COMMENTARY

Apr 23, 2021 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

April 23, 2021

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.

In This Week’s Podcast

For the week ending April 23, 2021, John Mandrola, MD comments on the following news and features stories.

First, a meta comment. I’ve occasionally said words like “This podcast has long felt....” or This Week in Cardiology believes....”

What I mean to say is that I feel that way. TheHeart.org | Medscape Cardiology hosts the podcast, but the opinions expressed our mine, and I take full responsibility.

COVID Stats and Vaccines

The Johns Hopkins site shows that the United States and European Union 7-day average is moving down again. Michigan is also in a steep decline in cases. Even Canada seems to have plateaued and may be heading down. This is very good news—and most experts agree it is due to the effects of vaccination.

I went back and looked at the Moderna and Pfizer vaccine papers in the NEJM and the results are truly amazing. In cardiology, we are used to 20% to 25% relative risk reductions. This often requires displaying the Kaplan Meier curves with a truncated y-axis, otherwise you can’t see the difference. Go back and take a look at these effect sizes. Professor Zeynep Tufekci wrote about the recent CDC paper describing an outbreak in a Kentucky nursing home in which the vaccine had greater than 85% efficacy. “Here was a worst-case scenario: elderly, congregate living, a variant with mutations associated with partial immune escape. And still, the vaccine was protective at a level that stood up to the trials.” This massive effect size is one way I’ve been persuading vaccine-hesitant patients who have COVID risk factors.

Obviously, the trouble spot now is India. Our thoughts are with our colleagues and their families there.

Cardiac Findings Post-COVID in Athletes

The day after this podcast dropped last week, Circulation published a large observational study from 42 universities and more than 3000 athletes who tested positive for SARS-CoV-2. Lead author was Nathanial Moulson from the Massachusetts General group led by Aaron Baggish. Their objective was to determine the prevalence and clinical implications of SARS-CoV-2 cardiac involvement in athletes who are elite enough to compete at the collegiate level.

This was an important study. Data were collected during 4 months at the end of 2020. The primary outcome was the prevalence of definite, probable, or possible SARS-CoV-2 cardiac involvement. Secondary outcomes included the diagnostic yield of cardiac testing, predictors for heart involvement, and/or adverse cardiac events.

The Massachusetts General Hospital was the study center, but the evaluations of the athletes were done at the individual institutions.

The choice of evaluations was also determined by docs at each of the 42 institutions—this included triad testing: ECG, troponin, and transthoracic echocardiogram. Cardiac magnetic resonance (CMR) imaging was done when felt to be indicated. Thus, this study was a pragmatic real-world collection of observations.

The background here is important:

  • Post-viral myocarditis existed long before COVID-19. It isn’t a common condition, but for a cardiologist, it isn’t rare either.

  • Myocarditis can cause arrhythmia and is on the differential diagnosis of syncope and sudden death of athletes, albeit very low on the differential. Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in young athletes.

  • This past summer, two CMR studies, one in patients recovered from COVID and the other in a small cohort of athletes, found scary-high percentages of “cardiac involvement.” Fear garners attention and one of these studies, by Puntmann and colleagues, published in JAMA-Cardiology, has 900,000 pageviews and 564 citations. Concern over these early findings led to the cancellation of organized sports and the development of expert consensus recommendations.

  • The problem is that the early studies were extremely flawed. The paper by Puntmann and colleagues had clear math errors and required a correction; they also included in their statistical analysis normal control CMR scans rather than just risk-factor-matched controls.

  • Subsequent studies in young people with COVID, from numerous groups, found a lower incidence of cardiac involvement.

  • And millions of people worldwide have been infected with SARS-CoV-2 and I have seen no reports of increasing heart failure cases due to myocarditis.

Results of this latest analysis by Moulson and colleagues were reassuring. In the overall cohort, 137 of 3000 (4.5%) athletes who had any form of cardiac testing had an abnormal test; 59% of these had SARS-CoV-2 related findings; 41% of the 137 had non-viral findings such as Wolff-Parkinson-White syndrome, atrial-septal defect, bicuspid aortic valve, dilated aorta, HCM.

  • Abnormal findings by ECG: 0.7%

  • Abnormal findings by ECHO: 0.9%

  • Abnormal troponin: 0.9%

In all, 198 of the 3000 athletes had CMR; 60% of scans were for indications, the others were done for screening. Recall that decisions for testing were left up to the docs at the centers. This allowed the authors to correlate findings with the reason for the scans.

Definite, probable, or possible SARS-CoV-2 cardiac involvement was found in 21 of 3018 athletes (0.9%) who underwent CMR (15 of the 21 had CMR because of concern over triad findings on ECG, troponin, or ECHO) and 6 of 21 positives had had screening CMR. The diagnostic yield for CMR was 4.2 times higher for clinically indicated scans vs screening scans. After adjustment, predictors for SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (odds ratio 3.1), and abnormal triad (odds ratio 37.4).

Clinical outcomes: No patient with definite, probable, or possible SARS-CoV-2 involvement on CMR had an adverse cardiac event. Five athletes required hospital admission for non-cardiac complications of COVID-19. (sub-massive PE, pleural effusion, palmar desquamation secondary to multisystem inflammatory syndrome). During 3-month follow-up, one athlete had a resuscitated cardiac arrest but CMR showed no findings suggesting of viral myocarditis and the authors deemed this non-COVID related.

Authors’ conclusions: The first finding of this paper–namely that cardiac evaluation post COVID conducted according to guideline recommendations—suggests CMR done based symptom burden and triad testing had a diagnostic yield for definite, probable, or possible cardiac involvement of 0.5%. Screening CMR found definite, probable, or possible SARS-CoV-2 cardiac involvement in 3.0% (95% CI:1.1,6.5). Thus, the lower and upper estimates for cardiac involvement by CMR in this study are bounded by 0.5-3.0%. But of course we don’t know the clinical significance of CMR findings.

Clinical predictors of SARS-CoV-2 cardiac involvement on CMR included cardiopulmonary symptoms and any abnormality on triad testing suggestive of SARS-CoV-2 cardiac involvement. A step-wise approach that used the presence of moderate severity or cardiopulmonary symptoms or any abnormal triad test to trigger a diagnostic CMR would have identified 9 of 11 (81.8%) athletes diagnosed with definite or probable heart involvement.

The caveat is that 3 of 6 athletes who had screening CMR with definite, probable, or possible cardiac involvement were asymptomatic or had mild symptoms and normal triad findings. In other words, symptoms and triad testing did not perfectly predict an abnormal CMR.

But the authors also qualify something I’ve said often on this podcast: CMR isn’t always specific. These authors also found isolated late gadolinium enhancement or abnormal T1 data, age indeterminant markers of myocardial fibrosis, or abnormal tissue architecture, in a small number of athletes with no other features suggestive of acute SARS-CoV-2 cardiac involvement.

The authors labeled these findings as “possible cardiac involvement,” but without control groups they can’t be sure these were causally related to COVID-19.

Remember, only one of these athletes had a severe clinical outcome and this patient did not have findings on CMR suggestive of viral myocardial involvement. And the denominator was >3000 athletes with documented infection.

In Sept 2020, in the midst of the scare over cardiac effects of COVID in athletes, I signed an open letter to professional societies in the United States and Europe that expressed caution over the use of CMR. This study—especially its reassuring clinical outcomes—and the other studies that preceded it support our take that a stepwise, common-sense approach to CMR testing is most appropriate.

The idea of sending asymptomatic or minimally symptomatic young people who do not have notable findings by ECG, troponin, or ECHO into an MR machine is terrible times 1000. Most young people scanned will not be part of a Mass General-sponsored study and would be at severe risk of iatrogenic harm from cascades and overzealous risk-averse doctors.

This doesn’t mean we should stop the study of post-COVID patients, but until we have proper control groups, use of CMR should be reserved for situations in which it would change management or research.

AF Ablation and Pulmonary Vein isolation

Circulation EP published a small but elegant study from a group at Copenhagen University Hospital. This was an RCT of 98 patients with low-burden paroxysmal atrial fibrillation (AF) who were assigned 1:1 to pulmonary vein (PV) isolation with either radiofrequency (RF) vs cryoballoon (CB) catheter.

The cool part of the study was that all patients went back for a repeat electrophysiology study at 4-6 months to assess the PVs. That’s a tough sell in the United States, because if a patient has a successful result, the risk,albeit small, of a study with a transseptal puncture is hard to justify. But the relationship between PV isolation and AF recurrence is an important scientific question.

The other notable aspect of this study is that all patients had loop recorder (ILR) devices implanted before ablation; these devices allow for near perfect detection of AF episodes. The primary endpoint was the number of durably isolated PVs. The study within a study was to correlate the effect of PV isolation durability on AF recurrence and AF burden. Those analyses were performed on the entire group of all patients.

A note on the patients. These were mostly thin males with small left atrial (LA) size, and pre-ablation the AF burden was 3%-5%. So, they were the absolute best patients to ablate.

The first finding was that durable PV isolation was similar with RF and CB: 76% of PVs were durably isolated in RF group and 81% in the CB group. This corresponded to 47% of patients in both groups with all PVs durably isolated.

Clinical outcomes were also similar in both groups. Seventeen (35%) patients in both groups had documented AF recurrence after the blanking period. But notably, both groups had average reductions of AF burden reduction of more than 99%.

Since the randomization was between RF and CB, the lack of difference is the most robust finding of the study. It largely confirms the FIRE AND ICE trial, which found no differences in clinical outcomes between RF and CB.

An important thing to note is that the Copenhagen group is a very experienced center and all ablation docs had done more than 1000 ablations. This was similar to FIRE AND ICE; the FIRE AND ICE principal investigator said that the operators in FIRE AND ICE were born to ablate AF. Why is this important? For external validity. Since the learning curve for RF is much longer than CB, a less experienced RF operator may not get the same PV isolation durability with RF and CB.

Now to the observational part of the study: Both RF and CB. AF burden after PV isolation significantly correlated to the number of durably isolated PVs but 9 out of 45 (20%) patients with durable isolation of all veins had recurrence of AF within 4-6 months after PVI (excluding a 3-month blanking period).

The word that comes to mind in interpreting this is parallax—which, roughly, means that the same image can look different depending on the position of the lens.

So, one way to view the correlation of durable PV isolation with AF suppression is that PV isolation is super-important, and we are on the right path. But the other way to see these results is that one in five thin male patients with low-burden PAF who had perfect PV isolation still had AF recurrence.

I fancy the more sober and humble viewpoint. You’d expect non-pulmonary vein triggers of AF in patients with more advanced atrial disease, but the fact that one in five patients in this cohort had recurrent AF despite PV isolation reinforces the mechanistic knowledge deficit we have with AF.

I get the sense that the authors agree with me. They cite “a large body of conflicting evidence regarding the importance of durable PVI.”

  • PV reconnection has been reported in 0% to 91% of patients without AF recurrence.

  • Durable PV isolation has been reported in 0% to 62% of patients with AF recurrence.

The authors suggest that one clinical implication of their study and the above inconsistency is that simply reisolating PVs in re-ablations in many cases will be insufficient to prevent any recurrence of AF.

I would go further: I would say that we as a field should be far humbler about the inelegance of this widely accepted and well-reimbursed procedure. Yes, it can in some patients reduce the surrogate measure of AF burden on an ECG or implantable loop recorder, but

  1. we still don’t understand the mechanism of AF;

  2. we have not reliably shown that this expensive, invasive, somewhat risky procedure improves hard clinical outcomes and that means it is done for quality of life improvements;

  3. We have not quantified the degree of placebo effect—which is surely large given the size of the caring signal an AF ablation puts out.

Bias Against Interventions

I’ve been getting a slight uptick in comments on theheart.org | Medscape Cardiology website. Thank you and please keep it up.

In the April 9th podcast I cited a meta-analysis of observational studies looking at transcatheter aortic valve replacement (TAVR) vs minimally invasive surgical AVR (SAVR). An interventional cardiologist took issue with my interpretation of this study and wrote:

John - I know that you enjoy pushing your narrative that TAVR is going to turn out to be inferior to SAVR but including this nonsense trial in your podcast is disturbing, and I can't help but to believe that it's only included because it "supports" your position. If the results had been reversed (ie it insinuated that TAVR had a lower midterm mortality) would you be mentioning it? Certainly not.

One of the studies that was used in the mortality data was a single center comparison of exclusively trans-apical TAVR vs mini SAVR. This data is useless and outdated. I've been involved with TAVR programs for 6 years now and have never seen a single TA case, and there is a lot of data that supports not using this approach.

It would be nice if you had a more balanced approach to your analysis of procedures that you are skeptical about, and perhaps included some discussion with colleagues that disagree with what you're saying.

First let me say that I love this comment. We need more of this in medicine. I welcome your rebuttals however strong.

Second, the great teacher of online discourse, Dr. Kevin Pho, teaches that it useful to read your harshest criticisms because there is often some truth there.

I went back and found that indeed it is true that when investigators used only the transfemoral TAVR studies, the relative risk for midterm mortality vs miSAVR was 1.77 and the CI ranged from 0.86-3.43 so, yes, statistically, the 77% increase was not statistically significant.

Third, I consider myself an outside observer of TAVR. In fact, as an EP doc practicing mostly EP, I am an outside observer of many aspects of Medicine. As a neutral Martian, I see TAVR as an amazing advance in science and a superb procedure for intermediate to high-risk risk patients. I often refer these types of patients to the structural team. But I also worry about the both the paucity and trends in the longer-term results of TAVR vs SAVR in lower-risk patients. I have practiced for 20 years, so I have seen my fair share of exuberance in procedures. My approach to any new therapy is a medically conservative one. In the case of the treatment of younger lower-risk patients with severe aortic stenosis, SAVR is the standard. The onus of proof that TAVR is superior or at least solidly noninferior in important outcomes like death, stroke, pacemakers, valve thrombosis over more than 1 to 2 years is on the proponents of TAVR.

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