Cardiac Rhythm News Issue 44 – March 2019

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Mapping dynamic patterns during atrial fibrillation can produce higher success rates In a late-breaking session at the 24th Annual International AF Symposium (24–26 January, Boston, USA), it was announced that a dipole density (DD) mapping and ultrasound imaging system to identify non-pulmonary vein (PV) targets in persistent atrial fibrillation (AF) performed safely and effectively, and with higher success rates than historical AF ablation trials. Results of the UNCOVER AF trial were presented by Atul Verma of Southlake Regional Health Centre (Newmarket, Canada).

Eric Prystowsky: The CABANA trial

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Sabine Ernst: AF education

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David Callans:

Profile

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More than 40% of patients with a history of atrial fibrillation attend the emergency department inappropriately

“B

ased on initial results,” Verma comments, “mapping dynamic patterns during atrial fibrillation and ablating them, in addition to traditional pulmonary vein isolation (PVI), can produce higher success rates in persistent AF patients.”

He continues that the AcQMap system (Actus Medical) used in the study, and an iterative, patient-specific treatment approach “warrants additional investigation.”

According to the authors, use of the AcQMap system with an iterative mapping, adaptive therapy approach resulted in 72.5% AF free, single procedure effectiveness at 12 months, and over 80% of patients had no AF burden recorded over the total duration of 24-hour continuous monitoring at 12 months.

Furthermore, they note that a decrease in arrhythmia burden was associated with symptom improvement, the ability to perform daily activities, and increased treatment satisfaction based on AFEQT scores.

Verma and colleagues comment that sinus rhythm at the end of the procedure was achieved in 98% of the patient cohort. The time to create atrial anatomy was 4.3±2 minutes and the mean total procedure time was 4.1±1.1 hours, they note, and on average, 5±3.4 focal, localised rotational activity (LRA) and/or localised irregular activity (LIA) patterns were identified per patient with 4.2 ± 2.8 patterns ablated.

In addition, AF freedom after one or two procedures was reported as 93% (95% CI 97%–87.1%) at 12 months, and of the 96 patients who underwent a single

procedure, 89.6% had zero episodes of AF lasting >30 seconds. After one or two procedures, 82.4% of patients experienced zero episodes of AF >30 seconds.

Predictors of 12-month AF free success included ablating >3 focal, LRA or LIA patterns, with an odds ratio of 9.39 (2–44.1) and a p-value of 0.004, while ablation termination to SR predicted a three times greater likelihood of SR at 12 months (odds ratio 2.97 [1.06–8.29], p=0.3).

According to the authors, safety events were adjudicated by an independent clinical events committee (one European and two US physicians).

They comment that “no major adverse events (MAEs) were adjudicated to be related to use of the AcQMap system,” however, a total of three MAEs were adjudicated to be “probably related” to the procedure.

Verma and colleagues describe acute efficacy as the procedural conversion to sinus rhythm within 12 hours of index procedures. Safety outcome was defined as freedom from device or procedure related MAEs within 24 hours of the ablation procedures. Chronic effectiveness was defined as freedom from AF >30 seconds, on or off antiarrhythmic drugs (AADs) with single procedure and multiple procedures, or freedom from AF, atrial flutter (AFL), or atrial tachycardia (AT) >30 seconds, on or off AADs with single procedure and multiple procedures.

This was the first use of the AcQMap system Continued on page 2

Patients with a previous diagnosis of atrial fibrillation who were assessed as attending the emergency department inappropriately did so because of fear, or as a result of advice from another person or self-monitoring, a study has found.

Benedict Glover from Schulich Heart Centre, Sunnybrook Health Sciences Centre (Toronto, Canada) presented the initial results of the Canadian AF-ED trial at the 24th Annual International AF Symposium (24–26 January, Boston, USA) during a late-breaking session.

THE MULTICENTRE TRIAL was conducted in Canada “to discover reasons why people with atrial fibrillation present inappropriately to emergency departments,” explained Glover. He added that the trial’s wider vision was “to try and develop a mechanism to stratify patients through other mechanisms so they do not need to come to the emergency department with atrial fibrillation”.

According to Glover, inappropriate hospitalisations and emergency department visits among people with atrial fibrillation are “a huge financial problem”. The annual cost of atrial fibrillation in the USA is more than US$6.7 billion, with “75% of this related to inpatient stay”. In Canada, smaller numbers are involved, but annual hospital costs of AF “are approximately CAN$815 million”. Glover stated that the researchers’ aim was to “try to reduce the hospitalisations and emergency department attendance of patients with atrial fibrillation” in Canada.

The Canadian AF-ED trial was run with the Canadian Arrhythmia Network (CANet), which comprises 29 universities, each of which has two Continued on page 2

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Top stories

Mapping dynamic patterns during atrial fibrillation can produce higher success rates

More than 40% of patients with a history of atrial fibrillation attend the emergency department inappropriately

Continued from page 1

Continued from page 1

combining ultrasound-based anatomy and high-definition charge density non-contact maps to guide iterative ablation therapy in a prospective, single-arm, multicentre study in patients with persistent AF, the authors remark.

They describe the system as a “high resolution imaging and mapping system,” incorporating “a noncontact 3D electroanatomic system capable of mapping all types of complex atrial arrhythmias; ultrasound anatomy reconstruction in as little as two minutes; fullchamber mapping, providing a clear view of cardiac activation; charge density mapping revealing conduction patterns in the substrate; and rapid re-mapping (1–2 minutes) allowing for a quick assessment of ablation effectiveness.” The system has received US FDA clearance and CE mark approval.

All 127 patients in the UNCOVER AF trial presented with persistent AF, defined as lasting longer than seven days, but less than one year. In 13 centres across Europe and Canada, these patients underwent atrial mapping prior to PVI. The investigators describe how an imaging and mapping catheter reconstructed atrial anatomy and mapped the atria. High-resolution DD maps then identified localised focal, LRA and LIA conduction patterns, before PVI was performed using irrigated RF. Re-map and ablation continued until termination or elimination of all targets. Freedom from >30 second AF was measured at three, six, nine and 12 months using a continuous 24-hour electrocardiogram (ECG) recording, and AF burden was calculated as the total percentage of time in AF across total ECG monitoring time for all follow-up visits.

The authors hypothesised that “identification and elimination of non-PV targets may improve outcomes in patients with persistent AF.” The purpose of the present trial was therefore to evaluate the safety and effectiveness of a non-contact ultrasound imaging and DD mapping system to identify non-PV sources during persistent AF ablation. The investigators also set out to demonstrate the value of real-time iterative mapping to guide an adaptive patient-specific therapeutic strategy.

Talking to Cardiac Rhythm News, Verma comments that “success rates in historical AF ablation trials were about 50 to 60% compared to the 70% demonstrated after one procedure in this trial.” On the limitations of the results, he notes that “this was a non-randomised, single-arm trial” and that “head-to-head randomised comparison will be required for future studies to fully assess efficacy”.

Editors-in-chief:

or three hospitals linked to it, 180 investigators and 24 industry partners.

CANet’s 10-year goal aims to achieve “a 10% drop in sudden cardiac death, a 20% drop in hospitalisation and emergency department visits in patients with atrial fibrillation, and a 30% drop in hospitalisation and emergency department visits in patients with a history of syncope”.

The study was conducted over a 14-month period and coordinated at a Benedict Glover centre in Ontario. If a patient with a known diagnosis of atrial fibrillation was admitted or attended the emergency department in any of the participating hospitals, they were asked to enrol in the study. They were asked a series of questions about why they had attended hospital. “We tried to work out whether it was an appropriate admission or attendance or not, and then what the outcomes of the attendance were, and whether there were any alternative strategies that may have worked better,” Glover explained.

Of the 356 patients recruited to the study, 71% attended because they had symptoms, such as palpitations, chest pain or shortness of breath.

However, almost a third of patients did not have symptoms.

Almost 10% of the patients without symptoms attended because they were scared they were going to die, have a heart attack or have a stroke.

Forty per cent of those patients who were scared they were going to have a stroke were not on oral anticoagulation even though their mean CHA2DS2VASc score was 2. Eighteen per cent of patients without symptoms attended because they had been advised to, in a third of cases by a cardiologist, while 2% attended as a result of self-monitoring.

Patients assessed as having appropriate reasons to attend (n=204; 57%) required hospital admission or electrical or chemical cardioversion. Patients with symptoms were more likely to have an appropriate reason to visit the emergency department, as were

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those who had had multiple visits previously, and female patients.

The remaining patients (n=152; 43%) would have been better managed in another setting. These patients had received previous advice from a physician or a nurse, or were not on an oral anticoagulant and were worried they were going to have a stroke, or were scared.

When asked about alternative treatment strategies, most patients stated they would attend a rapid assessment outpatient atrial fibrillation clinic instead of the emergency department, while a significant number believed that smartphone applications may be of benefit.

This prompted the researchers to develop the VIRTUES platform (Virtual Integrated Reliable Transformative User-driven E-health System), which is now being tested in a small pilot study in patients

Wearable biosensor technology enables the patient to record their physiological data, such as blood pressure.” with atrial fibrillation.

Wearable biosensor technology enables the patient to record their physiological data (such as ECG and blood pressure), which are transmitted via their cellphone to a central system linked to the hospital cardiology clinic and family practice clinic. The patient is then given feedback and advised what action to take instead of attending the emergency department.

Glover concluded by stating that he hoped the VIRTUES platform would help reduce emergency department attendances by patients with atrial fibrillation in the future. He also emphasised that it was important to ensure that patients with a CHA2DS2-VASc score of 2 are anticoagulated.

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4

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Radiation exposure

Use of a safety time out reduces radiation exposure during electrophysiology procedures A study carried out at the New York University Langone Health Electrophysiology Lab (New York, USA) showed significantly reduced radiation exposure levels after implementing a radiation safety time out before all electrophysiology procedures. Anthony Aizer (New York University School of Medicine, New York, USA) and others write in JACC: Clinical Electrophysiology that “electrophysiology laboratories, as well as other areas of cardiovascular medicine using fluoroscopy, should strongly consider the use of radiation safety time outs to reduce radiation exposure and improve safety”.

THE AUTHORS HYPOTHESISED that, as the use of surgical safety checklists has been proven to reduce the risk of patient morbidity and mortality, and as radiation exposure puts patients and operators at risk of adverse outcomes, “a radiation safety time out implemented before all electrophysiology procedures would reduce patient and operator radiation exposure.” They add: “To analyse this, we designed a sequential intervention study comparing radiation exposure prior to versus during implementation of a radiation safety time out.”

In this prospective cohort study, radiation usage was measured for all procedures performed on adults in the laboratory between October 2015 and June 2017.

Aizer and colleagues designed a seven-item radiation safety time out checklist that was implemented for use by operators in the electrophysiology laboratory in April 2016 and then withdrawn three months later. The primary endpoint of the study was dose area product, which assesses patient radiation exposure. Secondary endpoints were reference point dose, which assesses peak skin dose, fluoroscopy time, total procedure time, use of optional protective equipment and techniques, and use of alternative imaging.

For 1,040 procedures included in the study, median dose area product reduced by 21% from 18.7Gy∙cm2 before the time out to 14.7Gy∙cm2 during the first three months after implementing the time out (p=0.007). The

median reference point dose reduced from 163mGy before the time out to 122mGy during the time out (p=0.011). Secondary endpoints of note are the use of sterile disposable protective shields and ultrasound imaging for access, which increased significantly during the time out period.

During the 12 months after withdrawal of the radiation safety time out, the dose area product remained significantly reduced, as did the reference point dose.

However, fluoroscopy time did not show any significant change during or after the time out period.

While some authors have previously suggested that checklists should be implemented to reduce the risks of exposure to radiation in cardiovascular imaging, there is little evidence of their efficacy. One study by Kokorowski et al that involved paediatric ureteroscopy and another by Leschied et al that involved radiology students performing gastrointestinal or genitourinary imaging both demonstrated some reduction in fluoroscopy time with the use of checklists. However, both studies were limited with small sample sizes and a lack of assessment of permanence of the interventions.

In comparison, the present study included more than 1,000 patients and demonstrated a reduction in radiation levels for 12 months after the intervention was withdrawn. According to the authors, this is the first study to “demonstrate that a radiation safety

time out reduces radiation exposure levels in the electrophysiology lab.”

The authors also note: “in our analyses, one year after the radiation safety time out was withdrawn, radiation levels remained reduced, suggesting that the time out was not only effective, but also educational.”

However, Aizer and colleagues point out that there were some safety measures which the operators did not continue to use after the radiation safety time out was withdrawn. Few practitioners “checked to save fluoroscopy images over fluorography/cine images” and “only attending physicians checked for beam collimation.” Use of both of these safety techniques would help reduce the radiation that patients are exposed to and should be recommended, the authors suggest.

Some limitations of this study are noted. For example, the study only involved a single centre so further research is needed to confirm the results in other institutions and in other types of procedures involving radiation. Radiation exposure of operators in this study was estimated using dose area product and reference point dose but more accurate results may have been obtained using radiation dosimeter badges.

The authors conclude: “in light of the findings in our study … expansion of a pre-procedure radiation safety time out to additional areas of medicine should be considered.”

Patients with atrial fibrillation who are frail or have cognitive impairment “less likely” to be prescribed oral anticoagulation Malini Madhavan (Department of Cardiology, Mayo Clinic, Rochester, USA) and others reported the results of a study in American Heart Journal that found that patients with atrial fibrillation who have cognitive impairment or are frail were less likely to be given oral anticoagulant treatment despite having a higher rate of mortality and being assessed as being at higher risk of stroke and bleeding.

P

revious studies, such as those of Holt et al and Mohammed et al, have reported lower rates of oral anticoagulant prescribing in patients with atrial fibrillation who have dementia.

However, the use of oral anticoagulation has been shown by Jacobs et al to reduce the incidence of cognitive impairment in patients with atrial fibrillation.

Similarly, Bertozzo et al found a high rate of doctors stopping warfarin in patients with atrial fibrillation who they perceived as being frail or having low life expectancy, despite high rates of mortality, bleeding and stroke in these patients after discontinuing anticoagulation. It was not known whether frailty affected the outcomes of anticoagulation sufficiently to recommend this practice of withholding treatment.

With this study, therefore, Madhavan and colleagues aimed to investigate whether the incidence of cognitive impairment and/or frailty impact therapy and outcomes in atrial fibrillation. The authors analysed the Outcomes Registry for Better Informed Care in AF for patients with atrial fibrillation who have cognitive impairment and/or frailty and examined the association with oral anticoagulation in determining outcomes.

Of a total of 9,749 patients with atrial fibrillation who qualified for the study, 293 (3%) were diagnosed with cognitive impairment, 575 (5.9%) were identified with frailty and 67 (0.7%) were diagnosed with both cognitive impairment and frailty. Persistent or permanent atrial fibrillation was more common in patients with frailty than those without (54.1% vs. 44.2%). Oral

anticoagulants were prescribed to 7,445 patients (76.4%) at baseline: of these 6,965 were given warfarin and the remaining 480 were given dabigatran.

Using risk calculators, patients with cognitive impairment or frailty were assessed at being at higher risk of stroke and bleeding. However, oral anticoagulants were found to be less likely to be given to patients who were frail (68% vs. 77%, p<0.001) or to those who had cognitive impairment (70% vs.

77%, p=0.006).

The risk of dying was found to be higher in patients with cognitive impairment (HR: 1.34; 95% CI: 1.05– 1.72; p=0.0198) and in patients who were frail (HR: 1.29; 95% CI: 1.08–1.55; p=0.006). However, there was no association identified between cognitive impairment or frailty and stroke, transient ischaemic attack or major bleeding.

On the association between oral anticoagulation and different outcomes, there was found to be no interaction between either cognitive impairment or frailty and oral anticoagulant use in determining mortality, major bleeding

or composite end point of stroke, non-central nervous system systemic embolism, TIA, myocardial infarction or cardiovascular death.

The authors highlight a strength of this study: “a significant proportion of patients over the age of 75 years, a population that is underrepresented in randomised clinical trials.”

They also note some limitations of the study. As an observational study, it may be subject to unrecognised confounders so “these findings should be confirmed in future prospective studies”. The numbers of frail or cognitively impaired patients in the study are small so the results should be interpreted with caution and may not be generalisable to other populations.

It is possible that cognitive impairment and frailty were underdiagnosed in the original patient population and/or that new diagnoses of cognitive impairment or frailty were not performed during the follow-up period. There was a small percentage of patients treated with NOACs, so the data are only applicable to patients treated with warfarin.

Madhavan and colleagues recommend that: “atrial fibrillation patients with cognitive impairment should be considered for oral anticoagulation based on their clinical factors," and that “frailty should not be a contraindication to oral anticoagulation prescription” in such patients. They propose that future studies should consider whether routine assessment of frailty indices should be used to guide atrial fibrillation therapy.

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Debate

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Is CABANA a positive or negative trial?

Several treatment options are available for atrial fibrillation (AF), including pharmacological rate or rhythm control, and catheter or surgical ablation. However, consensus as to the most effective treatment remains elusive. The Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial was designed to address this issue. Eric Prystowsky argues that CABANA is a positive trial, whereas Peter Kowey and Munveer Thind believe it is a negative one. Here, they put forward their respective arguments.

Eric Prystowsky Peter Kowey Munveer Thind

patients treated with ablation based on the PP/TR analyses, while interesting and hypothesis generating, should not be used to make a significant change in clinical practice.

As mentioned, there were several secondary endpoints in CABANA that were considered clinically important.

Curiously, the original statistical analysis plan did not specify how alpha was to be apportioned to these secondary endpoints. Without such a contingency, secondary endpoints, such as CV hospitalisation and AF recurrence lack statistical reliability, and as such, must be regarded as “exploratory” and “hypothesis-generating.” The use of an alternative analysis decided upon midway through the recruitment process also has the potential to introduce bias.

Finally, many within the ablation community have become enamored of the idea of offering catheter ablation to older individuals with persistent AF, including those with congestive heart failure. They have made the argument that these subgroups in CABANA exhibit benefit akin to what was seen in CASTLE-AF, a seriously flawed study of patients with heart failure. What they fail to consider however, is that by ITT, and in most cases even by PP analyses, none of these sub-groups showed statistical benefit using standard interactional analyses.

If one were to pursue a “glass half full” philosophy, we learned that catheter ablation is as safe as antiarrhythmic drug therapy. In fact the adverse events seen in CABANA were remarkably low, a testimony to the experience and skill of the centres selected to participate.

Nevertheless, electrophysiologists, like all clinical investigators, need to adhere to the rules for interpretation of clinical trials. To do anything less will diminish our reputation in the scientific community, and cause our colleagues to question our judgement and integrity.

For the sake of our patients, this simply cannot happen.

+ –

Comment & Analysis

CABANA is a positive trial

The CABANA trial randomised 2,204 patients to ablation versus drug therapy.

The primary endpoint was a composite of death, disabling stroke, serious bleeding or cardiac arrest. In the intention-to-treat (ITT) analysis, the primary endpoint was 8% for ablation and 9.2% for drug therapy patients, not significantly different. So, is this a negative trial as some “purists” of randomised trials would have us believe, who refuse to consider any other data from such a trial having relevance? I say no, for there are many other factors to consider from the data presented, including how the entire trial results may help patients and clinicians position ablation as a therapy of choice. Let us examine these other outcomes.

Using a treatment received analysis, the primary endpoint was 7% and 10.9% in the ablation and drug groups, respectively (p=0.006). Similarly, for the per-protocol analysis the primary endpoint favoured the ablation group. The secondary endpoint of all-cause mortality or cardiovascular hospitalisation by ITT analysis was significantly better in the ablation group.

Atrial fibrillation recurrence rates by ITT were significantly reduced by ablation versus drug therapy. Last, in a different presentation, quality of life improved in both treatment groups, but more so in the ablation group.

Now, before all the PITON (Primary Intention to Treat Or Nothing) crowd send me nasty emails, I understand the problems of using such information when the primary ITT analysis shows no difference, but the other data are thought provoking.

For me, CABANA is a positive trial.

My reasoning is as follows: The primary endpoint is at worst Neutral, which is a major piece of new data on the issue of how to position ablation for AF. The guidelines assigned ablation as a first line treatment with a “dotted line” status and qualification.

I say fill in that line. Multiple studies have shown ablation to be superior to drugs to reduce AF recurrences, and now CABANA has shown no significant difference in major endpoints between drugs and ablation therapy. Some will say that the electrophysiologists (EP) in the trial are more expert in the use of ablation

and their results do not mirror the general EP community. Well, the same can be said for their use of antiarrhythmic agents, which often are prescribed by general cardiologists who do not have the same knowledge and experience in their use. I would hope the PITON crowd would not use such reasoning and agree that the trial showed no difference in major outcomes.

When CABANA was presented by Douglas Packer at the May 2018 HRS annual Scientific Sessions, I was the discussant. I was surprised at the volume of negative comments about the trial results, and this background noise still exists. Some of the loudest voices were from those who have never accepted the value of catheter ablation as a treatment option for patients with AF—the “druggies”. These CABANA bashers remind me of what happened when the AFFIRM trial results were published.

AFFIRM compared rhythm control using antiarrhythmic drugs with rate control, and the primary endpoint was cumulative mortality. The trial showed no significant difference between groups.

The message from this trial should have been that either treatment strategy is appropriate in patients who resemble the trial population. Yet, all too often the position taken was that rate control is easier and why bother with sinus rhythm?

Many patients have suffered because of this, and I still have patients referred to me with symptoms from AF who have been in it for years because their doctor took the easy way out—after years of persistent AF it is very difficult to restore and maintain sinus rhythm even with ablation.

Let us learn from this lesson and use the CABANA data to respond appropriately to the following letter: Dear Doctor, I have atrial fibrillation and want treatment for it. I desire to feel better, minimise my chances of a cardiovascular hospitalisation or dying, and reduce AF recurrences after therapy. What do you recommend?

Dear Patient, There was a major scientific study recently published, CABANA, that addresses your questions. Your best treatment option is catheter ablation.

However, antiarrhythmic drugs are still an option.

CABANA is a negative trial

About halfway into the CABANA trial, the death/stroke/bleeding/cardiac arrest composite secondary endpoint was elevated to become the primary endpoint when it became clear that the initial enrolment target of 3,000 patients would not be achieved and the number of deaths would not be large enough to draw reliable conclusions. The original primary endpoint, all-cause mortality, became a secondary endpoint.

By the prespecified intention to treat (ITT) analysis, there was no significant difference between drug therapy and catheter ablation with regard to the primary composite endpoint or all-cause mortality. However, there was a reduction in the composite outcome of death or cardiovascular (CV) hospitalisation and a reduction in AF recurrence in the ablation arm. Also prespecified were per protocol (PP) and treatment received (TR) analyses, which both showed a significant reduction in the primary composite endpoint and in death in the ablation group.

There are many who have examined the CABANA results who hypothesise that there may have been a real benefit of ablation compared to drug therapy but that the ITT analysis failed to demonstrate statistical significance due to a lower than expected mortality, and a higher than expected crossover and loss to follow-up, diluting the power of the study. They also suggest that the significance achieved in the PP and TR analyses, which curtail these postrandomisation biases, further supports this theory. However, these factors were known and acknowledged at the inception of the study, but were not deemed important enough to abandon the most powerful way of interpreting this important outcomes study, ITT. Intention to treat is the only analysis that maintains the integrity of the randomisation process and is the most powerful tool we have to mitigate bias.

This is why it was chosen as the principal analysis method when the statistical analysis plan was constructed. While the negative results may be due to low event rates, crossover, and loss to follow-up, it may also be due to unknown confounders that bias the result of the PP/ TR analyses. As such, the statistically significant reduction in mortality in

Eric Prystowsky is a cardiologist with St Vincent Medical Group and director of the Cardiac Arrhythmia Service, St Vincent Hospital, Indianapolis, USA. He is also a consulting professor of Medicine at Duke University Medical Center, Durham, USA. Peter Kowey is a professor of Medicine and Clinical Pharmacology at Thomas Jefferson University in Philadelphia, USA, and the William Wikoff Smith Chair in Cardiovascular Research.

Munveer Thind is a fellow in cardiovascular medicine at Lankenau Heart Institute, Wynnewood, USA.

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Wearable cardiofibrillator therapy

More research needed to justify wearable cardioverter defibrillator therapy for the prevention of sudden cardiac death Ahmad Masri (Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, USA) and others report in JACC: Clinical Electrophysiology that a systematic review and meta-analysis of the available evidence on the use of wearable cardiofibrillator therapy (WCD) found that the rate of patients who were appropriately treated was substantial and higher in observational studies than in the only available randomised controlled trial (RCT). They explain this was because “there was significant heterogeneity across the observational studies”, which “included mixed indications and high-risk patients”.

M

asri and colleagues report that, while the first WCD was approved for use by the US Food and Drug Administration (FDA) in 2001, studies about its effectiveness have had mixed findings and there have been no RCTs until the recent VEST (Vest Prevention of Early Sudden Death) trial in 2018, which compared the benefit of WCD with medical therapy in patients who had had a myocardial infarction and ejection fraction ≤35%, and which found no difference in mortality secondary to sudden cardiac death.

The authors therefore “sought to synthesise the available evidence on the use of the WCD” by performing a systematic review and meta-analysis of all published studies that reported on the rate of shocks delivered by a WCD, regardless of indication.

The authors compared the outcomes of 28 studies (27 observational studies and the WCD arm of the VEST RCT) on the use of WCDs. Reviewing data from the studies, the authors dentified 33,242 patients who had been treated with

WCD, with various indications, including ischaemic cardiomyopathy, nonischaemic cardiomyopathy, implantable cardioverter defibrillator explant and mixed indications.

They found the incidence of appropriate WCD therapy to be 5 per 100 people over 3 months for all indications (95% confidence interval [CI] 3.0 to 6.0, p<0.001), with a high heterogeneity (I2=93%). When focusing only on studies that involved patients with ischaemic cardiomyopathy, they found the incidence of appropriate WCD therapy to be much lower in the VEST trial at only 1 per 100 people over 3 months (95% CI: 1.0 to 2.0) than in the observational studies, which had an incidence of 11 per 100 people over 3 months (95% CI: 11.0 to 20.0; I2=93%).

The incidence of inappropriately treated patients was 2 per 100 people over 3 months (95% CI: 1.0 to 3.0; I2=93%) for all indications. Mortality while wearing WCD was found to be rare, with a pooled incidence of 0.7 per 100 people over 3 months (95% CI: 0.3

LifeVest 4000 (Zoll)

to 1.7; I2=94%, p<0.001).

The authors write: “Qualitative analysis shows that most studies were not indication-specific, thus diluting our knowledge on the indication-specific utility of WCD and in which patients it should be best used. Selection bias and including mixed indications in observational studies was likely the

Atrial tachyarrhythmias are not associated with increased mortality in patients with left ventricular assist devices A new study found that having atrial fibrillation or atrial flutter does not put patients with left ventricular assist devices (LVADs) at any greater risk of death, thromboembolism or bleeding. It also found that patients with LVADs who have paroxysmal or persistent atrial fibrillation (AF) do not experience improved outcomes when treated with rhythm control measures. The study by Andrew E Noll (Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, USA) and others was reported in JACC: Clinical Electrophysiology.

PRIOR TO THIS study, it was not clear to what extent AF and atrial flutter (AFL) affect mortality, thromboembolism and bleeding in patients who have LVADs. Additionally, the outcomes associated with rhythm control measures, such as antiarrhythmic medications, electrical cardioversion and catheter ablation, for patients with a LVAD who have AF/AFL have not previously been determined.

In this study, the authors aimed to “determine the prevalence of atrial arrhythmias in the LVAD population, to examine the effect of AF/AFL on mortality, thromboembolism and bleeding outcomes, and to investigate the effect of rhythm control measures on these outcomes.”

All adults (n=418) who had a LVAD placed between January 2004 and June 2016 at the Cleveland Clinic in Cleveland, Ohio, USA were identified and their clinical data were recorded from the time of LVAD implantation to transplantation, death, LVAD explantation, loss to follow-up or study end.

Before LVAD placement, 240 of the patients (57%) had AF/AFL, which increased to 302 patients (72%) after a median 445 days of follow-up. AF/AFL was

Strokes in AF/ AFL patients were less likely to be fatal or disabling than strokes in patients without AF/AFL.” found to be more common in men (83% vs 71%, p=0.005) and was associated with older age (median = 59 years vs 52 years, p<0.00001). Moderate or severe left atrial enlargement was more common in patients with AF/AFL (83% vs. 71%, p=0.005), as was cardiac resynchronisation therapy (49% vs. 30%, p=0.0004).

During the follow-up period, 161 patients died (39%), 156 received a heart transplant (37%), 11 had LVAD explantation (3%), 24 were lost to follow-up (6%) and 66 were still alive with an LVAD at the end of the study (16%).

Of the 161 patients who died, 117 had AF/AFL (39% of patients with AF/AFL) and 44 did not (38%

major determinant of the higher rate of appropriate treatment in patients prescribed a WCD as compared with the WCD arm of the VEST trial.”

The authors describe how the patients who were included in the two studies on which the FDA originally based its approval “do not represent the patients who are currently being prescribed WCD while on optimal medical therapy during the mandated 3 months waiting period before implantable cardioverterdefibrillator consideration.”

“The primary finding of our study is that the available evidence from observational studies is fraught with poor methodology, selection bias, and confounding concerns. The available evidence from the VEST trial shows that the rate of appropriate treatment

by WCD was low and that WCD was not associated with a decreased risk of sudden cardiac death,” the authors state.

Masri and colleagues conclude that “these findings suggest that WCD should not be used in primary prevention until further RCT data support its use.”

of patients without AF/AFL). There was no difference in all-cause mortality between patients with or without AF/AFL (p=0.81) or between patients with paroxysmal, persistent or permanent AF (p=0.77).

Arterial thromboembolism affected a larger proportion of patients without AF/AFL than of those with atrial arrhythmia (23% vs. 13%, p=0.009), mainly as a result of ischaemic stroke, which occurred in 19% of patients without AF/AFL compared with 7.9% of those with AF/ AFL (p=0.001).

A somewhat surprising finding was that “strokes in AF/AFL patients were less likely to be fatal or disabling than strokes in patients without AF/AFL”. The authors note that this is: “perhaps partly explained by different anticoagulation regimens between groups” as patients with AF/AFL were more likely to be discharged with an antiplatelet and an anticoagulant.

Major bleeding affected both groups similarly (138/302 [46%) of those with AF/AFL vs 57/116 [49%] without, p=0.53] and was similar across patients with paroxysmal, persistent or permanent AF (70/150 [47%] vs. 39/88 [44%] vs. 14/35 [40%], p=0.78).

Of the 238 patients who had paroxysmal or persistent AF, 166 (70%) were given rhythm control treatment.

Most were in the form of antiarrhythmics (n=163, 98%), primarily amiodarone (93%). Electrical cardioversion was performed on 34 of these patients (21%).

When comparing those patients with AF who underwent rhythm control and those who did not, there was no significant difference in mortality rates (43% vs 39%, p=0.57), thromboembolism (17% vs. 13%, p=0.41) or major bleeding (39% vs. 49%, p=0.16).

The investigators conclude: “AF/AFL was highly prevalent among LVAD patients but not associated with increased mortality or adverse events. Exposure to rhythm control measures among patients with paroxysmal or persistent AF did not appear to improve clinical outcomes.”

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Combining practical and scientific learning to meet educational needs at Europe’s largest atrial fibrillation symposium Mattias Duytschaever Sabine Ernst Comment & Analysis The Atrial Fibrillation Symposium is a long-standing initiative from Biosense Webster and the Johnson & Johnson Institute. Here, Sabine Ernst and Mattias Duytschaever talk to Cardiac Rhythm News about their roles at this year’s event (Atrial Fibrillation Symposium, 6–8 February, Copenhagen, Denmark). They also discuss their highlights from the meeting and what they consider to be the important educational requirements for both trainees and patients, in order to optimise patient outcomes in atrial fibrillation; a condition that continues to place an increasing burden on patients and healthcare systems.

What is your involvement with the Atrial Fibrillation Symposium?

Ernst: I have a long association with the Atrial Fibrillation Symposium. During my years as a senior fellow in Hamburg, Germany, I worked with the head of cardiology, Karl-Heinz Kuck, to support the development of the symposium programme (in conjunction with the other course directors at the time, Michel Haissaguerre and Carlo Pappone). It was when I moved to the Royal Brompton Hospital in London, UK, that I became involved in mapping out the practical programme that is aimed at our younger, up‑and‑coming leaders in the field.

Duytschaever: I too have a long-standing association with the Atrial Fibrillation Symposium, having been to every event since the inaugural symposium in 2001.

Over the years, my involvement has increased, to the point where I now contribute to the development of the scientific programme.

What are the advantages of having a joint practical and advanced programme?

Ernst: From the beginning, I felt strongly that in a fast-changing field, where new technologies and techniques are regularly trialed and validated, there is an educational need to gain practical experience to confidently perform new procedures as effectively and safely as possible.

A joint programme is an ideal way for consultants and senior fellows to implement their learnings from the sessions the moment they return to their clinical practice.

Duytschaever: When I first attended the Atrial Fibrillation Symposium, there were no practical sessions. In my opinion, combining practical and advanced sessions has significantly shortened the learning curve for training electrophysiologists. Rather than relying on a trial and error-like approach, young cardiologists now have an opportunity to train in a safe and controlled environment.

What have been the key advances shared during the symposium over the

years and how have they advanced treatment of atrial fibrillation?

Ernst: Advances in technology have revolutionised atrial fibrillation treatment. We are now able to assimilate ~10,000 data points to construct a highresolution, 3D electroanatomical map. Advanced mapping technology allows us to precisely target the cardiac tissue that is causing the arrhythmia, without causing collateral damage; such visual acuity also enables us to carry out the procedure without using fluorescence imaging. The use and practical implications of technology of this kind, working carefully on hand and eye coordination, were a main focus of this year’s

We need to educate our patients.

Unreliable sources of information can greatly increase anxiety, in particular in newly diagnosed patients.” practical sessions.

Advances such as these have allowed us to address key challenges in atrial fibrillation, each of which is associated with an educational and training need.

When I began my career, “curing” atrial fibrillation was an aspiration. Back then, we had a ~20% clinical success rate—now we are up to over 85% for cases of paroxysmal atrial fibrillation. So significant progress has been made, with the help of events such as the Atrial Fibrillation Symposium.

Duytschaever: During the first decade of the Atrial Fibrillation Symposium, the debate predominantly surrounded the need to electrically isolate the pulmonary vein. This is now beyond question. In my opinion, the major technological advancement over the past 10-15 years has been the ability to establish a durable pulmonary vein isolation, now considered a vital process

Atrial fibrillation

7

during catheter ablation. As a result, single-procedure freedom from atrial fibrillation has increased from 60% to over 85% in paroxysmal atrial fibrillation. Together with marked progress in cardiac imaging and patient selection, these advances are expected to improve ablation outcomes in patients with persistent atrial fibrillation.

What were your key highlights and learnings from this year’s symposium?

Ernst: One persistent problem we have had is a restricted view of the ablation site. Sessions from this year’s symposium have, however, demonstrated significant progress on lesion assessment, guiding how much energy we use, for how long, and where to perform the ablation. I was also interested to learn about new suturing techniques that reduce the risk of bleeding from the puncture site, a common complication that can affect up to 20% of ablation procedures.

Duytschaever: From a clinical trial perspective there was the new analysis, long-term follow-up and debate surrounding outcomes from the CABANA and CASTLE clinical trials, and the impact these studies have on clinical practice.1 From a practical perspective, I was particularly interested in the data surrounding electroporation and high-powered, short duration ablation, which appears to be the direction we are heading and preferable from an esophageal safety perspective. Finally, from a purely academic viewpoint, I was interested in the current thinking regarding the role of fibrosis in atrial fibrillation initiation and progression.

Finally, what are the key educational requirements in atrial fibrillation, now and for the future?

Ernst: One specific challenge we face when treating atrial fibrillation is that there is no margin for error.

One small mistake can have serious consequences. That knowledge informs the main educational challenge— how to train young clinicians safely and push them, without pushing them too far from their comfort zone.

Training the entire multidisciplinary team in as safe an environment as possible, and giving them specific scenario training, is also key to ensuring that in a high pressure, intense environment, the correct response becomes second nature. This is where the hands-on, practical sessions provide real, measurable and lasting value.

We also need to educate our patients. Unreliable sources of information can greatly increase anxiety, in particular in newly diagnosed patients. It is important that our patients are well informed on the ablation procedure itself and also the risk of more serious events, such as stroke and sudden cardiac death.

Duytschaever: From an academic perspective, our major challenge is to improve our understanding of the pathophysiology behind atrial fibrillation that is not mediated in the pulmonary vein. As mentioned previously, we have made great progress in securing durable pulmonary vein isolation, our next challenge is not how to ablate, but to understand where to ablate in patients with non-pulmonary-mediated atrial fibrillation.

Finally, we have to address under utilisation of ablative therapy in patients with atrial fibrillation. This can be achieved by informing both the patient as well as the referral centres on the major impact of catheter ablation on atrial fibrillation burden and progression.

The next meeting of the Atrial Fibrillation Symposium will take place 12–14 February, 2020, in Madrid, Spain.

Sabine Ernst and Mattias Duytschaever are both consultant cardiologists and scientific committee members of the practical and scientific faculty of the Atrial Fibrillation Symposium.

References 1. Marrouche N. Essential lessons learned from AF ablation mortality trials (ATAAC-AF, CASTLE-AF, CABANA. Atrial Fibrillation Symposium, Copenhagen, Denmark, 24–26 January, 2019.

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Interview

Profile

David Callans David Callans is associate director of electrophysiology at the University of Pennsylvania Health System and professor of medicine at the University of Pennsylvania, Philadelphia, USA. Here, he speaks to Cardiac Rhythm News about various aspects of his career, from clinical practice to teaching and research. He mentions his excitement about the potential for electroporation, the importance of mentors throughout his career, and what he considers to be the key unanswered questions in the field of electrophysiology. He urges his students to be passionate, to find something to investigate, and improve the field for the benefit of patients—something he strives to do on a daily basis.

When did you first decide on a career in medicine?

I decided early during college. I had gotten the idea that I wanted to be a psychologist, but was turned away from the “soft sciences” by early experiences in a sociology class. I always enjoyed science and was excited by my studies in biology, which naturally led to medicine. As it turned out it was an amazing choice. I am truly blessed by the opportunities medicine offers to interact with and help people. I continued to be really surprised by how rewarding both halves of my job are—taking care of people and teaching/investigating.

Why did you choose to specialise in cardiac electrophysiology?

I was drawn to cardiac electrophysiology by the strong charisma of my two most important mentors, Mark Josephson and Frank Marchlinski. They were excited about what they were working on, and their enthusiasm was infectious! I was fascinated in how much they could understand through interpretation of the ECG—an exercise which remains the soul of cardiac electrophysiology. All of this occurred in the days when electrophysiology was a purely intellectual pursuit. The present day of interventional electrophysiology is more exciting still.

What influence have these mentors had on your career?

I have been blessed by guidance from strong mentors.

Mark Josephson taught me so much electrophysiology, but more importantly so many life lessons. He stressed devotion to excellence and radical loyalty to your friends. Frank Marchlinski initially taught me how to write and was inspirational about using the EP lab to develop new concepts to further our field.

What are your current research interests?

I am interested primarily in the pathophysiology and treatment of ventricular arrhythmias. In my early career I did large animal research focused on mechanisms of VT and development of new ablation technology. Presently I am more engaged in clinical research regarding where ablation “fits” in the trajectory of advanced structural heart disease, how we can make ablation more safe and effective and the application of ablation in specific forms of heart disease (eg cardiac sarcoid). I am interested in these areas because there is so much at stake for patients with these problems.

What is the most interesting piece of research you have come across recently?

I am really fascinated by a collaborative study of investigators from Europe who mapped VT in healed infarction with the Rhythmia system (Martin R: Circ Arrhythm Electrophysiol. 2018;11:e006569. DOI: 10.1161/CIRCEP.118.006569). It is amazing how it

confirms much of the physiology of the VT circuit we guessed at, but had not previously been able to observe.

What is your proudest career achievement to date?

I am presently working on the sixth edition of the iconic Josephson textbook, Clinical Cardiac Electrophysiology: Techniques and Interpretations. The text is our bible for electrophysiologic investigation and it contains a treasure trove of amazing figures and Mark’s wisdom. It is not an achievement as yet, but I have worked out enough of the chapters to realise that I actually will complete it. I am so proud to have been entrusted with this work and so humbled by Mark Josephson’s intellect and insight.

What has been your greatest career disappointment?

I am disappointed that I (and we) have not learned more of the underlying mechanisms of the most important arrhythmia problems of our time: ventricular tachycardia (VT), especially how it relates to the sudden cardiac death syndrome and AF.

What is your most memorable patient case?

A patient I treated almost 20 years ago with several intrafascicular VT circuits in the setting of mixed cardiomyopathy. It was the first time I had encountered anything like this. He had multiple circuits of intrafascicular re-entry with variable exits. Although it was difficult for me to understand at the time, we were able to solve the puzzle and deliver a small, rational ablation strategy. I still see this patient and he has been free from VT recurrence all this time.

What do you think are the main challenges facing electrophysiology at the moment?

I am worried about the future of our field and of academic medicine in general. There are so many questions that we need to answer and although investigation continues with enthusiasm, there are two problems. First, the remaining questions are much more difficult than those we faced before. In the founding years of our field, observation in the EP

I think the most important development in the field of electrophysiology has been the discovery of pulmonary vein triggers of atrial fibrillation.”

laboratory provided direct answers to the questions of the day. It is unlikely that similar observation will lead to a deep understanding of the nature of atrial fibrillation. Second, and probably more threatening, protected time (as well as funding for physiologic research) is limited and the demands for clinical care are more pressing.

What are the potential solutions?

I am hoping that the solution to both problems is better cooperation between investigators with different skill sets. Many of our remaining mysteries are multisystem in nature, particularly in the interface between the heart and neural systems control. Reaching to expertise outside of medicine, machine learning, information technology, genetics etc. will also prove helpful.

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Fact File

There have been many! The development and refinement of substrate based ablation for VT in structural heart disease, the discovery of PVC triggered VF, our enhanced understanding of anatomy allowing treatment of LV ostial PVCs and mid-septal substrate based VT.

What do you consider could be the next breakthrough technology in cardiac rhythm?

I am very excited about the potential for electroporation. We have always wished for more powerful ablation technology, but until this development more power always has meant more capacity for damaging adjacent structures. Electroporation may be different in that different cell types have different susceptibilities—the myocardium (at least healthy myocardium, I am not aware of research in scarred myocardium) is much more susceptible than coronary arteries, the oesophagus or nerves.

What are your students most intrigued by in the cardiac rhythm world?

Interestingly, they are most interested in the same things that I was—SVT differential diagnosis is a great introduction to our field. Unfortunately, this is not such a big part of our life in the EP lab as it had been.

As a professor of medicine, what are the key unanswered questions in the field?

What has been the most important development in the field of electrophysiology during your career?

I think the discovery of pulmonary vein triggers of atrial fibrillation by Michele Haissaguerre leading to the development of AF ablation. AF ablation has completely changed our field, mostly for the better. It is really gratifying to be able to help patients that are suffering with severe symptoms of AF. Nonetheless, AF also remains a challenge because of our lack of understanding of underlying mechanisms.

You have been involved with the International VT symposium for over 10 years, what do you think has been a major advance in ventricular arrhythmias?

There is so much, I’m not sure I know where to start! We need to understand the genesis of VT circuits in structural heart disease. We need to understand the mechanism of AF (outside of PV dependent AF)—there are likely many different subtypes of AF. We need to understand the real impact of treatment of arrhythmias (both atrial and ventricular) in the contexts of the progression of the underlying disease processes that accompany them, particularly heart failure.

What advice would you give to someone starting their career in the field?

Be passionate! Find something to investigate and make our field better. There is so much that we still have to figure out!

Outside of medicine, what other hobbies or interests do you have?

I love cooking (and eating!). I am a very slow adult learner of the fascinating game of tennis. I love to travel.

If you had not been a medical doctor, what would you have been?

Probably unemployed! I was interested in computer sciences, but I am really happy that I made the choice that I did.

Current appointments

Associate director, Electrophysiology, University of Pennsylvania Health System Professor of Medicine, Department of Medicine University of Pennsylvania School of Medicine

Medical training

2003–present: Professor of Medicine, Department of Medicine University of Pennsylvania School of Medicine 1999–2003: Associate Professor of Medicine, Department of Medicine University of Pennsylvania School of Medicine 1996–1998: Associate Professor of Medicine, Department of Medicine MCP-Hahnemann School of Medicine 1993–1995: Clinical Assistant Professor of Medicine, Department of Medicine, University of Pennsylvania School of Medicine 1992–1993: Clinical Instructor of Medicine, Department of Medicine, University of Pennsylvania School of Medicine 1991–1993: Fellowship in Cardiology, Hospital of the University of Pennsylvania, Philadelphia 1989–1991: Fellowship in Cardiac Electrophysiology, Hospital of the University of Pennsylvania, Philadelphia 1987–1989: Resident in Medicine, Hospital of the University of Pennsylvania, Philadelphia 1986–1987: Intern in Medicine, Hospital of the University of Pennsylvania, Philadelphia 1982–1986: Doctor of Medicine, John Hopkins School of Medicine 1978–1982: Bachelor of Arts, University of Chicago (Biological Sciences)

Society membership (selected)

Heart Rhythm Society, Trustee, 2016–present Heart Rhythm Society, Education Committee chairman, 2013–2016 American Heart Association, Clinical Cardiology, Fellow, 2003 American College of Cardiology, Fellow, 1995

Research publications (selected)

Callans DJ, Wacker LS, Mitchell MC: Effects of ethanol feeding and withdrawal on plasma glutathione elimination in the rat. Hepatology, 1987;7(3):496-501.

Callans DJ, Marchlinski FE: Characterization of spontaneous termination of sustained ventricular tachycardia associated with coronary artery disease. Am J Cardiol 1991;67:50-54.

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Outcomes

Risk of life-threatening complications “minimal” when clinicians follow quality improvement programme Karim Abdur Rehman (Section of Cardiac Pacing and Electrophysiology, Cleveland Clinic, Cleveland, USA) and colleagues describe in Journal of American College of Cardiology a low incidence of life-threatening complications and no deaths resulting from atrial fibrillation ablation procedures at an established treatment centre in the USA. They note that “experience, volume, a quality improvement programme and proper back-up to deal with complications, have allowed excellent safety profiles and zero procedure-related death in more than 10,000 ablations over 16 years.”

ALTHOUGH CATHETER ABLATION to treat atrial fibrillation is generally considered safe and effective, reports of increasing rates of cardiac complications and deaths associated with the procedure in the USA prompted the authors to assess the incidence and outcomes of life-threatening complications associated with the procedure in a large US tertiary care centre with many years’ experience of performing catheter ablation.

In this prospective cohort study, Rehman and colleagues assessed all patients who were included in a data registry after undergoing atrial fibrillation ablation at one centre in the USA between 2000 and 2015, and identified those who had experienced life-threatening complications or death resulting from the procedure.

Of the 10,378 patients undergoing atrial fibrillation ablation during this time, 100 patients (0.96%) were found to have experienced life-threatening complications that occurred during the procedure, while in hospital or up to three months after the procedure.

The most common complications were pericardial effusion that required pericardiocentesis or emergent surgical intervention (n=57; 0.5%) and stroke (n=27; 0.3%). A few patients experienced vascular access problems with haemorrhagic shock (n=7), respiratory

failure (n=6), and myocardial infarction (n=3). Five of the patients (5%) experienced cardiac arrest as the result of a complication. There were no procedural deaths.

Pericardial drainage for patients with pericardial effusion was carried out in the electrophysiology lab with fluoroscopic and echocardiographic guidance, and patients were monitored overnight in the coronary intensive care unit. Seven of these patients (0.07%) needed emergent surgical repair for cardiac perforation.

All 57 patients requiring pericardiocentesis “recovered with no long term disability or surgery-related complications.” The investigators report that the rate of pericardial effusion “decreased from an average of 0.6% per year between 2000 and 2013 to 0.1%/year over the last 2 years of the study period.” They explain that this “correlates in clinical practice with the introduction of contact force sensing catheters.”

In this study a stroke was defined as “a neurological deficit lasting more than 24 hours with imaging, confirmed by a neurologist” and transient ischaemic attacks were not included. Of the 27 patients who had a stroke, most (n=25) had an ischaemic stroke, and six were diagnosed with stroke during atrial fibrillation ablation. Twenty-three of these patients experienced

residual neurological deficits. Rehman and colleagues note that the rate for stroke “decreased from an average of 0.9%/year during the years 2000–2006 to 0.1%/ year from 2007 to 2015 as practices evolved towards uninterrupted anticoagulation during ablation and an increase in the use of irrigated catheters.”

Of the seven patients experiencing haemorrhagic shock resulting from major vascular access bleeding, five needed urgent surgical intervention while two were managed conservatively. The authors point out that, of these cases, “six occurred between 2000 and 2008 while only one occurred after this period”.

According to the authors, respiratory failure that necessitated intubation was “secondary to pulmonary oedema (n=2), aspiration pneumonia (n=1), mediastinal haemorrhage (n=1), haemothorax (n=1) requiring surgical intervention and a neck haematoma (n=1) requiring emergent evacuation followed by a tracheostomy to relieve airway compression.”

Three patients experienced myocardial infarction due to left anterior descending artery dissection (n=1), right coronary artery ST elevation myocardial infarction (n=1) and air embolism in right coronary artery.

Cardiac arrest occurred in five patients who experienced procedure-related complications, due to cardiac perforation requiring emergent pericardiocentesis (n=3), respiratory failure (n=1) or a left anterior descending artery thrombus complicated by ventricular fibrillation (n=1).

The authors conclude that the very low risk of lifethreatening complications in their study “is most likely due to cumulative experience over the years in a high volume centre but may also reflect ongoing efforts to improve patient safety and quality of care including monthly meetings to discuss complications and interventions to reduce them, adoption of technologies which have improved the safety of the procedures and the availability of proper surgical and interventional back-up to deal with complications.”

His-optimisation may improve clinical and echocardiographic outcomes in advanced heart failure patients undergoing cardiac resynchronisation therapy

Pugazhendhi Vijayaraman (Geisinger Heart Institute, Wilkes-Barre, USA) and colleagues report in Circulation that optimising cardiac resynchronisation therapy by the use of sequential His bundle placing followed by left ventricular pacing (His-optimised cardiac resynchronisation therapy) improved electrical resynchronisation in patients with advanced heart failure.

Pugazhendhi Vijayaraman

ijayaraman and colleagues report that, while cardiac resynchronisation therapy is known to successfully treat many patients with cardiomyopathy, left bundle branch block (LBBB) and advanced heart failure, “as many as one-third of patients are nonresponders”. They note that “permanent His bundle pacing can result in significant narrowing and often normalisation of LBBB” and “is associated with dramatic QRS narrowing and left ventricular resynchronisation”.

The authors sought to “assess the feasibility and efficacy of His bundle placing followed by sequential left ventricular pacing (His-optimised cardiac resynchronisation therapy) to improve electrical resynchronisation in patients qualifying for cardiac resynchronisation therapy and evaluate clinical and echocardiographic response rates”.

Their retrospective, observational multicentre study included 27 patients

“In this series of patients, we are describing a novel approach to further optimise electrical resynchronisation by combining the concept of fused adaptive left ventricular pacing with His bundle pacing,” added the authors.

“His-optimised cardiac resynchronisation therapy resulted in more pronounced QRS narrowing to 120±15 ms (34% reduction) when compared with HBP alone (151±24 ms; 18%) reflecting improved electrical synchrony.”

Vijayaraman and colleagues suggest that “these preliminary findings from our study should be confirmed further by acute haemodynamic evaluation.

Modifying and designing new devices or lead-adapters to enable His-optimised cardiac resynchronisation therapy would be necessary to verify our hypothesis that His-optimised cardiac resynchronisation therapy would improve the response rate in most patients requiring cardiac resynchronisation therapy.”

V

with severe cardiomyopathy, with a mean left ventricular ejection fraction of 24±7%, and New York Heart Association (NYHA) functional class III or IV heart failure symptoms. Seventeen had underlying LBBB and five had intraventricular conduction defect with QRS duration ≥140ms, and five had complete atrioventricular block with LBBB escape rhythm. His bundle placing had failed to achieve normal QRS morphology and duration in all patients. Patients were treated with optimal medical therapy for three months before undergoing His-optimised cardiac resynchronisation therapy. Follw-up assessments occured at one month, three months and one year.

His-optimised cardiac resynchronisation therapy implantation was found to be a success in 25 patients (93%), four of whom had previously been unresponsive to conventional cardiac resynchronisation therapy. The

authors explain that electrocardiographic responses showed more significant narrowing of QRS duration to 120±16ms (p<0.0001 versus baseline, biventricular pacing or His bundle placing), while echocardiographic response showed that left ventricular ejection fraction improved from 24±7% at baseline to 38±10% during follow-up (p<0.0001).

In terms of clinical response, during follow-up, 21 of 25 patients improved by one NHYA functional class and did not experience hospitalisation because of heart failure. The investigators comment that “there was a significant improvement in overall NYHA class from 3.3±0.5 at baseline to 2.0±0.6 on follow-up”. Three of the four previous nonresponders to conventional cardiac resynchronisation therapy achieved clinical and echocardiographic response, with left ventricular ejection fraction increasing from 20±6% at baseline to 29±8%.

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Market insights

BIBABriefings

FGF-23 identified as a potential biomarker for atrial fibrillation WINNIE CHUA (Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK) and others report in the European Heart Journal that three clinical risk factors (age, sex, body mass index [BMI]) and two biomarkers (elevated BNP and elevated FGF-23) could be used to identify which patients should undergo further screening for atrial fibrillation (AF). Prior to Chua et al’s study, the relationship between FGF23 and AF was unclear.

The authors write that screening for AF in at-risk populations could identify those with the condition, allowing them to receive oral anticoagulation (and thus, reduce their risk of stroke). They add that known clinical risk factors for AF are used to identify patients who may benefit from undergoing screening but comment “these risk factors, individually or in combination, have modest predictive ability and their determination requires specialist knowledge, presenting a challenge for effective screening”. Furthermore, while biomarkers (in addition to clinical risk factors) have the potential to support community screening programmes, studies looking at AF biomarkers have been hypothesis generating and only involved single or a small selection of biomarkers. Thus, Chua et al report: “To enable a data-driven analysis of AF-specific biomarkers, we quantified 40 cardiovascular biomarkers in an unselected cohort of patients.”

Using data from the Birmingham and Black Country Atrial Fibrillation registry, they identified 720 patients with diagnosed AF or at least two CHA2DS2-VASc risks factors for stroke. The cohort was divided into “discovery” (215 patients no AF and 169 AF) and “validation” (129 patients no AF and 125 patients AF) programmes. Via forward selection process, three clinical risk factors (male sex, older age, and higher BMI) and three biomarkers (BNP, FGF 23, and TRAIL-R2).

However, while both BNP and FGF-23 were both robustly associated with AF, TRAIL-R2 was not—reduced TRAIL-R2 was associated with AF but there was no difference in TRAIL-R2

concentrations between patients with AF and those without AF. Chua et al observe that this finding confirms that BNP is a marker for AF and for atrial dilation.

However, they comment that “until now” the relationship between FGF-23 and AF was unclear.

They add: “As FGF-23 promotes myocardial remodelling and cardiac hypertrophy, it can cause or enhance hypertrophy-related ectopic activity and automaticity, leading to AF”.

The authors compared the efficacy of using clinical risk factors and biomarkers for identifying patients for AF screening with age alone and with only clinical risk factors. They found that the clinical risk factors alone performed better than age alone, adding: “The addition of biomarkers to the clinical risk factors resulted in a significant net gain in reclassification of 11.2% (35 correctly reclassified, 16 incorrectly reclassified; p=0.008) for patients who had AF and 6.5% for patients without AF (28 correctly reclassified, 14 incorrectly reclassified;

New AHA treatment guidelines for use of blood thinners with atrial fibrillation A new type of blood-thinning medications, non-vitamin K oral anticoagulants (NOACs), is now recommended as the preferred alternative to warfarin for reducing the risk of stroke associated with atrial fibrillation, according to a focused update to the 2014 American Heart Association/American College of Cardiology/ Heart Rhythm Society Guideline for the management of patients with atrial fibrillation.

TO REDUCE STROKE risk in appropriate atrial fibrillation (AF) patients, a newer class of anticoagulants known as non-vitamin K oral anticoagulants (NOACs) is now the preferred recommended drug class over

the traditional medication warfarin, unless patients have moderate to severe mitral stenosis or have an artificial heart valve. NOACs include dabigatran, rivaroxaban, apixaban and edoxaban.

“New scientific studies show that

p=0.021), yielding an overall Net Reclassification Index of 0.178 (p<0.001).”

“A simple assessment of age, sex, BMI, BNP, and FGF-23 can identify patients with AF, e.g. to enrich populations undergoing ECG screening.

BNP and FGF-23 may also be useful to stratify patients with AF,” Chua et al conclude.

BIBA Briefings

BIBA Briefings is a new platform that provides in-depth analysis of the latest market intelligence from BIBA MedTech Insights, reviews the latest technology developments, and looks at pipeline developments.

For more information about BIBA Briefings or BIBA MedTech Insights, please contact Merveille Anderson merveille@bibamedical.com

NOACs may be safer for patients because there is less risk of bleeding, and they may also be more effective at preventing blood clots than warfarin,” said Craig January, co-chair of the focused update published simultaneously in the American Heart Association journal Circulation, Journal of the American College of Cardiology and the Heart Rhythm Society journal, HeartRhythm.

Recommendations with the highest level of evidence have more than one randomised controlled trial reporting similar results, whereas the lowest-ranked recommendations are based on the clinical experience of experts. Along with the strong recommendation to use NOACs in favour of warfarin for many patients, the new guidelines recommend weight loss for overweight or obese patients.

Studies find that losing weight can reduce the health risks associated with or even reverse AF. It can also lower blood pressure (high blood pressure is often associated with AF).

New drugs are available to reverse the effect of NOACs (called reversal agents). These reversal agents, while used infrequently, are helpful when there are signs of severe bleeding caused by a NOAC or when a patient on a NOAC needs an emergency surgical procedure.

The new guidelines also suggest that NOACs could even be used in people at lower risk of stroke than previously thought. Although the evidence for this recommendation is not yet definitive, emerging research is beginning to suggest that the benefit of NOACs for reducing stroke risk outweighs the risk of taking them, said January.

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Studies

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Clinical News First patient enrolled in ICEAFIB clinical trial

A press release reports that the first patient has been enrolled in the ICEAFIB clinical trial (AtriCure). Following Investigational Device Exemption (IDE) approval by the US Food and Drug Administration (FDA), the first patient was treated by Niv Ad, at Washington Adventist Hospital in Takoma Park, USA. The trial will evaluate the safety and effectiveness of the cryoICE Ablation System for the treatment of persistent and long-standing persistent atrial fibrillation during concomitant open-chest cardiac surgery.

The ICE-AFIB trial is a prospective, multicentre, single-arm study of up to 150 patients at up to 20 US centres. The study will enrol patients with persistent and long-standing atrial fibrillation undergoing cardiac surgical procedure(s) for heart valve repair or replacement and/ or coronary artery bypass procedures.

The study defines persistent and longstanding persistent atrial fibrillation in accordance with the Heart Rhythm Society (HRS) 2017 atrial fibrillation expert consensus statement.

The cryoICE system in conjunction with an AtriClip left atrial appendage (LAA) occlusion device will be used to perform the Cox-Maze III lesion set in this trial. Primary effectiveness is defined as freedom from atrial fibrillation, atrial flutter, and/or atrial tachycardia lasting greater than 30 seconds and will be evaluated 12 months after the procedure.

Long-term effectiveness will be evaluated three years post procedure.

“Cryothermal energy has been a mainstay of surgical ablation for a long time. The ICE-AFIB IDE trial is the first of its kind designed to assess the safety and sustained effectiveness of cryothermal ablation as a standalone energy source for surgical AF ablation,” said Niv Ad, director of Clinical Research at Washington Adventist Hospital and the national principal investigator of ICE-AFIB. “While AtriCure’s ABLATE clinical trial confirmed that the usage of the Isolator Synergy Ablation System (radiofrequency ablation [heat]) when

CryoICE ablation probe

supplemented with select lesions created with cryothermal energy (cold) is an effective treatment for persistent and long-standing persistent atrial fibrillation during cardiac surgery, the ICE-AFIB trial is a unique opportunity to generate systematic clinical evidence on the safety and effectiveness of cryosurgery for the treatment of such patients,” said Michael Carrel, president and chief executive officer of AtriCure. “The ICE-AFIB trial is yet another testament to AtriCure’s commitment to and leadership in improving the lives of atrial fibrillation patients undergoing cardiac surgery.”

The cryoICE ablation system was 510(k) cleared by the FDA in 2009 for the cryosurgical treatment of cardiac arrhythmias by freezing target tissues, which creates an inflammatory response (cryonecrosis) that blocks the electrical conduction pathway.

First trial of in-heart micro device for left atrial pressure monitoring launched

Vectorious Medical Technologies has announced the initiation of the VECTOR-HF first-in-human (FIH) clinical trial, and the successful first “inhuman” implantation of the V-LAPTM monitoring device. A press release reports that the trial will enrol up to 30 patients in six European sites across Germany, Israel, Italy and the UK. It adds that VECTOR-HF is a prospective, multicentre, single-arm, clinical trial designed to assess the safety and performance of the V-LAP system in preparation for receiving the CE mark.

According to the press release, V-LAPTM sensory device is the world’s first digital, wireless, battery-less device that is able to communicate from deep within the body using high-resolution waveform morphology. Since the pressure of the heart’s left atrium is the earliest and most accurate real-time indication of heart failure exacerbation, the actionable feedback provided by the V-LAP will enable a significant improvement in ongoing management of heart failure patients. Once patients are implanted with the V-LAP, they will be able to measure left atrial pressure daily

Monitoring device

at home via an easy, noninvasive method using a small, portable external unit.

Implantation of the device in this first “in-human” trial was completed in just six minutes. It was fixated within the patient’s interatrial septum of the heart using a standard minimallyinvasive percutaneous procedure under fluoroscopy and echocardiographic guidance, with the application of local anaesthesia.

William T Abraham (Ohio State University, Columbus, USA) comments: “The increase of left atrial pressure is the most specific and earliest sign of impending heart failure exacerbation— long before clinical symptoms occur.

V-LAP’s unmet clinical need has been evident for years, and the cardiology profession will benefit greatly from the availability of technology that can provide this valuable indication noninvasively on a daily basis.”

Horst Sievert (CardioVascular Center Frankfurt, Germany), who performed the first implantation, states: “This technology will really change the way we manage patients with severe heart failure.

This is the first device that specifically enables us to monitor pressure within the left side of the heart—and because of its cloud-based system, we can access patient data on-demand, monitoring the atrial pressure and managing dosages, medications and overall quality of life consistently and remotely.”

The press release states that the V-LAP system was designed and developed

by Vectorious Medical Technology to provide better treatment for heart failure. It is described as a simple, minimally-invasive device implanted into the left atrium to monitor pressure, enabling easy-to-access data through a Cloud-based system. The Vectorious system intend to increase chronic heart failure patient quality of life and reduces readmission rates. With its user-friendly external home-unit, physicians can get daily ‘push button’ readings of patient haemodynamic pressure to provide early, accurate physiological indication of cardiac decompensation. This not only helps physicians save lives and cut healthcare and hospital costs, but also enables patients to enjoy ongoing, personalised care with an improved

quality of life.

First atrial fibrillation patient treated in US IDE study evaluating high power, short duration ablation catheter

Johnson & Johnson announced that Biosense Webster has enrolled and treated the first patient in its US Investigational Device Exemption study, which evaluates the company's QDOT MICRO Radiofrequency (RF) Ablation Catheter used for the treatment of symptomatic drug-refractory paroxysmal atrial fibrillation. The first atrial fibrillation patient was treated at NYU Langone Health's Heart Rhythm Center (New York City, USA), one of up to 30 centres participating in the study that will enrol up to 185 patients across the USA. “The delivery of 90 watts of RF power in a short, four-second ablation session is a significant advancement in the treatment of paroxysmal atrial fibrillation,” said Larry A Chinitz, electrophysiologist and director of the Heart Rhythm Center at NYU Langone Health, who treated the first patient in the study.

Current catheter technologies deliver RF ablation at an average power level between 20–40 watts and for a duration of 20–40 seconds. The QDOT MICRO RF Ablation Catheter, which is only available for investigational use in the USA, is the first to deliver 90 watts of RF power in a short, four-second temperature-controlled session. Its temperature control and micro-electrode technology is designed to provide more efficient and consistent lesion creation with advanced diagnostics.

"The QDOT MICRO RF Ablation Catheter is an example of the innovations we've been focused on developing to elevate the standard of care for patients with cardiac arrhythmias," said Uri Yaron, worldwide president of Biosense Webster.

The QDOT MICRO IDE follows the commencement of the STELLAR US Investigational Device Exemption study in November, which will evaluate the safety and effectiveness of the HELIOSTAR Multi-electrode Radiofrequency Balloon Ablation Catheter.

14

Mar

Product News AtriCure announces launch of the cryoICE cryoSPHERE probe

AtriCure recently announced that it has launched the cryoICE cryoSPHERE probe in the United States. The cryoSPHERE probe is the first device in the cryoICE family solely dedicated to blocking pain by temporarily ablating peripheral nerves.

The cryoSPHERE probe offers a unique 8mm ball-tip design, a bendable distal shaft, and an ergonomic handle to provide cardiac, thoracic, and general surgeons ease of use when applying the device to the targeted peripheral nerves to block pain. The launch of the cryoSPHERE probe demonstrates AtriCure’s commitment to continued innovation in Cryo Nerve Block Therapy (cryoNB).

“The addition of the cryoSPHERE probe to our pain management portfolio is a major breakthrough in cardiac and thoracic surgery,” said Mike Carrel, president and chief executive officer. “cryoSPHERE is the first of its kind, designed specifically to freeze nerves in the chest wall. With cryoSPHERE, surgeons can use cryoNB therapy to reduce their patients’ postoperative pain.”

The cryoSPHERE technology uses a unique freezing method to temporarily block nerves from transmitting pain signals. The block typically lasts several months, during which time the nerve regenerates, giving the body time to heal.

Because of the long-lasting nature of the therapy, physicians are adopting cryoNB as an adjunct to their pain management modalities, offering a unique solution for patients undergoing cardiothoracic surgery.

“Since incorporating the technique of a cryoNB in my thoracic surgical practice several years ago, I have seen a remarkable improvement in overall management of postoperative pain, postoperative recovery times, and patient satisfaction,” said Curtis Quinn, Cardiothoracic Surgeon, Elliott Health System, Manchester, USA. “The cryoSPHERE probe is an impressive new tool dedicated to managing pain in patients undergoing cardiothoracic surgery.”

Catheter, Sensor Enabled, which is helping more physicians integrate ablation with 3D mapping to advance the treatment of people with atrial fibrillation.

A new ablation catheter designed to help physicians accurately and effectively treat atrial fibrillation has been introduced. Abbott has received US Food and Drug Administration (FDA) approval of the TactiCath Contact Force Ablation Catheter, Sensor Enabled.

Similar to Abbott’s other sensorenabled mapping and ablation treatment catheters, TactiCath Sensor Enabled delivers more precise images of the heart overlaid with real-time electrical activity information. The catheter also utilises the advanced ergonomic design found in the company’s FlexAbility ablation catheter for superior reach and manoeuvrability during cardiac ablation procedures.

One of the most common cardiac arrhythmias in the world, atrial

New option available for physicians treating patients with atrial fibrillation Approval has been granted for Abbot’s TactiCath Contact Force Ablation

Abbott TactiC

fibrillation, can affect how efficiently the heart pumps blood through the body, causing symptoms such as dizziness, shortness of breath or lightheadedness.

The condition can also increase the risk of stroke. To treat conditions like atrial fribillation, physicians can use ablation catheters to scar tissue in the heart that is generating abnormal electrical signals and disrupting a patient’s natural heartbeat. As the number of patients receiving cardiac ablation therapy worldwide has grown, Abbott has prioritised ablation technology that adds efficiency and accuracy to ablation procedures. Abbott cardiac ablation technology is currently used to treat patients in more than 84 countries worldwide.

Not all ablation technology is the same, however. Physicians have started exploring the use of new tools such as “contact force” technology during ablation procedures to help them avoid applying too much pressure to heart tissue, resulting in complications, or insufficient pressure which may reduce the effectiveness of the procedure. In addition, Abbott has also invested in technology to improve the accuracy of cardiac mapping to support cardiac ablation procedures.

Over the last two years, Abbott has also launched the Advisor HD Grid Mapping Catheter, Sensor Enabled, and the FlexAbility Ablation Catheter, Sensor Enabled.

Calendar of events 17–19 March

EHRA: European Heart Rhythm Association – Annual Congress Lisbon, Portugal

www.escardio.org

Issue

19 44

Market watch

8–11 May

40th Heart Rhythm Society’s Scientific Sessions San Francisco, USA www.hrssessions.org

25–28 May

ESC: European Society of Cardiology Heart Failure 2019 Athens, Greece

31 August–4 September

ESC Congress 2019 together with World Congress of Cardiology Paris, France

www.escardio.org

3–5 October

Venice Arrhythmias 2019 Venice, Italy

www.venicearrhythmias.org

24–27 October

APHRS: Asia Pacific Heart Rhythm Society – 12th Scientific Session Bangkok, Thailand

2–5 November

XVI World Congress of Arrhythmias Buenos Aires, Argentina www.wsa-icpes.com

5–6 November

Europe AF London, UK

www.europeaf.com

www.aphrs2019thailand.com

www.escardio.org

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