Mar 24, 2023 This Week in Cardiology Podcast

John M. Mandrola, MD


March 24, 2023

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In This Week’s Podcast

For the week ending March 24, 2023, John Mandrola, MD comments on the following news and features stories.

Fitness and Longevity

This podcast has long promoted the benefits of exercise. Any exercise is good, but exercise that increases fitness is surely better. My level of evidence for this is not based on trials. It could never be based on trials, because how can you randomize people to be sedentary? So, we have to rely on observational studies. The problem with these studies is confounding.

The Journal of the American College of Cardiology (JACC) has published a beautiful example of this. The authors studied veterans who had multiple exercise treadmill tests (ETTs) over the past 20 years. This included about 93,000 mostly males.

  • The authors assessed exercise tolerance at baseline and follow-up, and assigned individuals to quintiles based on their age-predicted fitness. Then they followed them for 6 years.

  • Cardiorespiratory fitness (CRF) increased by at least 1 MET in approximately 29% of the participants and decreased in approximately 46% of participants.

  • An increase in CRF of 1.0 MET or more from the initial evaluation was associated with a progressively lower mortality risk regardless of CRF status at baseline. Simple words. Gaining fitness was associated with better survival, no matter the baseline level of fitness.

  • A decrease in fitness was associated with a progressive increase in mortality risk, except in those with high baseline fitness.

The authors conclude: “These findings strengthen previous reports from comparatively small studies assessing sequential CRF by a standardized ETT and by a recent large study using self-reported fitness assessments.”

Comments. I love exercise. Likely you do too. I tell my patients that daily exercise is like a super drug. It helps the mind, the body and, if there is a soul, that too. But, when I wear my Stop and Think, Science Hat, I am not sure about these sorts of studies.

It’s tempting to believe, as the authors urge us to, “...that the structural and functional physiological changes resulting from participation in aerobic activities render an individual more resistant to injury or disease, ultimately resulting in lower mortality rates independent of genetic factors.”

Instead, I see this as a shining example of bias. No matter the ‘statistical adjustments,’ bias in that people who gain fitness are extremely likely to have “other” factors that lead to longer life. And conversely, those who lose fitness, surely have “other” factors that cause lower survival.

Also, this could easily be reverse causation, in that healthier people can gain fitness, while unhealthier people lose fitness.

So, as with coffee, blueberries, quinoa, sauna studies, the scientific enterprise could save resources by not doing these studies.

Exercise could be put in the no-smoking category. We don’t do studies on the risks of smoking and benefits of quitting because it’s not needed. Exercise goes in that category. Healthwise, normal daily exercise is like a parachute.

Sudden Cardiac Death in Sports

JACC has published an observational study from a European consortium of three registries of athletes in France, the Netherlands, and Sweden. The investigators, first author, Orianne Weizman, sought to assess the incidence, characteristics and outcomes of women presenting with sports-related sudden cardiac death (sr-SCA). The findings surely inform screening policies.

  • Over a decade, these registries documented 34,000 episodes of sudden cardiac death (SCD) with 760 (2.2%) related to sport. This included only 54 women.

  • Incidence of sr-SCA in women was 0.19 per million; in men it was 2.63 per million. That’s more than 13 times higher in men.

The authors concluded: “These findings emphasize the dramatically lower risk of sr-SCA in women compared with men, despite similar subject characteristics. This should be considered in designing preparticipation screening strategies in the future.”

Comments. Anne Curtis and Jan Tijssen wrote the accompanying editorial. It’s worth a read.

  • They make the point that in overall populations, women have a lower risk of sudden death. These findings parallel that. Interesting also, is that in the risk of SCD increases with age in men but not in women.

  • Another perhaps tangentially related sex-related difference in sports cardiology, is that women athletes seem not to have the increased risk of atrial fibrillation (AF) with high levels of exercise that men do.

  • Adrian Elliot and colleagues published a study in the European Heart Journal in which they looked at the UK biobank and found that the association between physical activity and incident AF declined in females up to 5000 MET-min/week, whereas there is a clear signal from their’s and other’s studies that high levels of exercise in males associates with higher AF risk.

This makes me think there must be reasons for these sex-related differences in the arrhythmic risk from sport. Things such as differences in substrate, degree of atherosclerosis, ischemia, plaque rupture, or even the protective effect of estrogens.

But I would not spend too much time on why. I think this study, as well as many others cited in the paper and editorial, confirm a lower risk of sr-SCA in women. This is a good thing.

The two main conclusions I would make:

  • We should absolutely promote exercise in women in men.

  • And crucially, since the net benefits of pre-participation screening is extremely dubious in men, given the 13 times lower rate of SCA in women, we surely should not recommend pre-participation screening in women.

Always remember those 2x2 tables we learn in medical school. When you are dealing with such a low-incidence condition as SCA in women athletes, the vast majority of positive screens would be false positives, which, are horrible because they cause direct harm to healthy people.

EVOLUT Three Year Data

The ACC meeting brought news about transcatheter aortic valve implantation (TAVI) vs surgical aortic valve replacement (SAVR), specifically the 3-year results of the EVOLUT trial in low-surgical risk patients with severe aortic stenosis (AS).

I’ve discussed TAVI vs SAVR many times. One of my main concerns is long-term outcomes. And that is why it’s good to have 3-year results. Registry data shows that TAVI has now surpassed SAVR for AS.

It’s sort of understandable, right? If you can get the same results with TAVI, patients will obviously favor the less invasive procedure. And it doesn’t hurt that cardiologists control the patients, and we do love our procedures.

In high-risk patients, there is no argument. But I’ve long worried that acceptance of TAVI in lower-risk patients has outstretched its evidence. The teaser here is that the EVOLUT data was encouraging for TAVI. Before I tell you the 3-year results, let’s briefly do some basics.

There are two types of TAVI – balloon expandable and self-expandable. One of my colleagues favors the former, and another colleague favors the latter. Of course, anatomy often plays into the decision. The EVOLUT trials studied self-expanders. It measured death and stroke as primary endpoints. These are good endpoints.

Other differences in the two procedures (TAVI and SAVR) include:

  • Time of recovery;

  • Paravalvular aortic insufficiency (AI);

  • Hemodynamics (or how well it opens);

  • Ease of coronary access – to do coronary angiography after a self-expander requires putting a catheter through the cage before entering the coronaries;

  • Leaflet thrombosis and structural deterioration;

  • Heart block and need for perm pacing.

Now let’s talk about the original EVOLUT trial.

  • About 1400 low-risk patients with AS were randomly assigned to TAVI or SAVR. Mean age 74.

  • This was a noninferiority (NI) trial.

  • Results were tricky to interpret because they analyzed 2-year data when half the patients had reached 1 year. I know that sounds weird.

  • At 24-month follow-up, data was available for 72 patients in the TAVR group and 65 patients in the surgery group. That’s only 10% of patients in each group.

  • Stroke or death occurred 5.3% of TAVR and 6.7% of SAVR. That 1.4% absolute risk reduction (ARR) was good enough for a > 99% chance of NI. But it was hard to make much of these Kaplan Meier (KM) curves because so few patients had been followed for 2 years.

JACC published the 3-year data, which looked reassuring. For the primary endpoint, the TAVI held a 2% ARR at 2 years, and 2.9% ARR at three years. Close your eyes and imagine the 1-year KM curves that continue the same separation at 3 years.

This is good for TAVI proponents, because in the balloon-expander trials, specifically the 2-year results of PARTNER 3, low risk the stroke/death curves came together at 2 years.

Now the important secondary outcomes that I mentioned above.

  • In EVOLUT 3 years, TAVI held an edge for hemodynamics, aka, better opening, lesser gradients.

  • Mild AI was much more common with TAVI, but moderate to severe AI did not differ.

  • Pacemaker placement was also much higher in the TAVR arm (23.2% TAVR vs. 9.1% SAVR).

Comments. The primary endpoint data is reassuring but low risk patients who are 74 years old have a far greater timeline than 3 years.

Unknowns remain, such as valve longevity; and how much the higher rate of AI and pacers pull on long-term outcomes. I have come to love pacemakers because it such pure medicine, as in sick patients need our help, and pacers make them better, immediately. But avoiding heart block and permanent pacers is a huge advantage for SAVR. You don’t want a permanent device in your heart unless it’s necessary.

Covering access to the coronaries also seems like a big deal. My colleagues say it’s mostly easy to engage coronaries, but sometimes it is not, and if you are having an ST-elevation myocardial infarction (STEMI), that is not a small thing.

Bottom line: We have to be totally transparent with patients about the uncertainties beyond 3 years. In a perfect world, patients would get the benefit of advice from a totally neutral heart team. Do we live in such a perfect world? I am asking.

Nudging – Behavioral Psychology

I want to mention two studies from ACC that looked at nudging as a way to improve medical quality. The first trial looked at improving flu vaccination.

In the NUDGE -FLU trial, Danish investigators studied the effects of nine different types of nudging letters to Danish citizens. After excluding about 20% of citizens, nearly a million people were randomly assigned to receive these different letters. If you are into behavior psychology of the Tversky and Kahneman type you will love the study methods.

But first some background.

  • Recall that the IAMI trial found that flu vaccine given shortly after MI led to lower rates of major adverse cardiac events MACE at 1 year.

  • And the DANFLU-1 trial, reported at European Society of Cardiology meeting last year, found that elderly adults who received a high-dose quadrivalent influenza vaccine compared with a standard dose saw significantly reduced risk of death and hospitalization for influenza or pneumonia.

There can be debate as to the benefits of flu vaccine in healthy young people, but the evidence in older adults, especially those with heart disease, surely favors flu vaccine as a benefit. And the Nudge-FLU trial enrolled older adults.

The psychology of the letters was so cool. There was a standard informational letter; there were letters with gain-framing; letters with loss-framing; letters with collective goal-framing; letters with expert authority-framing; and letters with cardiovascular (CV) gain-framing.

For instance, the CV gain letter stated, “In addition to its protection against influenza infection, influenza vaccination also seems to protect against cardiovascular disease such as heart attacks and heart failure.”

  • The primary endpoint was receipt of influenza vaccination on or before January 1, 2023

  • The main results were depicted in a Forest plot as you see in meta-analyses.

  • The standout was CV-benefit framing letter. Most others hovered the null line of no effect.

  • Compared with usual care, influenza vaccination rates were higher in the group receiving an electronic letter highlighting potential cardiovascular benefits of vaccination.

  • But, the actual numbers were 81.00% vs 80.12%; a difference of 0·89 percentage points the p<0·0001.

Comments. I love the trial design. They studied different framing in a randomized controlled trial (RCT) design.

My favorite framing question is this: Before cardioversions in patients on dual oral anticoagulants (DOACs), we used to ask patients “Have you taken all your anticoagulant meds?”. Very few answered no. Then we changed the question: “In the last 3 weeks, how many doses of the anticoagulant have you missed?” Now we postpone a lot of cardioversions. I wish we were smart enough to do an RCT.

The point is that the arrangement of words matter a lot!

Another teaching point from this trial is the notion of how a tiny difference — less than 1% -- can result in a super-tiny P-value.

This is a statistically robust finding, but I struggle to understand how the difference between 81% vaccinated vs 80.12% is clinically significant. Big numbers in studies can lead to tiny P-values for very small ARR.

You can imagine that Denmark is probably a tough country to show benefits of nudging, because so many are vaccinated. If you tried this in a place with lower vaccination rates, you might get different results.

Lancet published this paper. It’s brilliant and worth a read.

Better Care HF. JACC published this pragmatic cluster randomized trial, from authors at NYU, comparing the effectiveness of two electronic health record (EHR)- embedded tools vs usual care in the prescribing of mineralocorticoid receptor antagonists or MRAs in patients with heart failure with reduced ejection fraction (HFrEF).

I like this trial, for many reasons. First is that I liken spironolactone as a secret weapon. It shouldn’t be because little old spironolactone has some of the strongest data there is in HF. In RALES, an RCT of patients with HFrEF, the inexpensive MRA reduced mortality (yes, mortality, not heart failure hospitalizations) by a whopping 11% in absolute terms.

The second reason I like this trial is that the EHR is over-wrought with alerts, and before anyone adds another one, it should be studied empirically. Good intentions are not enough when it comes to distracting doctors.

  • In Better Care-HF, cluster randomization involved the cardiologists.

  • One alert came up during individual patient visits in the right-hand column of the EHR and it had important information: systolic blood pressure, EF, estimated glomerular filtration rate, and potassium level.

  • Another EHR tool was a monthly automated message linking a loss of patients who met MRA eligibility.

  • The third arm was usual care.

  • Both e-tools worked.

New MRA prescribing occurred in 30% of patients in the alert arm, 16% in the message arm, and 12% in the control arm. These were significant.

Comments. We under prescribe MRAs, and we surely under-study policy interventions. So good on the investigators.

I would add one word of caution. The absolute number of prescriptions is an endpoint, but it is a surrogate endpoint. A better, but harder trial, would be to see if the patients in the e-alert category have better outcomes. I say that because prescribing MRAs requires labor and attention to detail. You have to check potassium, watch for drug interactions, and, while the drug performed amazingly in a trial environment, real-world use may be different.

Another Coffee Study

This study was a cross-over RCT of the acute effects of coffee consumption led by Greg Marcus at UCSF.

  • 100 volunteers who were willing to abstain from coffee for at least 2 straight days were recruited and fitted with ECG recording devices and step counters.

  • Individuals were randomly assigned to consume coffee or to avoid coffee for 2-day periods.

  • The primary endpoint was the number of premature atrial contractions (PACs)

  • They found no difference: 58 with coffee vs 53 without.

  • Premature ventricular contractions (PVCs) were higher on the coffee days but it was 154 vs 102. Given that humans have 100,000 heart beats per day, this is like .15 vs .10% PVC burden. It’s not clinically significant.

  • Caffeine consumption days were associated with 30 minutes less sleep, but again, wrist worn sleep monitors aren’t super accurate, and this was a secondary endpoint.

Comments. Caffeine is a drug. When it’s delivered in coffee, it is extremely pleasant. When it is delivered in energy drinks, not so much. Toxicity, of anything, even water, turns on dose.

We put huge burdens on patients with AF. We ask them to lose weight, exercise daily, attend to their sleep, reduce or stop alcohol.

What I take from this study, along with the mountain of reassuring observational data with coffee, is that patients can have their coffee, if it does not cause them trouble. And I will say this again, I don’t think we need more studies of coffee. Sleep, yes. Alcohol, yes. Even yoga. But I am satisfied with our knowledge base of coffee, which seems like one of life’s safest pleasures.


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