in FED, 45% of eyes saw ≥0.4 Snellen and 10% saw ≥0.63 Snellen (≤0.4 and ≤0.2 LogMAR, respectively). Two years after surgery, 83% saw ≥0.4 Snellen, and 62% saw ≥0.63 Snellen. Pre-operative, in trauma, 6% saw ≥0.4 Snellen

Outcomes of corneal transplantation in Europe

FIGURE 3. Kaplan-Meier curve: Surgical techniques for Fuchs endothelial corneal dystrophy in ECCTR showing lower two-year graft survival in DMEK (71%) compared to DSAEK (93%) and PK (97%), P<0.001. DMEK=Descemet membrane endothelial keratoplasty; DSAEK=Descemet stripping automated endothelial keratoplasty; PK=Penetrating keratoplasty.

and 2% saw ≥0.63 Snellen. Two years after surgery, 31% saw ≥0.4 Snellen, and 20% saw ≥0.63 Snellen.

7.4 Discussion In this registry study, we analyzed the outcomes of 12,913 corneal transplants from ten EU member states and the UK and Switzerland. Overall graft survival was high, measuring 89% two years after surgery. However, graft survival differed considerably between indications and techniques. Corneal transplants for keratoconus had the best graft survival of all

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TABLE 2. The Lundström-matrix showing the distribution of corrected distance Snellen visual acuity at baseline and two years after surgery in the ECCTR (complete cases analysis).4 Red numbers indicate worse two-year visual acuity category compared to baseline, green numbers indicate improvement in visual acuity category, and gray numbers indicate no change in visual acuity category. For example, 28% of eyes with preoperative vision 0.63-0.8 Snellen achieved 1.0 Snellen after surgery.

Outcomes of corneal transplantation in Europe

graft survival is negatively impacted independent of surgical technique by a depleted pool of peripheral corneal endothelial cells and ocular comorbidities, such as glaucoma and uveitis. Endothelial keratoplasty was the method of choice for treating FED and PBK. DMEK showed significantly lower graft survival compared to DS(A)EK for both indications. The high failure rate in the immediate postoperative period after DMEK likely reflects a real-world learning- curve.6 Since DMEK is a relatively new surgical technique, it will be interesting to follow-up on its outcomes, especially given reports on lower rejection rates that could have a positive impact on long-term graft survival.7 Registries such as ECCTR are poised to investigate the uptake of emerging treatments and take into account the effect of a learning curve by evaluating outcomes over time. Interestingly, regrafting was the second most common indication for corneal transplantation, surpassed only by FED. This is an important finding as the volume of repeat transplants is projected to increase as the population ages, and survival of each subsequent graft is shorter compared to the previous graft.8 For repeat transplantation, PK showed significantly better graft survival compared to both DMEK and DS(A)EK. However, this may depend on the primary indication.9 Graft failure represents a common endpoint that can be reached by different pathways. In our cohort, in eyes with specified graft failure, endothelial decompensation was the most common cause (34%), followed by primary graft failure (23%). Primary graft failure rate represents 2.7% of the 3,048 cases with available survival data which is in line with the literature.10,11

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indications, measuring 98% two years postoperatively. This may be attributed to a low graft rejection rate in this patient group with few local and systemic comorbidities. In line with the literature, PK and DALK for keratoconus showed comparable outcomes, although DALK eliminates the risk of endothelial rejection.5 In the current study, corneal endothelial pathology, i.e. FED and PBK, was the most common indication for transplantation. Survival rates were significantly better for FED compared with PBK, irrespective of the surgical technique used. Corneal transplantation in PBK may be technically more challenging and

In the last decades, the most important outcome parameter in corneal transplantation shifted from graft survival to visual acuity. In the current study, we explore vision outcomes after corneal transplantation using the Lundström matrix4 for the first time (Table 3). The percentage of eyes reaching functional vision inversely depended on preoperative vision. Generally, a higher proportion of eyes with low preoperative visual acuity will gain greater improvement in vision compared to eyes with higher levels of preoperative visual acuity. This information underlines the challenge of operating on patients with good preoperative visual acuity as these have the highest chance of losing vision. However, even in these cases, transplantation may be warranted, as patients routinely seek treatment for symptoms related to other

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TABLE 3. Distribution of preoperative and two-year postoperative Snellen corrected distance visual acuity (CDVA) of corneal transplants for the six most common indications in ECCTR (complete case analysis). Values are percentages. Two years after surgery, CDVA was highest in keratoconus and FED, with more than 60% seeing 0.63 Snellen (0.2 LogMAR) or better.

Registries, like the ECCTR, have several limitations. The ECCTR is still young and two-year follow-up is not available yet for all grafts. Participating clinics indicated lost to follow-up in 2% of cases – meaning that follow up in these cases is not expected even two-years after surgery. Nonetheless, in 23% of cases performed two years or more before data extraction follow up data is not yet available in ECCTR. We are directing efforts to obtain this information. Importantly, there were no relevant differences in characteristics between groups, suggesting the data is missing at random. Other limitations include the lag-time in receiving data on surviving grafts compared with failed grafts, baseline variations between receiver subgroups, and loss to follow-up over time. We included censored transplants in probability estimates of graft survival to the evaluation point preceding their censoring and performed complete case analyses for vision outcomes. Coverage of ECCTR differs between countries. In countries with national registries, coverage of ECCTR is complete. In countries without national registries, determining coverage is challenging as the volume of corneal transplantation is undisclosed in many European countries.

CF=count fingers; FED=Fuchs endothelial dystrophy; KC=Keratoconus; LogMAR=Logarithm of the Minimum Angle of Resolution; NP=no light perception; PBK=pseudophakic bullous keratopathy.

In summary, in this second report from the ECCTR, 12,913 corneal transplants from ten EU member states and the UK and Switzerland were analyzed and outcomes reported. We show that overall graft survival of corneal transplants is high, measuring 89% two years after surgery. Across all indications, there is an overall improvement in vision after surgery, but in a relevant number of cases, postoperative vision deteriorated. The ECCTR invites all European national registries, clinics, and individual surgeons to join this registry. Existing national registries can be incorporated in ECCTR and individual surgeons can upload data using a secure web-based form (for more information visit https://www.ecctr.org).

domains of vision such as glare.12

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Identifying objective core outcome measures to evaluate the effectiveness of corneal transplantation is crucial for patients, physicians, and clinical researchers.13 However, benefit, as perceived by patients, is not necessarily revealed by clinical outcome measures and may vary between individuals with similar objective outcomes. This subjective dimension may be captured by patient-reported outcome measures (PROMs). Since the last data extraction, ECCTR incorporated a questionnaire for measuring subjective visual functioning, the Catquest-9SF. This questionnaire is translated and validated in multiple languages and was recently validated in the context of corneal transplantation.14 The Catquest-9SF consists of seven items related to difficulties in performing daily activities and two items related to difficulties and satisfaction with vision and is Rasch validated. Incorporating PROMs will facilitate Heath Technology Assessment and integration of value-based healthcare systems.15

7.5 Value Statement WHAT WAS KNOWN •

Graft survival and visual outcomes of corneal transplantation have been reported in cohort studies and from some registry data.

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• •

•

Outcomes of corneal transplantation in Europe

WHAT THIS PAPER ADDS

References

This paper describes corneal graft survival and visual outcomes from a large European cohort of 12,913 grafts. This paper provides real-world estimates of graft survival and visual outcomes for a variety of indications and surgical techniques to support benchmarking. This study reports a relationship between baseline and postoperative visual acuity to aid in patient selection and counseling.

1. Gain P, Jullienne R, He Z, Aldossary M, Acquart S, Cognasse F, Thuret G. Global Survey of Corneal Transplantation and Eye Banking. JAMA ophthalmology. 2016;134(2):167-173. 2. Armitage WJ, Jones MNA, Zambrano I, Carley F, Tole DM. The Suitability of Corneas Stored by Organ Culture for Penetrating Keratoplasty and Influence of Donor and Recipient Factors on 5-Year Graft Survival. Invest Ophthalmol Vis Sci. 2014;55(2):784-791. 3. Sherman RE, Anderson SA, Dal Pan GJ, Gray GW, Gross T, Hunter NL, LaVange L, Marinac-Dabic D, Marks PW, Robb MA, Shuren J, Temple R, Woodcock J, Yue LQ, Califf RM. Real-World Evidence - What Is It and What Can It Tell Us? N Engl J Med. 2016;375(23):2293-2297.

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4. Lundstrom M, Dickman M, Henry Y, Manning S, Rosen P, Tassignon MJ, Young D, Stenevi U. Femtosecond laser-assisted cataract surgeries reported to the European Registry of Quality Outcomes for Cataract and Refractive Surgery: Baseline characteristics, surgical procedure, and outcomes. J Cataract Refract Surg. 2017;43(12):1549-1556. 5. Keane M, Coster D, Ziaei M, Williams K. Deep anterior lamellar keratoplasty versus penetrating keratoplasty for treating keratoconus. Cochrane Database Syst Rev. 2014(7):Cd009700. 6. Price DA, Kelley M, Price FW, Jr., Price

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12. van der Meulen IJ, Patel SV, Lapid-Gortzak R, Nieuwendaal CP, McLaren JW, van den Berg TJ. Quality of vision in patients with fuchs endothelial dystrophy and after descemet stripping endothelial keratoplasty. Arch Ophthal. 2011;129(12):1537-1542. 13. Seligman WH, Salt M, la Torre Rosas A, Das-Gupta Z. Unlocking the potential of value-based health care by defining global standard sets of outcome measures that matter to patients with cardiovascular diseases. Eur Heart J Qual Care Clin Outcomes. 2019;5(2):92-95. 14. Claesson M, Armitage WJ, Bystrom B, Montan P, Samolov B, Stenvi U, Lundstrom 15. M. Validation of Catquest-9SF-A Visual Disability Instrument to Evaluate Patient Function After Corneal Transplantation. Cornea. 2017;36(9):10831088. 158

16. Mandeville KL, Valentic M, Ivankovic D, Pristas I, Long J, Patrick HE. Quality Assurance of Registries for Health Technology Assessment. Int J Technol Assess Health Care. 2018;34(4):360367.

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8.1 The right procedure for the right patient by the right surgeon A randomized controlled trial (RCT) is the most robust research method to determine whether a cause-effect relationship exists between an intervention and an outcome. Although RCTs are designed to reduce bias, they cannot eliminate variability. To date, three RCTs of similar sample size have compared ultrathin DSAEK to DMEK over a one-year period: The DETEC Trial (DETECT) by Chamberlain et al published in 2019,1 our study published in 2020 (Chapter 1),2 and the latest study by Matsou et al published in 2021.3 It is important to examine the methodology of these trials to provide context for their individual outcomes. First, the trials differed in regard to the number of participating centers and surgeons. In Matsou’s trial, a single surgeon performed all surgeries in the UK; in the DETECT, surgeries were performed by two surgeons at two clinics in the US; and in our trial, surgeries were performed by six surgeons at six clinics in the Netherlands, including academic and non-academic centers. Multicenter trials are preferable as outcomes from single centers tend to overestimate treatment effects.4

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Second, the DETECT included eyes with Fuchs endothelial corneal dystrophy (FECD) as well as Pseudophakic bullous keratopathy whereas our study and the trial by Matsou included eyes with FECD only. Third, in the DETECT and the trial by Matsou, some surgeries were combined with cataract extraction and intraocular lens placement, respectively, whereas in our study, all surgeries were single procedures. Fourth, fellow eyes in our trial and Matsou’s trial were not eligible to avoid dependency between eyes. The DETECT did include fellow eyes and the statistical analysis was adjusted for vision-related quality of life (QOL)5 but not for other outcomes.1,6 Fifth, the primary outcome was assessed by masked assessors in the DETECT and Matsou’s trial and unmasked assessors in our trial, which could introduce bias. Sixth, the DETECT and our trial used gold-standard ETDRS charts, whereas Matsou’s trial converted Snellen values to LogMAR. Seventh, Matsou et al excluded a patient with primary graft failure from analysis whereas the DETECT and our study followed a stringent per-protocol analysis. Lastly, all three studies followed a different protocol for ultrathin DSAEK preparation resulting in substantial differences in graft thickness. However, this may not be an issue,

General Discussion

as a recent meta-analysis of 47 studies reported that graft thickness in the range of <80 µm - 130µm is not a significant factor for postoperative visual acuity.7 Despite these methodological differences, the outcomes of these trials are remarkably similar. The DETECT and Matsou’s trial reported a significant 0.2 and 0.07 logMAR best-correct visual acuity (BCVA) difference in favor of DMEK whereas our group found a non-significant difference of 0.07 logMAR. Combined, these results suggest an approximately one-line ETDRS difference in favor of DMEK, which is considered the lower limit of a clinically relevant effect. Independent-samples t-tests using mean, standard deviation, and sample size show that the corresponding treatment arms between the trials did not differ significantly (all P>0.05). This outcome is not surprising given that all DSAEK variations suffer from optical degradation due to the irregularity of the posterior corneal surface.8 Although the DETECT has published follow-up data suggesting that DMEK leads to better vision two years after surgery, it has not yet been established whether this trend continues long-term.9 In a prospective study of DSAEK (graft thickness 155 ± 51 µm), visual improvement continued for five years.10 This is likely due to corneal remodeling which smoothes out irregularities of the posterior corneal surface over time. Consequently, any advantage of DMEK may also diminish over time. Interestingly, vision-related quality of life (QOL) improved equally after surgery with both techniques and no trial found any significant or clinically relevant differences at any point in time.2,3,5 It is currently unknown whether this is due to the nature of the treatments being perceived as equal, insufficient power, or poor sensitivity of the instruments. The most important short-term complication after endothelial keratoplasty is graft detachment necessitating intracameral gas reinjection (rebubbling). It is noteworthy that the DETECT and our trial found higher rates of rebubbling after DMEK compared to ultrathin DSAEK (24% vs. 4%, both trials) which is in line with the Ophthalmic Technology Assessment of the American Academy of Ophthalmology (29%).11 In comparison, Matsou’s trial reported only a single rebubbling in each treatment arm (4%). This may be due to the trial being younger and the surgeon more experienced. A large retrospective analysis of

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a tertiary center supports this notion, showing that DMEK complication rates of individual surgeons decrease over multiple years.12 For the most important long-term complication, graft rejection, ultrathin DSAEK has been reported to suffer from a considerably higher rate than DMEK (6.9% vs. 2.6% at five years).13,14 Taken together, the case for DMEK as the primary treatment option for eyes with corneal endothelial dysfunction is strong. But this is not to say that DMEK ought to replace ultrathin DSAEK entirely. Beyond the analysis of empirical evidence from published data, surgical decision-making must be informed by pragmatic determination of the right procedure for the right patient by the right surgeon. The RCT performed by our group included “simple” cases of corneal endothelial dysfunction without vision-limiting comorbidities. This design reduces heterogeneity between treatment groups and isolates the treatment effect but the results are only applicable to a narrow band of patients. In eyes with vision-limiting comorbidities, the type of keratoplasty probably matters little in terms of vision, and achieving maximum vision potential may be secondary to achieving long-term graft survival. In eyes with complicated anterior chamber situations (e.g., aphakia, glaucoma drainage devices), ultrathin DSAEK may be easier to position and fix to the recipient stroma.

8.2 To operate or not to operate

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In 2016, our group showed preoperative BCVA of the typical Fuchs patient was better in DSAEK compared to Penetrating keratoplasty (PK) (0.68 vs. 0.9 logMAR).15 In a subsequent study using the same registry, preoperative BCVA of eyes receiving DMEK was in turn better again (0.45 logMAR, Chapter 4). These trials suggest that the threshold for intervention gradually lessened over time, coinciding with the uptake of various modern corneal transplantation techniques. In other words, the average Fuchs patient we treat now with DMEK or ultrathin DSAEK is different to the average Fuchs patient we treated with PK and DSAEK from a few years ago. In light of this shift in practice patterns, it may be useful to define the minimum disease state where the benefit of treatment outweighs the risk of transplantation. To date, various staging classifications exist to aid decisionmaking. FECD is most commonly staged based on the distribution of guttae

General Discussion

and the presence of corneal edema using slit-lamp biomicroscopy. This method can easily be performed but it only assesses morphology instead of endothelial function and shows large interobserver variability. Specular microscopy of the central cornea is routinely performed to visualize endothelial architecture and detect guttae. The usefulness is limited as FECD cases in which guttae have reached central confluence have no discernible central endothelial cells that can be analyzed. Moreover, the imaged area is just a fraction of the cornea and findings cannot be extrapolated to other corneal zones. Central corneal thickness (CCT) is commonly reported in clinical trials as a surrogate marker for edema but CCT differs greatly across humans and it is not possible to distinguish between physiologically thick and pathologically thick corneas in absence of a baseline measurement prior to corneal swelling. A variation of CCT is the central to peripheral corneal thickness ratio. Although this technique eliminates variability between eyes and the need for baseline measurement, it may result in a false negative when the swelling is located paracentrally. Other parameters indicative of endothelial dysfunction such as corneal backscatter or corneal higher-order aberrations are not sensitive enough when edema is subclinical. In 2019, the group of Sanjay Patel described three tomographic features of Scheimpflug imaging that are indicative of subclinical edema in FECD: loss of parallel isopachs, displacement of the thinnest point of the cornea, and focal posterior corneal surface depression.16 Three stages are defined based on slit-lamp evaluation and the number of tomographic features present: clinically definite edema (based on slit-lamp examination), subclinical edema (presence of tomographic features without clinically definite edema), or no edema (no tomographic features or clinically definite edema). This technique shows high intra- and interobserver agreement,17 predicts the prognosis of the disease,18 and corneal improvement after DMEK for FECD.19 Eyes without tomographic signs are unlikely to be compromised and any visual disturbance that the patient may experience in absence of tomographic features is more likely to be caused by other pathology. The lowest threshold for intervention in eyes with FECD, based on objective measures only, should therefore be a positive tomographic feature indicative of (subclinical) corneal edema.

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8.3 Outcomes that matter As the amount of published data continues to grow, it becomes increasingly important to set a minimum standard of reporting through a consensusbased approach. For RCT results of treatment modalities for corneal endothelial dysfunction to be actionable, i.e., results included in systematic reviews and considered for decision making, the outcomes must be defined consistently across trials and address the needs of all stakeholders. The World Health Organization recognizes this need, stating that “choosing the most important outcome is critical to producing a useful guideline.”20 A core outcome set (COS) is a minimum set of outcomes, agreed on by various stakeholders, that will be measured and reported in research addressing a given disease or treatment. Ophthalmology lags behind other medical fields in terms of development. A review identified COS for three eye diseases, but not for corneal disease.21 Harmonizing outcomes across trials through the development of core outcome sets will require a concerted and sustained effort by all stakeholders involved in the corneal transplantation chain. The most important outcome measure for corneal transplantation has changed over time. When PK was the only surgical treatment option, the typical outcome measure was graft survival. Then, DSAEK established itself as the technique of choice due to improved visual outcomes and better safety profiles. This lowered the threshold of intervention15 and led to BCVA becoming the most relevant outcome parameter. This cycle repeated when ultrathin DSAEK and DMEK replaced standard DSAEK as the preferred techniques. Patients with even lower levels of disability were routinely treated, occasionally when visual acuity was still in an age-adjusted healthy range. These patients would experience disturbances in other domains of vision such as contrast sensitivity or glare disability. 166

BCVA is currently the most important parameter in clinical trials and will likely remain the primary outcome for the foreseeable future. In all three RCTs comparing DMEK to ultrathin DSAEK, the primary outcome was high-contrast BCVA (Chapter 1).1,3 It is important to measure visual acuity in a standardized manner for research purposes using ETDRS charts and logMAR notation as was done in the DETECT and our trial, but not in Matsou’s trial. When patients seek treatment for poor vision despite good visual acuity, an assessment of quality of vision may provide the information to determine which vision

General Discussion

dimension is affected. Interestingly, quality of vision is rarely reported in the context of corneal transplantation despite its clinical value. To the best of my knowledge, all RCTs comparing treatments for corneal endothelial dysfunction that reported quality of vision parameters were conducted by our research group (Chapter 2).22,23 Importantly, objective measures of disease are just a piece of a bigger puzzle and they may not align with individual experience. Attention is increasingly given to measuring patient experience in a standardized manner using Patient reported outcome measures (PROMs). PROMs measure a wide range of outcomes including general health status, quality of life (QOL), treatment satisfaction, and disease-specific symptoms, and are useful for evaluating the comparative benefits of different medical interventions to treat the same condition.24 To compare general and vision-related QOL in FECD patients undergoing ultrathin DSAEK and DMEK, all three RCTs comparing DMEK to ultrathin DSAEK used a variation of the generic questionnaire National Eye Institute Visual Function Questionnaire (NEI VFQ) and did not find any significant or clinically relevant differences (Chapter 2).3,5 Notably, these trials were powered for the primary outcome (BCVA) and underpowered for this particular outcome. The NEI VFQ is widely used in clinical ophthalmic research and was the best instrument available at the time. However, the questionnaire is not diseasespecific or validated in the context of corneal transplantation. Recently, two short and validated questionnaires have been introduced: The V-FUCHS allows for standardized quantification of visual disability in patients with FECD,25 and the Catquest-9SF26 is a validated instrument for measuring visual disability in patients who have undergone corneal transplantation. While the staging of disease and traditional assessment of visual function may provide data on objective functioning, these novel instruments reveal insights into the perceived quality of an individual’s daily life before and after an intervention. Vision-related QOL measurements should factor in the status of the fellow eye and any comorbidities that may affect vision. A clinical trial assessing one or more treatments for corneal endothelial dysfunction should provide information on the disease (e.g. FECD or PBK) and the severity of the disease before and after treatment (corneal morphology and function, as outlined above), and measure objective clinical impact,

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General Discussion

the eye.

i.e., standardized measurement of high-contrast BCVA and quality of vision parameters, assess QOL using validated questionnaires, and report the incidence of relevant adverse events. Although clinical impact outcomes are most important for patient care, corneal parameters should be measured to show the specific treatment effect on the cornea, especially when outcomes are confounded by concomitant treatment as is often the case.

The regenerative medicine approach to endothelial disease is based on the observation that corneal transplants performed in eyes with preserved CECs in the peripheral cornea show better graft survival than in eyes with widespread CEC loss. This led to the conceptual basis of Descemetorhexis without endothelial keratoplasty (DWEK), also known as Descemet stripping only (DSO), a technique where only the diseased Descemet membraneendothelium complex is stripped to allow centripetal migration of healthy peripheral CECs.1 Inhibition of ROCK signaling in CECs has been shown to promote cell adhesion, inhibit apoptosis, and enhance cellular proliferation in human CECs. As mentioned above, ROCK inhibitors can also be used in combination with cell-based therapies.

8.4 Future perspectives Despite the success of corneal transplantation and the proliferation of eye banks in recent decades, the number of transplant surgeries that can be performed is severely limited by the availability of donor tissues. A global survey showed that one donor cornea is available for every 70 eyes in need and only a third of donor corneas are suitable for transplantation.27 Moreover, global adoption is limited by specialized surgical expertise, high costs, and the risk of allogeneic graft rejection.

Alternatively, a physical barrier may be implanted at the posterior stroma blocking the influx of water from the anterior chamber into the cornea.30 However, such a device lacks the pump function of healthy CECs and no clinical data is available to support its current use.

Great effort is therefore directed towards developing alternative approaches to replace corneal endothelial cells (CEC). These approaches can generally be divided into cell-based therapies that use in vitro cultivation of human CECs population from cadaveric donor corneas, and regenerative medicine in which damaged cells are repaired or existing functional CECs are redistributed to replace damaged or lost cells. Unlike conventional corneal transplantations where one donor is limited to the treatment of just one or a few recipients, propagation of functional CECs through cell cultures from a single donor cornea could theoretically yield sufficient cells for the treatment of thousands of patients.

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In cell-based therapies, cultured CECs can be delivered into recipients’ diseased corneas via cell injection or a tissue-engineered construct. In a landmark study, Kinoshita et al injected cells in conjugation with a rhoassociated protein kinase (ROCK) inhibitor into the anterior chamber of 11 individuals with bullous keratopathy.28 After treatment, the authors noted an increase in ECD, deswelling of corneal thickness, and better visual acuity, suggesting successful treatment of corneal endothelial failure.29 Cultured CECs may also be used to produce tissue-engineered endothelial constructs. Engineered corneal endothelial grafts are seeded with expanded CECs onto biological or synthetic scaffolds, and stabilized before transplantation into

Another important research arm focuses on improving current therapies. Our group recently secured funding from The Netherlands Organization for Health Research and Development (ZonMw) to develop an evidence-based cost-effective immunomodulatory strategy after DMEK surgery. One of the main advantages of DMEK over previous techniques is the low rejection rate (1-2% per year vs. >5% per year). Despite this, rejection prophylaxis follows the same high-potency immunosuppressive regimen that burdens patients with overtreatment and steroid-induced side effects. We hypothesize that a lowpotency regimen provides adequate immunosuppression and reduces side effects. The Dutch Ophthalmological Society (Nederlands Oogheelkundig Gezelschap) recognizes the urgency and places the development of an optimal short- and long-term immunosuppressive protocol after corneal transplantation within its Top 10 knowledge gaps (Available at https://www. oogheelkunde.org/files/files/NOG_Kennisagenda%202020.pdf, Accessed April 7th, 2022). 1

Actually, the first description of what we consider nowadays DSO predates endothelial keratoplasty. In 1953, Frenchman Louis Paufique published a paper titled “posterior peeling of the cornea, treatment of endo-epithelial Fuchs dystrophy” in which he describes a technique that is in essence DSO (Paufique et al. Bull Mem Soc Fr Ophtalmol, 1953). However, DSO only recently gained traction as a viable treatment option.

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Developments are also happening in terms of how we measure effects and conduct clinical research. Traditionally, in the hierarchy of medical evidence, (meta-analyses of) RCTs provide the highest standards of quality when comparing the efficacy of different therapeutic strategies. Intensive monitoring and specialized research personnel ensure adherence to a research protocol that defines study procedures and ensures data precision. However, the high internal validity is achieved at the expense of low generalizability, especially when the study population differs in significant ways from those encountered in routine clinical care. The same is true for carefully conducted single-center case series, which often provide comparative data but outcomes cannot be generalized.31 Moreover, the cost of conducting RCTs has been growing steadily and recent estimates suggest costs will further increase. In contrast to the rigor and restrictiveness of RCTs, registries such as the NOTR (Chapters 3 & 4) and ECCTR (Chapters 5 & 6) are open and inclusive. Registries can amass great quantities of data at a low cost, provide insights into practice patterns on a national and multinational level, and offer precise estimates of effects, rapid detection of safety signals, and the ability to conduct meaningful analyses in subgroups of patients. On the other hand, they are burdened with imprecise and incomplete data and lack randomization modules. International registries also face complex challenges such as harmonizing parameter lists and handling personal data that originates from different legal entities.

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In recent years, registry-based randomized controlled trials (R-RCTs) have emerged as the next disruptive technology, combining the strengths of conventional RCTs and large registries. R-RCTs can address comparative effectiveness research questions in real-world settings.32 Integrating a randomization module into registries enhances the generalizability of findings, facilitates rapid consecutive enrollment, and lowers costs compared to traditional trials.33 Moreover, modern registries will also provide new possibilities by enabling access to linked information such as biobanks, electronic medical records, PROMs, automatic and semiautomatic electronic monitoring devices, and social media.

General Discussion

References 1. Chamberlain W, Lin CC, Austin A, et al. Descemet Endothelial Thickness Comparison Trial: A Randomized Trial Comparing Ultrathin Descemet Stripping Automated Endothelial Keratoplasty with Descemet Membrane Endothelial Keratoplasty. Ophthalmology. 2019;126(1):19-26. 2. Dunker SL, Dickman MM, Wisse RPL, et al. Descemet Membrane Endothelial Keratoplasty versus Ultrathin Descemet Stripping Automated Endothelial Keratoplasty: A Multicenter Randomized Controlled Clinical Trial. Ophthalmology. 2020;127(9):11521159. 3. Matsou A, Pujari R, Sarwar H, et al. Microthin Descemet Stripping Automated Endothelial Keratoplasty Versus Descemet Membrane Endothelial Keratoplasty: A Randomized Clinical Trial. Cornea. 2021;40(9):11171125. 4. Unverzagt S, Prondzinsky R, Peinemann F. Single-center trials tend to provide larger treatment effects than multicenter trials: a systematic review. Journal of clinical epidemiology. 2013;66(11):1271-1280. 5. Ang MJ, Chamberlain W, Lin CC, Pickel J, Austin A, Rose-Nussbaumer J. Effect of Unilateral Endothelial Keratoplasty on Vision-Related Quality-of-Life Outcomes in the Descemet Endothelial Thickness Comparison Trial (DETECT): A Secondary Analysis

of a Randomized Clinical Trial. JAMA ophthalmology. 2019;137(7):747-754. 6. Duggan MJ, Rose-Nussbaumer J, Lin CC, Austin A, Labadzinzki PC, Chamberlain WD. Corneal Higher-Order Aberrations in Descemet Membrane Endothelial Keratoplasty versus Ultrathin DSAEK in the Descemet Endothelial Thickness Comparison Trial: A Randomized Clinical Trial. Ophthalmology. 2019;126(7):946-957. 7. Béal L, Navel V, Pereira B, et al. Efficacy of thin and ultrathin DSAEK and influence of graft thickness on post-operative outcomes: systematic review and meta-analysis: Influence of graft thickness in UT-DSAEK. American journal of ophthalmology. 2022. 8. Dickman MM, van Maris MP, van Marion FW, et al. Surface metrology and 3-dimensional confocal profiling of femtosecond laser and mechanically dissected ultrathin endothelial lamellae. Investigative ophthalmology & visual science. 2014;55(8):51835190. 9. Rose-Nussbaumer J, Lin CC, Austin A, et al. Descemet Endothelial Thickness Comparison Trial: Two-Year Results from a Randomized Trial Comparing Ultrathin Descemet Stripping Automated Endothelial Keratoplasty with Descemet Membrane Endothelial Keratoplasty. Ophthalmology. 2021;128(8):1238-1240. 10. Wacker K, Baratz KH, Maguire LJ,

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McLaren JW, Patel SV. Descemet Stripping Endothelial Keratoplasty for Fuchs’ Endothelial Corneal Dystrophy: Five-Year Results of a Prospective Study. Ophthalmology. 2016;123(1):154-160. 11. Deng SX, Lee WB, Hammersmith KM, et al. Descemet Membrane Endothelial Keratoplasty: Safety and Outcomes: A Report by the American Academy of Ophthalmology. Ophthalmology. 2018;125(2):295-310. 12. Schrittenlocher S, Schaub F, Hos D, Siebelmann S, Cursiefen C, Bachmann B. Evolution of Consecutive Descemet Membrane Endothelial Keratoplasty Outcomes Throughout a 5-Year Period Performed by Two Experienced Surgeons. American journal of ophthalmology. 2018;190:171178. 13. Price DA, Kelley M, Price FW, Jr., Price MO. Five-Year Graft Survival of Descemet Membrane Endothelial Keratoplasty (EK) versus Descemet Stripping EK and the Effect of Donor Sex Matching. Ophthalmology. 2018;125(10):1508-1514.

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14. Madi S, Leon P, Nahum Y, et al. FiveYear Outcomes of Ultrathin Descemet Stripping Automated Endothelial Keratoplasty. Cornea. 2019;38(9):11921197. 15. Dickman MM, Peeters JM, van den Biggelaar FJ, et al. Changing Practice Patterns and Long-term Outcomes of Endothelial Versus Penetrating Keratoplasty: A Prospective Dutch

General Discussion

Registry Study. American journal of ophthalmology. 2016;170:133-142. 16. Sun SY, Wacker K, Baratz KH, Patel SV. Determining Subclinical Edema in Fuchs Endothelial Corneal Dystrophy: Revised Classification using Scheimpflug Tomography for Preoperative Assessment. Ophthalmology. 2019;126(2):195-204. 17. Patel SV, Hodge DO, Treichel EJ, Spiegel MR, Baratz KH. Repeatability of Scheimpflug Tomography for Assessing Fuchs Endothelial Corneal Dystrophy. American journal of ophthalmology. 2020;215:91-103. 18. Patel SV, Hodge DO, Treichel EJ, Spiegel MR, Baratz KH. Predicting the Prognosis of Fuchs Endothelial Corneal Dystrophy by Using Scheimpflug Tomography. Ophthalmology. 2020;127(3):315-323. 19. Patel SV, Camp JJ, Hodge DO, Baratz KH, Holmes DR, III. Predicting Corneal Improvement after Descemet Membrane Endothelial Keratoplasty for Fuchs Endothelial Corneal Dystrophy. Ophthalmology Science. 2022;2(2). 20. World Health O. WHO handbook for guideline development. 2nd ed ed. Geneva: World Health Organization; 2014. 21. Saldanha IJ, Le JT, Solomon SD, et al. Choosing Core Outcomes for Use in Clinical Trials in Ophthalmology: Perspectives from Three Ophthalmology Outcomes Working Groups. Ophthalmology. 2019;126(1):6-9.

22. Dickman MM, Dunker SL, Kruit PJ, et al. Quality of vision after ultrathin descemet stripping automated endothelial keratoplasty: a multicentre randomized clinical trial. Acta ophthalmologica. 2019;97(4):e671-e672. 23. Cheng YY, van den Berg TJ, Schouten JS, et al. Quality of vision after femtosecond laser-assisted descemet stripping endothelial keratoplasty and penetrating keratoplasty: a randomized, multicenter clinical trial. American journal of ophthalmology. 2011;152(4):556-566 e551. 24. Mandeville KL, Valentic M, Ivankovic D, Pristas I, Long J, Patrick HE. Quality Assurance of Registries for Health Technology Assessment. Int J Technol Assess Health Care. 2018;34(4):360367. 25. Wacker K, Baratz KH, Bourne WM, Patel SV. Patient-Reported Visual Disability in Fuchs’ Endothelial Corneal Dystrophy Measured by the Visual Function and Corneal Health Status Instrument. Ophthalmology. 2018;125(12):1854-1861. 26. Claesson M, Armitage WJ, Bystrom B, et al. Validation of Catquest-9SF-A Visual Disability Instrument to Evaluate Patient Function After Corneal Transplantation. Cornea. 2017;36(9):10831088. 27. Gain P, Jullienne R, He Z, et al. Global Survey of Corneal Transplantation and Eye Banking. JAMA ophthalmology. 2016;134(2):167-173.

28. Kinoshita S, Koizumi N, Ueno M, et al. Injection of Cultured Cells with a ROCK Inhibitor for Bullous Keratopathy. The New England journal of medicine. 2018;378(11):995-1003. 29. Numa K, Imai K, Ueno M, et al. FiveYear Follow-up of First Eleven Cases Undergoing Injection of Cultured Corneal Endothelial Cells for Corneal Endothelial Failure. Ophthalmology. 2020. 30. Auffarth GU, Son HS, Koch M, et al. Implantation of an Artificial Endothelial Layer for Treatment of Chronic Corneal Edema. Cornea. 2021;40(12):1633-1638. 31. Williams K KM, Galettis R, Jones V, Mills R, Coster D. The Australian Corneal Graft Registry - 2015 Report. 32. Li G, Sajobi TT, Menon BK, et al. Registry-based randomized controlled trials- what are the advantages, challenges, and areas for future research? Journal of clinical epidemiology. 2016;80:16-24. 33. Lauer MS, D’Agostino RB, Sr. The randomized registry trial--the next disruptive technology in clinical research? The New England journal of medicine. 2013;369(17):1579-1581. 173

CHAPTER 9

Summary

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Dutch Summary

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9.1 Dutch Summary Dit proefschrift toont de klinische uitkomsten van DMEK en UT-DSAEK, evenals de practice pattern en uitkomsten van hoornvliestransplantaties in Nederland en Europa. In een multicenter gerandomiseerde gecontroleerde studie (RCT) waarin we ultrathin Descemet stripping automated endothelial keratoplasty (ultrathin DSAEK) hebben vergeleken met Descemet membrane endothelial keratoplasty (DMEK), toonden beide technieken een vergelijkbare visus, refractiefout en endotheelcelverlies. Echter was het percentage DMEK dat 0.8 Snellen of beter zag aanzienlijk hoger dan in de ultrathin DSAEK groep, desondanks traden er ook meer postoperatieve complicaties na DMEK op, met name lamelloslatingen waarvoor een intrakamerale reinjectie van lucht en gas (rebubbeling) nodig was (hoofdstuk 2). Terwijl DMEK zowel sneller herstel van contrastgevoeligheid en strooilicht als lagere posterior-corneale hoger order aberraties toonde, vonden we vergelijkbare verbeteringen in zichtgerelateerde kwaliteit van leven bij ultrathin DSAEK (hoofdstuk 3). Dit kan erop duiden dat de patiëntervaring van beide technieken gelijk was of dat het meetinstrument onvoldoende gevoelig was om het verschil te kwantificeren. Inmiddels zijn er specifiekere instrumenten voor hoornvliestransplantaties ontwikkeld die hierop in de toekomst wellicht antwoord kunnen geven.

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Voor hoofdstuk 3 - 7 hebben we gebruik gemaakt van data die afkomstig is van registraties. In de laatste jaren worden nationale en internationale kwaliteitsregistraties steeds vaker erkend als een waardevol instrument om de gezondheidszorg te verbeteren door het gebruik van ‘’real-world’’ data. Twee voorbeelden hiervan zijn de Nederlandse Orgaantransplantatie Registratie Cornea (NOTR Cornea) op nationaal niveau, en de European Cornea and Cell Transplantation Registry (ECCTR) op Europees niveau. Het belangrijkste kenmerk van “real-world” data is gerelateerd aan de context waarin deze is verzameld: in een klinische zorgomgeving. Derhalve zijn registratiestudies een waardevolle aanvulling op traditionele comparatieve studies die geschikt zijn het effect van interventies te isoleren (zoals in hoofdstukken 2&3), maar waarvan de bekende beperkingen het moeilijk maken om bevindingen te generaliseren. In hoofdstuk 4 hebben we prospectief verzamelde data vanuit NOTR

Summary

Cornea geanalyseerd om de uitkomsten van DMEK in de dagelijkse praktijk in Nederland te evalueren. We merkten op dat de transplantaatoverleving in de beginjaren van de techniek erg laag was en in de loop van der tijd steeg. Dit duidt op een leercurve op nationaal niveau en laat tevens zien wat de gevolgen zijn van de invoering van nieuwe chirurgische technieken. Evenals we in ons multicenter RCT hebben geconstateerd (hoofdstuk 2), was de meest voorkomende complicatie een lamelloslating die met een rebubbling behandeld werd. In hoofdstuk 5 zijn we dieper in de NOTR data gedoken om na te gaan wat de reden voor een lamelloslating en vroegtijdig transplantaatfalen zijn. NOTR bevat een legio waardevolle geanonimiseerde gegevens met betrekking tot donor-, patiënten- en transplantaatkarakteristieken waarmee we een risicofactoranalyse hebben kunnen uitvoeren. Met betrekking tot lamelloslating vonden we dat zowel een hogere leeftijd van patiënt als een chirurgische complicatie onafhankelijke risicofactoren zijn en m.b.t. vroegtijdig transplantaatfalen waren dit chirurgische complicatie en transplantatiedatum vóór 2016. Het feit dat de factoren complicatie en transplantatiedatum in de beginjaren van de techniek (vóór 2016) als risicofactoren naar voren kwamen bekrachtigt ons vermoeden dat de data een nationale leercurve weerspiegelt. In hoofdstukken 6&7 hebben we gebruik gemaakt van data van de ECCTR, een jonge Europese registratie die destijds 12,913 hoornvliestransplantaties omvatte, om te onderzoeken wat de practice pattern en uitkomsten van hoornvliestransplantaties in Europa zijn. Hoofdstuk 6 biedt het meest uitgebreide overzicht van hoornvliestransplantaties in tien Europese landen en de UK en Switzerland. We ondervonden dat Fuchs endotheel dystrofie de meest voorkomende indicatie voor transplantatie is, met als voornamelijk doel het zicht te verbeteren, en DS(A)EK de meest toegepaste techniek is. In hoofdstuk 7 hebben we laten zien dat de totale overleving van hoornvliestransplantaties erg hoog is, namelijk 89% twee jaar na de operatie. We ondervonden dat hoornvliestransplantatie voor alle indicaties leidt tot een verbetering van visus, echter in een klein aantal gevallen verslechterde de visus na de operatie. Bovendien hebben we realistische schattingen geschetst van de postoperatieve visus voor diverse indicaties, verschillende chirurgische technieken en de relatie tussen baseline en postoperatieve visus. Deze informatie is met name waardevol voor corneachirurgen om hun uitkomsten te benchmarken en verwachtingen voor de patiënt te schetsen.

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9.2 Impact Paragraph The Dutch National Health Care Institute (Zorginstituut Nederland) advises the Dutch Ministry of Health, Welfare and Sport about the content of the standard health insurance package in the Netherlands. In December 2010, it published a decision, based on the limited number of publications available at the time, that there is insufficient evidence to conclude that Descemet membrane endothelial keratoplasty (DMEK) is effective and safe (Available at https:// www.zorginstituutnederland.nl/werkagenda/zintuigen-en-huid/standpuntdmek-hoornvliestransplantatie, accessed 27.06.2022). Accordingly, DMEK was not included in the standard health insurance package. In the following years, although many studies suggested that DMEK leads to better outcomes compared to Descemet stripping automated endothelial keratoplasty (DSAEK) and ultrathin DSAEK, high-level evidence from randomized controlled trials (RCTs) was lacking. In 2018, the Ophthalmic Technology Assessment (OTA) by the American Academy of Ophthalmology (AAO) reported great variance in outcomes and safety between studies on DMEK, adding to the uncertainty of the technique.1 Nonetheless, in the Netherlands and other countries, interest in the technique grew among corneal surgeons and many adopted the technique despite a lack of supporting evidence (Chapters 3&5). The purpose of our trial was to provide this evidence. We evaluated the efficacy of DMEK versus ultrathin DSAEK in the context of a multicenter RCT (Chapters 1&2) and the practice pattern and effectiveness of DMEK in routine clinical care in the Netherlands (Chapters 3&4). In the RCT, patients regained good vision after transplantation irrespective of the technique used. Recovery of some vision parameters (i.e., straylight, higher-order aberration, contrast sensitivity) was faster after DMEK but one year after surgery, both techniques did not differ significantly in terms of vision or vision-related quality of life. In terms of safety, more complications occurred after DMEK, i.e., a clinically relevant graft detachment, although this may reflect the surgeons’ relative inexperience with the technique at the time of the study.2

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It is well known that medical interventions perform differently in experimental clinical trials versus real-world clinical practice, reflecting a phenomenon known as the efficacy-effectiveness gap. Analyzing the outcomes of all eyes that underwent DMEK surgery in routine clinical care in the Netherlands, we found comparable visual acuity, endothelial cell loss, and complication rates to the DMEK arm of the RCT (Chapters 3&4). On one hand, this bolsters the

Summary

confidence of the data included in the Netherlands Organ Transplantation Registry Cornea (NOTR Cornea) while on the other hand, also providing external validity to the outcomes reported in the RCT. The results of these studies are important for the scientific community and corneal surgeons, payers, patients, and other stakeholders of the corneal transplantation chain (e.g., eye banks). Scientific community. The results were disseminated (oral and poster presentations) at the annual meetings of the Dutch Ophthalmological Society (NOG), the European Society of Cataract and Refractive Surgeons (ESCRS), the European Society of Cornea & Ocular Surface Disease Specialists (EuCornea), the Association for Research in Vision and Ophthalmology (ARVO), and the European Eye Bank Association (EEBA). The results were also shared with the Dutch cornea patient society (HPV) and the Dutch Transplant Society (NTS). The journal Ophthalmology, a top journal in the field, invited a commentary to discuss the study outcomes and its implications, highlighting the relevance of the study to the scientific community and corneal surgeons.3 Health Insurance Act. After the study outcomes were published, members of the study team who are also members of the cornea working group of the Dutch Ophthalmological Society requested a re-evaluation of the National Health Care Institute’s ‘established medical science and medical practice’ policy on DMEK. Based on the current body of evidence, including the work presented in this thesis, the National Health Care Institute found sufficient evidence to conclude that the DMEK technique is both effective and safe for eyes with simple corneal endothelial dysfunction. DMEK therefore meets the institute’s ‘established medical science and medical practice’, and the intervention will be included in the insurable services of the Health Insurance Act. Industry collaboration. Prior to the study, our research group collaborated with the eye bank ETB-BISLIFE (Leiden, The Netherlands) to implement a precut DMEK service. This service offers quality assurance for donor tissue, reduces expensive time in the operating theater, and eliminates complications related to the preparation of donor tissue, thereby preventing wastage of a precious commodity. To date, precut DMEK is the technique of choice for corneal surgeons in the Netherlands, with hundreds of surgeries performed annually (Chapter 3).

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Registry. A member of our study team is also a steering group member of the European Cornea and Cell Transplantation Registry (ECCTR, http://www. ecctr.org), a European Consortium that built an EU web-based registry in the field of corneal transplantation. The ECCTR provides a common assessment methodology and established a network for academics, health professionals, and authorities to assess and verify the safety, quality, and efficacy of corneal transplantation. Using data from the ECCTR, which includes more than 12,000 corneal transplantations across 13 countries, we provided for the first time a bird’s eye view of the practice patterns (Chapter 5) and outcomes (Chapter 6) of corneal transplantation in Europe. The peer-reviewed published reports in ophthalmological journals as well as oral and poster presentations at national and internal conferences raised awareness of this young registry, motivating other countries and individual eye clinics to join. Meta-analysis. The current body of research consists of three RCTs including two reports from our RCT and multiple large non-randomized prospective and retrospective studies. It yields itself well for future synthesis of evidence in the form of a meta-analysis which to the best of my knowledge has not yet been conducted. Patient care. The cornea is the most transplanted solid tissue across all fields of medicine, approximating 180,000 transplantations annually. The primary indication for corneal transplantation is FECD with DMEK and (ultrathin) DSAEK being the current techniques of choice. In 2016, a survey among American corneal surgeons showed that an RCT is highly anticipated, with half of the responders stating it is ‘highly likely’ they would change their current practice based on RCT outcomes.4 By providing solid evidence, publishing in highimpact journals, and extensive dissemination at national and international conferences, many corneal surgeons and by extension patients are impacted by the results of our studies.

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References 1. Deng SX, Lee WB, Hammersmith KM, et al. Descemet Membrane Endothelial Keratoplasty: Safety and Outcomes: A Report by the American Academy of Ophthalmology. Ophthalmology. 2018;125(2):295-310. 2. Schrittenlocher S, Schaub F, Hos D, Siebelmann S, Cursiefen C, Bachmann B. Evolution of Consecutive Descemet Membrane Endothelial Keratoplasty Outcomes Throughout a 5-Year Period Performed by Two Experienced Surgeons. American journal of ophthalmology. 2018;190:171178. 3. Busin M, Yu AC. The Ongoing Debate: Descemet Membrane Endothelial Keratoplasty Versus Ultrathin Descemet Stripping Automated Endothelial Keratoplasty. Ophthalmology. 2020;127(9):1160-1161. 4. Chamberlain W, Austin A, Terry M, Jeng BH, Rose-Nussbaumer J. Survey of Experts on Current Endothelial Keratoplasty Techniques. Journal of clinical & experimental ophthalmology. 2016;7(5).

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