Feb 4, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD


February 04, 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 February 4, 2022, John Mandrola, MD comments on the following news and features stories.

Shunts and Clinical Trials

The lead story today has two messages: one small and specific, the other general and massive. The specific message deals with the efficacy of an interatrial shunt device for patients with heart failure (HF).

The Lancet has published the REDUCE-LAP-HF-2, a randomized, blinded, sham-controlled, multicenter trial of 626 patients with symptomatic HF, an ejection fraction (EF) of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mmHg while exceeding right atrial pressure by at least 5 mmHg. One group received a device that creates a shunt in the interatrial septum; the other group got a sham procedure.

The primary endpoint was a hierarchical composite of cardiovascular (CV) death or non-fatal ischemic stroke at 12 months; rate of total heart failure events up to 24 months; and change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 months.

There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8–1·2]; P=0·85) or in the individual components of the primary endpoint.

Steve Stiles wrote the news coverage. His second paragraph is superb:

Hopes were high, for example, for an investigational interatrial shunt implant (IASD System II, Corvia Medical) that promotes left atrial (LA) unloading after a 2017 trial and earlier research suggested it improved intracardiac pressures at exercise — a goal of some heart failure drug therapies — in selected patients with HFpEF.

  • The specific message here is that a device that is hemodynamically plausible and was found hopeful in small studies that measured surrogate endpoints (like intracardiac pressures) did not pass muster when compared against the sham control in a trial that measured important clinical outcomes.

  • But the incredible value of the randomized sham control study is the most important message here. Imagine where we would be without either randomization or sham-control.

First the randomization. Let’s say we just used observational data and compared a group that got shunted vs a group that did not, and then we did stats adjustment, and the group who got the shunt did better. We wouldn’t know if the shunt worked or if healthier patients got the procedure.

If this device was simply compared to meds and the shunt device did better, we would never know if the procedure had a placebo effect, or the meds had a nocebo effect, or both. That is why when you want to show if a device is effective the best test is a randomized controlled trial (RCT) against a sham. If not for the ORBITA sham-controlled trial of single-vessel percutaneous coronary intervention (PCI), we would still believe that PCI and stenting relieved angina and increased exercise time.

In Steve Stiles’ story you will read about how proponents of this device want to divert your attention to some subgroups that may benefit. You will read this from principal investigator Dr Sanjiv Shah: “We hypothesized that if we enriched for responders based on screening echo and invasive exercise hemodynamics, we would find the right group," that is, patients with an HFpEF phenotype that might respond especially well to treatment with the interatrial shunt device.

Do not be distracted. The trial showed no average effect. No signal. None. Any subgroup analysis is purely speculative and to me most likely a spurious chance finding. Regarding the notion of finding a population of responders, this is possible, but the onus is on the proponents to show us a group of patients that succeed in a proper sham-controlled trial. Thus far they haven’t.

Chronic Stress

This podcast has never covered a study from Nature Translational Psychiatry. But thanks to the Portuguese edition of Medscape, I was alerted to a paper looking at the issue of chronic stress.

My AF clinic is full up with these folks. CEOs, engineers, lawyers, doctors, nurses, many of whom have been divorced once or twice. They exude chronic stress. They look inflamed—not in an infectious way, in an angry way. They look older than their stated age.

I’ve long been interested in this relationship of chronic stress and health. I say that because we’ve all seen older patients who look younger than their stated age. I often ask them probing questions as to how they accomplish this. Almost always they say their lives are low in stress. They are married, living below their means, have a big happy family, don’t smoke, don’t drink too much etc.

The research paper was from the Yale department of Psychiatry; first author Zach Harvanek. The endpoint is something called – and I am not making this up — GrimAge. It estimates an epigenetic clock by combining many biomarkers, and previous studies have shown such measures predict biological age and mortality.

The authors recruited more than 400 volunteers to assess the impact of cumulative stress, stress physiology, and resilience on accelerated aging. The study is complicated and some of the P-values are barely significant but here are the three main findings:

  • Cumulative stress was associated with the acceleration of GrimAge and stress-related physiologic measures of adrenal sensitivity (cortisol/ACTH ratio) and insulin resistance (HOMA).

  • Psychologic resilience factors moderated the association between stress and aging, such that with worse regulation of emotions, there was greater stress-related age acceleration, and with stronger regulation of emotions, any significant effect of stress on GrimAge was prevented.

  • Self-control moderated the relationship between stress and insulin resistance, with high self-control blunting this relationship.

In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge acceleration, even when demographic, physiologic, and behavioral covariates were accounted for.

I can’t dissect this sort of study in the way I can dissect a pure cardiology study; the findings fit my priors, so I could be deceived. But still, these results make us think a lot about the non-procedural, non-pharmacologic factors that could help us help our patients. We can’t just tell people to reduce their stress, or change their personalities, but we can recognize the importance of lifestyle, life choices, and coping techniques. This study doesn’t tell us what to do. But it does remind us that health stems from far more than pills and procedures.

Anxiety, Neuroticism, and Cardiac Risk

The Journal of the American Heart Association published a related type of observational study, comprising about 1500 men from a longitudinal cohort study. The authors studied the association between two anxiety facets — neuroticism and worry — and cardiometabolic risk (CMR) factors. I had no idea that one can measure neuroticism and worry, but I guess you can, with something called an Eysenck Personality Inventory‐Short Form.

Longitudinal studies let researchers measure variables at baseline and over time, and then make correlations between these variables. It’s called regression but it’s basically correlations or associations. The main results:

  • Higher neuroticism and worry levels were associated with elevated CMR across time.

  • Neuroticism was associated with 13% and worry with 10% greater risk of having six or more high‐risk CMR markers, adjusting for potential confounders.

  • The authors concluded that anxious individuals may experience deteriorations in cardiometabolic health earlier in life and remain on a stable trajectory of heightened risk into older ages.

Again, we should not make any causal assumptions that being neurotic and anxious leads to cardiac disease via higher cardiometabolic risks. And you can’t just tell people to be less anxious or neurotic. But stress and how one handles stress is likely quite relevant to vascular health. Clinicians would do well to not ignore it.

One thing that absolutely positively drives me bananas is when clinicians contribute to neuroticism and anxiety with our words or actions. So much of what an electrophysiologist does is remove fear and anxiety. People have plenty of things in their lives that lead to anxiety. Our words should not be one of them. The thing that depresses me most about our profession is when we augment fear and anxiety of the people we are charged with helping. It took me a long time in my career to be aware of how much damage we can do in our messaging. I am still no bedside guru. I am far from perfect. But a little voice in my brain goes off every time I begin to explain an issue: John, how are you going to arrange your words and posture so as to heal, not harm. To all my young listeners, please be super careful with your words. They have immense power to both heal and harm.

Transcatheter Aortic Valve Replacement

The journal JACC-Interventions has published a report from the Bern TAVR registry from 2012-2019. The purpose of the study was to investigate the rates, predictors, and prognostic impact of technical success in patients undergoing transcatheter aortic valve replacement (TAVR).

About 1600 patients were stratified according to VARC-3 technical success. VARC-3 stands for the Valve Academic Research Consortium.

VARC-3 success requires four outcomes:

  • Freedom from death;

  • Successful access, delivery of the device, and retrieval of the delivery system;

  • Correct positioning of a prosthetic heart valve into the proper anatomical location;

  • Freedom from surgery or intervention related to the device or to an access-related or cardiac structural complication.

This seems quite reasonable. Here’s the thing that surprises me: one in 10 patients (11.6%) undergoing TAVR with contemporary devices and techniques experiences technical failure, according to this reasonable definition. This is especially worrisome because patients not achieving success had significantly higher rates of CV death and stroke.

Now I realize it’s 2022 and this study went through 2019, but still, I suspect the surgical failure rate is not one in 10. This sobering finding further reiterates my contention that TAVR has been fantastic invention, especially for patients in whom surgical risk is intermediate or high. But when we start moving to lower-risk patients, registry data like this must be taken seriously. Perhaps things have improved over the past 2 years, let me know if I am off base here, but it seems like when it comes to replacing aortic valves in patients who could have this done surgically at low risk, we would want ironclad evidence that TAVR is just as safe and efficacious—not just in trials, but in real world registry data.


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