Mar 25, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD


March 25, 2022

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only.

In This Week’s Podcast

For the week ending March 25, 2022, John Mandrola, MD comments on the following news and features stories.

My Trip to Denmark

First, a few brief comments about my venture to Denmark last weekend. I went to speak to one of the younger research programs in Denmark, at Zealand University Hospital in Roskilde, about 20 miles west of Copenhagen. My topic: communication of science and use of social media. I went to teach, but my gosh, I am 100% certain I learned more than I taught.

Here are four of many things I learned:

  • To be a cardiologist in Denmark, you must complete a PhD. This explains the tremendous output of research from this small country. Imagine a world where all cardiologists spent years doing research: we’d be almost immune to being bamboozled by spin. I didn’t see any Watchman procedures.

  • Danes trust their government. Pause on that.

  • Danes really do focus on family, and value things like paying trainees a good wage, getting home for family dinner, and providing generous maternity leave.

  • All Danes get free health care, and to prevent delays, there is a law that if a GP refers a patient to a specialist, that specialist has 30 days to see the patient. And if the specialist recommends a procedure, they have 30 days to get it done. If not, the patient can go to a private hospital and the public hospital has to pay.

Thanks again to Drs Anne-Christine Hud Ruwald and Niels Eske Bruun for inviting me and for their incredible hospitality. Thanks also to Soren Diedrickson for the bike tour of Copenhagen and Uffe Gang and Camilla Asferg for letting me spend a day in a Danish electrophysiology lab.


Circulation has published an important trial of atrial fibrillation (AF) care called RAFT-AF. The trial was first presented last year during the American College of Cardiology (ACC) conference.

Canadian investigators studied the use of primary AF ablation vs rate control in patients with AF and heart failure (HF). It’s a massively important question because so many patients with AF have HF. This was a basic pragmatic trial, but its interpretation is hard.

Two brief background points:

It is often hard to know the sequence in patients with HF and AF. Did the AF cause the HF? If this is the case, then eliminating the AF with ablation will clearly help. However, AF may be a bystander, and if so, fixing the AF may do little to help.

Second, the CASTLE AF trial led by Nassir Marrouche, compared primary AF ablation and antiarrhythmic drugs in patients with HF. It found a dramatic benefit for ablation but, importantly, the Kaplan Meier curves took time to separate. This suggests that if the effects of ablation are real, they accrue over years.

(The two issues with using CASTLE AF as a prior are a) there were internal validity issues, like high lost to follow-up rates, and low event rates, so there is uncertainty in its findings; and b) CASTLE AF compared ablation with antiarrhythmic drugs (AAD), whereas RAFT compared ablation and rate control, so the comparators were different.)

Now to RAFT. In 21 centers, most of which were in Canada, patients with high-burden AF and New York Heart Association class 2-3 HF and increased BNP were randomly assigned to ablation-based rhythm control or rate control.

  • The primary outcome was a composite of all-cause death and all HF events with a minimum follow-up of 2 years. Secondary endpoints included quality of life (QOL), 6 minute walk test, and ejection fraction.

  • The trial began in 2011. It ran to 2018. The planned enrollment was for 600 patients. But they were only able to enroll 411 total.

  • In 2017, the Data safety monitoring Committee (DSMC) recommended enrollment be terminated and follow-up continued for a minimum of 2 years on all patients. The decision was based on lower than expected enrollment and perceived futility. They made this decision based on data from 363 patients.

Statistics professor Andrew Althouse has a great thread on details of this and I will link to it. Basically, the DSMC calculated that the trial had a 19% probability of concluding benefit if it finished. More on that in a minute.

But in sum, there were about 200 patients in each arm. Mean age 67 years, half were female.

Important components of the rate control arm: about one-third of the rate control arm had AV node ablation and cardiac resynchronization therapy devices. Heart rate control was targeted for less than 80 beats/minute at rest and < 110 beats/minute for the 6-minute walk test. This is aggressive (more on that later).

Here we go to the results:

  • The primary outcome occurred in 23.4% of patients in the ablation-based rhythm-control group and 32.5% of patients in the rate-control group (hazard ratio 0.71 95% CI (0.49, 1.03), P=0.066). In other words, the 29% reduction did not reach the threshold of significance. Confidence intervals that include 1”” include the possibility of no effect.

  • 34 patients died in the rate control arm vs 29 in the ablation arm. The Delta is 5 deaths. Sadly, the authors do not tell us the cause of these deaths. A table of cause of deaths would have been extremely helpful.

  • 48 patients had a HF event in the rate control arm vs 38 in ablation. Delta is 10 HF events (remember, this was not a blinded trial).

  • The authors also measured QOL outcomes and change in 6-minute walk test, which favor ablation, but I seriously discount these because of the lack of sham control.

Adverse events (AEs) are important. In the table of AEs, the authors list tons of bad things, some of which are unrelated to the treatments, including AF (it was an entry criteria), HF, and death (these were outcomes and already counted), and non-cardiovascular events, which are unlikely to be affected. This really bothers me. What we want to know about are AEs directly related to the strategy and not counted in the efficacy analysis.

What do you think the AF ablation AE event rate was? What do you quote patients? Get this: in RAFT AF, there was an 11% major complication rate of AF ablation; eight major bleeds, one iliac dissection, nine perforations or esophageal injuries, and one death.

This is an important finding and it also speaks to the downsides of ablation because if complications are this high in specialized centers in Canada, during a trial, you can be sure that they are that high in low-volume centers across the United States and Europe.

The authors conclusions varied depending on the place in the paper.

  • In the abstract, they wrote: “In patients with high burden AF and HF, there was no statistical difference in all-cause mortality or HF events with ablation-based rhythm-control versus rate-control, however, there was a non-significant trend for improved outcomes with ablation-based rhythm control over rate-control.”

  • In the discussion section, which far fewer folks read, they wrote more succinctly, “In this trial of patients with AF and HF, ablation-based rhythm-control did not significantly affect the primary composite outcome as compared to rate-control.”

They then go to offer possible reasons that statistical significance was not achieved. First is that ablation is not in fact better than rate control. Another explanation is that it was a type 2 error. A false negative. In other words, ablation was better but because of early termination and not enough patients there was not enough power to sort out signal from noise.

In support of the real signal idea is the fact that ablation of AF takes time to show its benefits in HF, as seen in CASTLE AF.

Here are my six take-home points on RAFT AF:

1) First on the trial stoppage for futility, go to S11 in the supplement. This shows that after 363 of 411 patients had been enrolled, in 2017, after 6 years, there were more events in the ablation arm. The hazard ratio (HR) was 1.32. So, the DSMC saw a 32% higher rate of events in the ablation arm.

The authors made some complex calculations that of course I don’t understand, but just look at the big picture: with the majority of patients enrolled, you have a 32% higher rate of events in the ablation arm. It seems unlikely that they were going to show benefit.

The corollary here is that 1 year later, with about 40 more patients, they went from a 32% harm in the ablation arm to a final result of 29% benefit in the ablation arm final analysis. That is a lot of positive results at the end of the trial. And maybe it is all due to the fact that it takes time to accrue benefit, or maybe it is just noise from an underpowered trial, but the swing is striking.

2) Another reason I think this is a null trial, as this podcast has discussed previously, HF hospitalization is a clinician-dependent decision. The trial is performed at ablation centers populated with ablation proponents. Clinicians know the treatment assignment. There may be a non-nefarious bias in having different thresholds for admission for ablation and rate-control patients.

Since the difference (10) was so small, a couple of decisions could have swayed the data.

3) The rate control arm called for very aggressive rate control. This could have biased against the rate control arm. In patients with permanent AF, the RACE II trial comparing lenient vs strict rate control found lower rates of bad outcomes with lenient rate control. It was a bit of a different population, but still, I find it quite hard to get HF patients to that low a rate.

4) The AE clearly favor the rate control arm. An 11% rate of serious complications with ablation is a crucial finding. It’s obscured in the AE table. There were only a handful of AEs directly related to rate control.

5) There will be soon be meta-analyses combining the AF heart failure trials. I worry about these. As I said, CASTLE AF compared two rhythm control strategies—ablation vs AAD. RAFT is different: ablation vs rate control. AATAC was ablation vs amiodarone.

6) Taken together, I see RAFT as a solidly nonsignificant trial for AF ablation vs the much simpler rate control.

This study does not change my status as a reluctant conservative AF ablation doctor. It should make us more aggressive about AF ablation. I remain worried that history will prove our exuberance of AF ablation as mistaken.

Transcatheter Aortic Valve Implantation (TAVI) vs surgical aortic valve replacement (SAVR)

I knew TAVI procedures had become more common, but I did not know that there have been more than 800,000 done in 65 countries. That is a lot. While transcatheter procedures have been an amazing advance, SAVR remains a proven procedure.

The question of the day involves (fairly) comparing these approaches so as to better inform our patients. To do that, we need clear and agreed upon endpoints for trials.

A group called the Valve Academic Research Consortium (VARC) met in 2021 and came up with numerous endpoints to assess bioprosthetic valve dysfunction. It’s the third time this group of experts have met, and the newest document, VARC-3, has proposed clinical endpoints such as mortality and neuro events (which are unbiased, and everyone agrees are important). They have also proposed some more controversial endpoints, such as rehospitalizations, valve-related thrombus, bleeding, myocardial infarction (MI), and new left bundle branch block (LBBB).

Recently, a consortium of heart surgeons published a rebuttal to some of these endpoints, which they say bias comparisons of the two procedures in favor of TAVI. Journalist Patrice Wendling has a nice recap on Medscape Cardiology. Here is my summary: VARC-3 proposes use of rehospitalizations. The surgeons say, come on, we know SAVR requires more recovery, and it’s expected to have higher early rates of readmission. I totally agree with them.

  • Take PARTNER-3: TAVI vs SAVR in lower-risk patients with aortic stenosis (AS). While every other transcatheter vs surgical AS trial used stroke or death as endpoints, PARTNER-3 mysteriously adds rehospitalizations in the primary endpoint and to the surprise of no one makes, TAVI look better in the short run. It makes no sense to use it in the primary endpoint comparing TAVI and SAVR, at least without a blanking period.

  • How to define valve thrombosis is another issue. Using the older VARC-2 definition, the PARTNER-3 low-risk trial showed a thrombus rate of 2.6% in TAVI vs 0.7% in SAVR. This is concerning because valve thrombus increases the risk of future valve dysfunction—a big issue in lower-risk patients expected to live longer.

  • The new VARC-3 definition raises the bar to call a valve thrombosis. Now you have to have clinically significant thrombus. This will decrease the number of thrombosis endpoints. But the surgeons make a good point: these subclinical thrombi seem important to measure because studies have shown they increase the odds of valve deterioration.

VARC-3 has recognized the need for permanent pacing as an important safety endpoint. That is good. Because higher pacer rates with TAVI is a downside, especially for lower risk patients. However, they did not include new LBBB as an important endpoint. I agree with the surgeons on their criticism of this. New LBBB is bad, because it creates dys-synchrony and increases the risk of heart failure due to HF with reduced EF.

Finally, I love TAVI. It’s a great procedure and it is iterating and getting better. But there are uncertainties—especially over longer-term follow-up in lower risk patients. SAVR is a well-established successful procedure. If we are going to compare the two therapies for AS, it ought to be fair. And the surgeons make excellent points.

Cerebral Vascular Disease (CVD) Is Similar to Coronary Artery Disease (CAD)

The American Academy of Neurology (AAN) has published a new guideline on treating stroke caused by intracranial atherosclerotic disease – this was based on a systematic review and meta-analysis. symptomatic large artery intracranial atherosclerosis (sICAS) is defined as TIA or ischemic stroke attributed to 50% to 99% atherosclerotic stenosis of a major intracranial artery. Therapeutic clinical trials of sICAS mostly include lesions of the middle cerebral, intracranial carotid, basilar, and vertebral arteries. Journalist Sue Hughes has great coverage of the lengthy document.

Here is what I was drawn to:

  • Recommendations related to percutaneous transluminal angioplasty (PTAS) and stenting are informed by several randomized trials that showed no benefit of PTAS (with either self-expanding or balloon-mounted stents) over medical therapy.

  • Three randomized controlled trials (RCTs) have shown a higher rate of periprocedural cerebrovascular events and death from PTAS and no benefit of stroke prevention during follow-up compared with medical therapy in patients with sICAS.

  • Instead, the AAN recommends antiplatelets, statins, and lifestyle modifications to prevent recurrent stroke in patients with high-grade stenoses.

I highlight this story because it is highly predictable if you consider atherosclerosis a systemic disease. Treatment of focal stenoses does very little to modify the systemic disease. And it is quite similar to the coronary situation. I wonder if neurologists will be more successful than cardiologists in ignoring the urge to “fix” local blockages with intervention.

Now of course the caveat here is that intracranial stenoses pose a far greater challenge to intervention—smaller vessels and more tortuosity. But in cardiology we have many more than three RCTs showing no reduction in hard outcomes with focal interventions outside the acute setting. Yet the practice continues.

Rhythm Control of AF

The Journal of the ACC (JACC), has published a small, non-randomized, convenience sample study of echocardiographic parameters, with the conclusion that “Management of AF should focus on restoration of sinus rhythm (SR) to induce anatomical and/or functional cardiac cavity reverse remodeling and reduce severity of functional regurgitation.”

Let me repeat the first part: Management of AF should focus on restoration of SR.

Let me tell you about the study, and then you will see why this conclusion sitting in a major journal is a problem.

  • French researchers studied 117 patients who were hospitalized for AF. They did serial second and third transthoracic echocardiography (TTE) at admission, 6 months, and 12 months.

  • Three groups were defined according to the type of management for AF and the cardiac rhythm at 12 months.

    • 47 patients had active restoration of SR;

    • 31 patients had spontaneous SR;

    • 39 patients remained in AF.

  • The authors report extensive amounts of data on third echocardiograms. The bottom line was that restoration of SR improved anatomical and functional parameters like lower bi-atrial and right ventricular volumes and improved left ventricular end-diastolic volume.

  • They also found that in the active SR group, there was less functional mitral and tricuspid regurgitation.

Comments. I want to start with the positives: this was a detailed paper with tons of echo data. It’s real-world data and I commend the collection and reporting of such data. My problems are the conclusions and here I blame the authors, editors, and peer-reviewers.

The editorial does a good job of pointing out some of the many limitations: small numbers, some dropout, multiple comparisons, and technical dependence of third echocardiogram on acquisition settings.

I would go further and point out the severe confounding. A clinician decided to pursue rhythm control. That decision was based on variables that were likely different among the groups. Table 1 of patient characteristics show oodles of differences, and these are just the variables that make the spreadsheet.

It shocks me that the peer-reviewers let the authors make causal conclusions from non-randomized comparisons of groups with that many baseline differences in baseline variables. It is likely that patients chosen for rhythm control or those who convert are inherently healthier and would have more favorable echos.

But that is not all. Echocardiographic parameters, especially these highly specific ones, are surrogate endpoints. I have never had a patient with AF mention their index of atrial volumes.

The decision to choose rhythm control in the patient in front of you is one of the most complex decisions we electrophysiology docs make. Yes, everyone agrees that SR is better; that is not the question. The question is whether the potential harms of intervention are worth the risk of trying to get to SR, because the path to the treasure of SR is like a mountain bike trail: it’s often populated with areas of “high consequence, and harm.”

I just don’t think echo parameters factor in the decision. If this paper were in an echocardiography journal and were free of therapy recommendations, I’d have far fewer objections. But here it sits in JACC with topline results urging clinicians to pursue rhythm control.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.