Cardiovascular News - Medtronic Supplement May 2021

May 2021 | Educational Supplement

Patients at high risk of bleeding, a forgotten population in PCI? Latest evidence and perspective from experts

cardiovascularnews.com

This educational supplement has been sponsored by Medtronic

Understanding HBR

The evolving evidence-base for short-duration DAPT With contemporary strategies for short-duration dual antiplatelet therapy (DAPT) continuing to be shaped by studies in the field, Cardiovascular News speaks to David Kandzari (Piedmont Heart Institute, Atlanta, USA) and Davide Capodanno (University of Catania and Azienda OspedalieroUniversitaria Policlinico “G Rodolico-San Marco”, Catania, Italy) to understand the latest thinking.

AS NEWER-GENERATION drug-eluting stent (DES) technologies have brought to the table improvements in safety and efficacy outcomes, percutaneous coronary intervention (PCI) using a DES has evolved to reach a wider patient population.

Among these patients are those who may be considered at high risk for bleeding events—a challenging patient cohort requiring tailored strategies to limit their risk of harm.

According to David Kandzari high bleeding risk (HBR) patients represent a significant proportion of those undergoing PCI, and therefore understanding the optimal approach in this group is fundamental. “Most commonly, HBR patients have more than one HBR characteristic. They might be also on an oral anticoagulant, be very elderly, or may have experienced a prior stroke or bleeding event. They usually have multiple bleeding risk criteria rather than just one singular feature. HBR criteria rarely exist in isolation,” he explains.

Trade-offs

With expanding DES usage over time, concerns over stent thrombosis in patients undergoing PCI initially drove clinicians to administer at least one year of DAPT after the completion of the procedure, Kandzari explains. DAPT involves the combined use of aspirin and a P2Y12 receptor inhibitor to reduce recurrent ischaemic events.

However, this long-term strategy comes at the potential expense of an increased risk of major bleeding in high-risk patients, a factor which has consequently limited the use and study of DES within this group. “Several studies and meta-analyses have demonstrated that bleeding is associated with worse outcomes—specifically with higher risks of death and myocardial infarction,” says Kandzari. “Expectedly, longer durations of DAPT are associated with higher risks of bleeding—and shorter durations of DAPT are, intuitively, associated with less bleeding.”

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in general, with options to shorten this therapy to three months or one month in those without an acute coronary syndrome.

In patients with acute coronary syndromes, however, the default recommendation is 12 months of DAPT, or six months in those with a high risk of major bleeding.

The picture is changing, with a greater understanding of the benefits of using shorterduration DAPT in the HBR population and accumulating trial data suggest that DES placement followed by three- or even one-month DAPT post-PCI may be safe in selected patients.

Capodanno explains: “LEADERS FREE was the first study to show that if you need to give only one month of DAPT because of the HBR of the patient, you have better efficacy and similar safety with a DES than a baremetal stent.”

Onyx ONE studies add to evolving evidence

David Kandzari

Davide Capodanno

Awareness of HBR patients

This point is echoed by Davide Capodanno, who says that awareness has evolved over the need for suitable strategies for the treatment of HBR patients undergoing PCI with a DES. “The awareness of bleeding [post-PCI] has become even more important now that we have stents that perform well, meaning that there is less risk of thrombosis or stent-related complications. We know

The awareness of bleeding has become even more important now that we have stents that perform well.” that DAPT may cause some degree of risk, particularly in these [high-risk] patients,” he explains. “I think the challenge is to make the right choice in terms of the duration of DAPT based on individual patient factors and circumstances.”

Current guidelines from both the American College of Cardiology (ACC) and American Heart Association (AHA), updated in 2016, as well as from the European Society of Cardiology (ESC), updated in 2017, recommend a six-month DAPT regime

This understanding has further evolved through the Onyx ONE Month DAPT Programme, comprised of the Onyx ONE Clear study and Onyx ONE Global trial, which evaluated the use of the Resolute Onyx DES (Medtronic), compared to the BioFreedom (Biosensors) drug-coated stent, in HBR patients combined with a one-month DAPT regime. Findings from the Onyx ONE month DAPT programme contributed to the CE mark approval of the Resolute Onyx device for a one-month DAPT indication in Europe in June 2020, followed by a further labelling update by the US Food and Drug Administration (FDA) in October 2020— making Resolute Onyx the first device to one-month approvals in the USA and Europe.

“There are several advantages to how this trial programme was performed that enable these data to advance clinical practice,” comments Kandzari. “First of all, the trial was very broad in its inclusion criteria. There were very few restrictions other than limiting the study to HBR patients. To that end, it is quite representative of the patients whom we routinely encounter in clinical practice,” he explains.

Examining short-duration DAPT in the HBR population

Additionally, comments Kandzari, the Onyx ONE study programme is the largest to date to evaluate a one-month DAPT duration— including more than 2,700 patients at up to 130 sites worldwide. “Whereas most studies were evaluating three or six months, this study has advanced that timeline to one month of DAPT, which may be very relevant to many high-risk patients who have upcoming surgery, or who represent a very May 2021

HBR: The forgotten population?

I think the challenge is to make the right choice in terms of the duration of DAPT based on individual patient factors and circumstances.” high risk of bleeding complications.”

In terms of shaping the understanding of the optimal treatment strategies available for those at high risk of major bleeding, Kandzari comments that these studies underscore the importance of having access to “a very effective stent that has evidence behind it that would support a shorter duration of DAPT”.

He adds: “Ultimately, these studies reassure clinicians regarding the safety of one-month DAPT, independent of the patient complexity, [in those] who are treated with a Resolute Onyx stent.”

Consider the patient's needs

Furthermore, the data point towards the need for clinicians to consider the individual circumstances of each patient when they are weighing up their bleeding versus ischaemic risk and how this may influence DAPT May 2021

40%

Proportion of patients undergoing PCI with high bleeding risk (HBR) characteristics

strategies. Kandzari notes: “It requires very individualised, careful patient selection, with regard to deciding which patients should be treated with one month of DAPT and there may be other HBR patients for whom longer DAPT durations may be indicated,” he states.

Capodanno comments that reducing the risk of bleeding after PCI is “just one strategy” to consider. He says: “The next evolution is to look not just at the risk of bleeding, but simultaneously at the risk of bleeding plus having myocardial infarction or stent thrombosis. Based upon that; if you have a risk of thrombotic events that is higher than the risk of bleeding events, then you will go for a more intensive strategy.

Otherwise, for the patients with a higher risk of bleeding than the risk of having thrombotic complications you will go for a more conservative strategy.”

David Kandzari is the chief of the Piedmont Heart Institute and Cardiovascular Service Line; director, interventional cardiology of the Piedmont Heart Institute; and chief scientific officer for Piedmont Healthcare in Atlanta, USA. He specialises in cardiovascular disease, peripheral arterial disease and interventional cardiology.

Davide Capodanno is associate professor of cardiology at the University of Catania and interventional cardiologist at the CardiacThoracic-Vascular Department, Azienda Ospedaliero-Universitaria Policlinico “G Rodolico-San Marco” in Catania, Italy. He is also the editor-in-chief of EuroIntervention.

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Onyx ONE

Onyx ONE: The latest data for PCI in the high risk patient population

Onyx ONE Clear

(16.9%)

Resolute Onyx DES (N = 1,003) BioFreedom DCS (N = 993)

Event Rates (%)

In order to add to these findings, Onyx ONE Clear took a different approach. The single-arm study included HBR patients in the USA and Japan treated with one-month DAPT with Resolute Onyx, clear of adverse events and DAPT-compliant at one month.

These patients were pooled with similar patients treated in the Onyx ONE Global Understanding of the size and complexity of the high bleeding risk (HBR) patient study, totalling approximately 1,500 patients population, and the best treatment options for these patients, continues to that were included in the primary endpoint develop. What is currently known is that this is a large, growing, and challenging analysis. The study’s primary composite set of patients that until very recently have had little clinical evidence to guide endpoint of cardiac death or MI was 7%, treatment decisions during and after percutaneous coronary intervention (PCI). beating the pre-specified performance goal of 9.7% at one-year post-procedure.

The rate of stent thrombosis was THIS WAS THE RATIONALE Unlike previous drug-eluting stent low at 0.7% at one year. “By behind Medtronic’s Onyx ONE Month studies, Onyx ONE had no lesion combining the data from Onyx DAPT programme. Azeem Latib or vessel limitations, and included ONE and Onyx ONE Clear, we (Montefiore Medical Center, New York, >50% acute coronary syndrome now had a larger group —one of USA) was among the investigators in the (ACS) patients. “That is what is the largest groups of patients with Onyx ONE programme. Here he speaks impactful, because if you do that 30 days of DAPT. What it did to Cardiovascular News about the design, it means then that the results are for us is essentially confirmatory. implementation and findings of the research, applicable to daily practice and to Azeem Latib It confirmed everything that we and importantly, its implications in the the kind of patients we see every learned and suspected as far as the modern cath lab. day,” says Latib. safety and efficacy of the stent,” comments The Onyx ONE Programme comprises The study’s one-year results, first Latib. two components—Onyx ONE Global, the presented at the 2019 Transcatheter prospective, randomised trial, and Onyx Therapeutics Scientific Symposium (TCT Impact of the evidence ONE Clear study, a prospective, single-arm, 2019; 24–29 September, San Francisco, Latib considers that the evidence taken from multicentre analysis, which taken together USA), showed that Resolute Onyx met the Onyx ONE programme will provide have enrolled 2,700 patients at up to 130 a primary composite endpoint of cardiac an important focus for the treatment of sites worldwide. death, myocardial infarction (MI), or stent high bleeding risk patients in the future. thrombosis (ST), showing non-inferiority He says: “Before, these patients were very Onyx ONE Global versus the BioFreedom stent. As well as common in our cath labs, but they were Onyx ONE Global sought to compare meeting the primary endpoint, the study under-recognised. Thanks to Onyx ONE and the safety and efficacy of the Resolute showed superior acute performance for other studies like this, we are now actively Onyx (Medtronic) durable polymer-based, Resolute Onyx versus BioFreedom, with looking for these patients. For the first zotarolimus-eluting stent, to the polymerdevice success of 92.8% versus 89.7%, time we are now calculating scores to try free biolimus A9-drug coated BioFreedom respectively [p=0.007]. Furthermore, and evaluate bleeding risk in our patients (Biosensensors) stent, which is the first there was low (2.8%) target lesion undergoing PCI.” stent to have been shown to be efficacious revascularisation (TLR) for Resolute Onyx Findings from Onyx ONE should provide with one month of dual antiplatelet therapy versus 4% for BioFreedom. Additionally, confidence to interventional cardiologists (DAPT). stent thrombosis (ST) for Resolute Onyx to be implement shorter-duration DAPT in The study enrolled 2,000 high bleeding was low (1.3%) versus BioFreedom (2.1%). patients require such a strategy, Latib adds. risk patients undergoing PCI with planned Commenting on the relevance of the “When I came to the USA two years ago, one-month DAPT (aspirin and an oral findings, Latib said: “The main takeaway is there were still bare metal stents on the shelf P2Y12 inhibitor). An important aspect that if you have a patient who, for whatever in my cath lab. When I told physicians that of the study design—and one that makes reason, can only take 30 days of DAPT and we need to take them off, and only use drugit such an impactful piece of research in for whatever reason has to stop DAPT, now eluting stents, they were hestitant due to a Latib’s eyes—is the broad inclusion criteria. we have a stent that is safe and effective.” lack of data. With Onyx ONE, I was able to show the data to my colleagues and say ‘get PRIMARY ENDPOINT Scan here for rid of the bare metal MET WITH RESOLUTE p = 0.43 more informaONYX DES (17.1%) stents’. We have done NON-INFERIOR TO tion on Onyx 14.7 that.”

13.4 BIOFREEDOM DCS p = 0.43

p = 0.22

4.5

2.1

1.3 ST

MI

Cardiac Death

Components of Primary Endpoint

4

3.7

p = 0.17

2.8

4.0

TLR

ONE

Azeem Latib is medical director of Structural Heart Interventions at Montefiore Medical Center, New York, USA.

May 2021

ARC-HBR app

HBR: The forgotten population?

Assessing HBR in practice: The ARC HBR app Marie-Claude Morice (Institut Hospitalier Jacques Cartier, Massy, France) tells Cardiovascular News about the importance of having a simple and speedy method of identifying high-bleeding risk (HBR) patients which can be used anywhere, at any time—the ARC-HBR mobile application. Developed by the ARC-HBR Consortium, the app is modelled on a consensus definition of high bleeding risk (HBR) for patients who are candidates for treatment with a coronary stent.

Why is it important to identify HBR patients?

It is very important to identify these patients, because they can have significant haemorrhagic complications with the antiplatelet treatment we give them following angioplasty. So by identifying them, we can adapt our strategy to prevent these complications from occurring in the first place.

What are the clinical implications of the identification of HBR patient:

The consequences for patients are very significant. In the past, HBR patients were in fact excluded from so-called “allcomer” studies, and were often not given access to angioplasty Marie-Claude Morice for fear of bleeding complications, or were treated with stents to reduce the duration of antiplatelet therapy, What is ARC-HBR, and why is or unidentified and exposed to disastrous its work important? bleeding complications.

The academic research consortium was formed a long time ago with the aim of How does the ARC-HBR app streamlining definitions used in different determine which patients have a studies, in order to be able to compare and high bleeding risk? possibly pool the data. It is important to have The app is a practical and effective tool that a universal understanding of certain terms allows you to identify at the bedside if the when pooling data so that everyone is on the patient fits the criteria for a patient at high same page. The endpoints of the stent studies, risk of bleeding, and quantifies the risk; the which encompassed cardiovascular death, app has recently been enriched with new myocardial infarction (MI), target lesion data, making it possible to quantify, for a revascularisation (TLR), and stent thrombosis given patient, the respective weight of the (ST), have now been homogenised, as risk of bleeding and their risk of thrombosis, have rates of bleeding and many other making it possible to better adapt your cardiovascular pathologies. therapeutic strategy.

The consortium founders asked us to organise a working group on patients at How easy to use is this tool high risk of bleeding and a group of 30 can it be used by clinicians in experts, supported by 20 pharmaceutical or any setting? medical device companies, worked for two The app is available on any type of device, years to establish and to publish, first of all, and extremely easy to use. You just have definitions concerning HBR patients, and to find the patient file, or ask the patient a then the endpoints and trial design of the series of questions that will then allow you to studies concerning these HBR patients. establish their individual risk score.

How has ARC-HBR sought to help clinicians in understanding HBR patients?

Of the dozens of studies published before the ARC-HBR initiative, only two used the same definitions; otherwise, the inclusion criteria were disparate. Since the publication of our report, the homogenised definitions, endpoints, and trial design we recommended have been widely-used in several completed and ongoing studies, justifying the importance of the ARC-HBR initiative.

May 2021

What are the next steps for ARC-HBR?

More generally, with the success of the ARC-HBR app, we realised that it would be useful to group all the ARC initiatives (ARC, BARC, neuroARC VARC….) under an ARC app, in order to have access to everything without having to search for each individual publication. We are currently in the process of doing this—the ARC Portal and BARC Bleeding Definitions should be available soon.

The ARC-HBR mobile app is a new tool to aid in the identification of HBR patients

Scan here to access the ARC-HBR mobile app

Marie Claude Morice is director of interventional cardiology at Institut Hospitalier Jacques Cartier, Massy, France.

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Strategies for HBR

Balancing ischaemic benefit and bleeding harm in HBR patients For Roxana Mehran (Mount Sinai School of Medicine, New York, USA), treating high bleeding risk (HBR) patients in the cath lab is a near-daily occurrence. Finding the optimal strategy to prevent the risk of a harmful bleeding event following percutaneous coronary intervention (PCI) while also achieving the best possible ischaemic benefit is a fine balance. Recent advances in understanding of the benefits and risks associated with a short course of dual antiplatelet therapy (DAPT) following stent implantation in HBR patients—gained in through the Onyx ONE Global and Onyx ONE Clear studies, among others— will arm interventional cardiologists with a stronger body of evidence as to the best treatment strategies for these vulnerable patients, Mehran suggests.

“IT IS REALLY IMPORTANT TO note that every day we see a HBR patient come to the cath lab,” explains Mehran.

“In fact, in databases that we have looked at, approximately 30‒40% of the allcomers patient population exhibit clinical and comorbid conditions that significantly increase their risk of bleeding, and you would be a little bit wary about giving them potent P2Y12 inhibitors [or] a prolonged duration of DAPT.”

Who are the HBR patients?

Bleeding after PCI is an important predictor of mortality, Mehran comments, which makes the identification of HBR features one of the chief concerns in maximising outcomes and reducing harm in these patients. The first step is to understand which patients are at the most risk—but classifying which patients fall into the HBR category has not always been simple. “This is the question that everyone asks,” comments Mehran. “If we are going to talk about HBR patients, we should clearly define who these patients are,” she says.

“In my mind, one of the most important unmet needs is to understand how to identify these patients and what evidence we have to inform their treatment with respect to the choice of stents and duration of a DAPT,” Mehran adds.

One recent development intended to streamline the identification of HBR PCI patients is the Academic Research Consortium for High Bleeding Risk (ARC-HBR) consensus document, which was published in Circulation in 2019 and has since become a cornerstone of post-PCI treatment development.

The consensus document provides a framework for stratifying patients at risk from PCI-related bleeding based

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upon “major” and ”minor” criteria, which include age, comorbidities, and bleeding history. More detail on the application of the ARC-HBR criteria can be found on page 5.

Setting the right strategy

Once these HBR patients have been identified, it is then important to dictate the right strategy to manage their bleeding risk, whilst also achieving the best outcomes, including deciding upon whether a shorter DAPT duration may provide sufficient ischaemic protection. On this need for balance, Mehran comments: “It is a difficult challenge, because those are the same patients who present with the

In my mind, one of the most important unmet needs is to understand how to identify these patients and what evidence we have to inform their treatment with respect to the choice of stents and duration of a DAPT.” most complex anatomy, require extensive revascularisation, and would theoretically benefit from prolonged or potent antiplatelet regimens. So, how do you balance the risk

versus benefit? One way is to make sure that, during the procedure, you are getting the best possible result with the best possible devices according to Roxana Mehran the available evidence in HBR patients, using intravascular imaging whenever possible to achieve optimal stent expansion at the time of procedure. I think it is a very important part of how we plan and strategise taking care of HBR patients.” Among recent studies to address the management of bleeding risk in HBR patients undergoing PCI is Onyx ONE Global, which alongside Onyx ONE Clear study makes up the Onyx ONE Month DAPT programme, comprising over 2,700 HBR patients worldwide.

Evolving evidence base

Onyx ONE Global compared the Resolute Onyx (Medtronic) zotarolimus eluting-stent to the BioFreedom (Biosensors) polymerfree biolimus A-9 drug-coated stent in HBR patients with planned one-month DAPT. This prospective, multicentre, single-blind trial enrolled 2,000 HBR patients who were randomised 1:1 at 84 global sites. At one year, the trial met its primary hypothesis of noninferiority of the Resolute Onyx stent to the BioFreedom stent with respect to the composite endpoint of cardiac death, myocardial infarction, or stent thrombosis (17.1% vs. 16.9%), with similar bleeding rates between both treatment groups.“That is where we started to get the best possible evidence that we have,” comments Mehran, noting that the result was seen in a population usually excluded from clinical trials.

Onyx ONE—The latest HBR evidence

Meanwhile, the prospective, multicentre, single-arm Onyx ONE Clear study pooled HBR patients who were treated with one month of DAPT after PCI with the Resolute Onyx stent from Onyx ONE with the USA and Japan registries. The study included analysis of 1,506 patients who fulfilled “onemonth clear” criteria—defined as DAPT adherence and freedom from major adverse events during the first month following May 2021

HBR: The forgotten population?

The Onyx ONE trial actually did show excellent device performance for the zotarolimuseluting stent. I feel very confident that I now have a tool in my toolbox that is safe and effective to use for my patients with HBR.” is also fundamental, according to Mehran, in taking these findings forward. “Let's follow them [HBR patients] diligently to make sure that we protect them against bleeding harm and understand that we can give them a short duration of DAPT, and go and drop one of the antiplatelets and follow them closely,” she adds.

“This programme shows you that on the stent side we can take care of this with the best possible stent technology, and the rest is up to us as clinicians to care for our patients and give them the best possible therapy that is out there. Optimal medical management of these patients is absolutely key.”

PCI. Results of the trial showed a primary composite endpoint of cardiac death or myocardial infarction which stood at 7%, beating the study’s pre-specified performance goal of 9.7% at one year post-procedure.

Furthermore, the study reported a rate of stent thrombosis of 0.7% at one year.

Reflecting on the key messages from the Onyx ONE study programme, Mehran, who was a primary investigator in the trial, comments that a high proportion of the patients had multiple HBR features, giving the findings greater significance. She says: “HBR criteria were met in a large number of these patients with a mean criteria of about 1.6. Close to 50% of the patients had two of the HBR criteria, which really pushes it over the edge of a HBR patient population.”

The results reflect the safety and efficacy of the zotarolimus-eluting Onyx stent allied with a one-month DAPT regimen in a HBR patient population, Mehran says, and should

provide reassurance in the use of this device in the HBR population. “The Onyx ONE trial actually did show excellent device performance for the zotarolimus-eluting stent. I feel very confident that I now have a tool in my toolbox that is safe and effective to use for my patients with HBR.”

Roxana Mehran is professor of medicine and director of Interventional Cardiovascular Research and Clinical Trials at the Zena and Michael A Wiener Cardiovascular Institute at Mount Sinai School of Medicine, New York, USA.

The right fit for the right patient

Taking these findings into consideration, Mehran concludes that the route to success in the treatment of HBR patients lies in understanding the needs of the individual.

Asked for her tips on the optimal strategy, she comments that this involves, “[…] really customising the care of the patients according to their need, their presentation, their anatomy, their bleeding risk, and, of course, their ischaemic burden. We have to put it all into one equation and figure out what fits best for which patient.”

Vigilance over outcomes in these patients

Scan here to watch the full interview with Roxana Mehran

All rights reserved. Published by BIBA Publishing, London T:+44 (0)20 7736 8788, publishing@bibamedical.com.

The opinions expressed in this supplement are solely those of the featured physicians and may not reflect the views of Cardiovascular News.

May 2021

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UP TO % OF PATIENTS UNDERGOING PCI ARE AT HIGH 1 BLEEDING RISK IDENTIFYING PATIENTS AT HIGH RISK OF BLEEDING*

AGE (≥75 YEARS)

AGING

RENAL DISEASE

LIVER DISEASE

COMORBIDITIES

ACTIVE CANCER

ANEMIA OR LOW PLATELET STROKE, ICH, bAVM TRANSFUSION COUNT

LABORATORY

CNS

BLEEDING DIATHESIS

PRIOR BLEEDING

BLEEDING HISTORY

OAC

NSAIDS, STEROIDS

SURGERY ON DAPT

IATROGENIC

FIRST DES CE INDICATED FOR 1-MO DAPT IN HBR PATIENTS Based on Onyx ONE Global Study results

Resolute Onyx™ DES

1 Ueki Y, Bär S, Losdat S, et al. EuroIntervention 2020;16:371-379 * Urban P, Mehran R, Colleran R et al. Circulation 2019;140(3);240-261.

See the device manual for detailed information regarding the instructions for use, indications, contraindications, warnings, precautions, and potential adverse events. For further information, contact your local Medtronic representative and/or consult the Medtronic website at medtronic.eu.

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