Mar 10, 2023 This Week in Cardiology Podcast

John M. Mandrola, MD


March 10, 2023

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In This Week’s Podcast

For the week ending March 10, 2023, John Mandrola, MD comments on the following news and features stories.

Three Brief Comments on the ACC Meeting

The first thing to say about the American College of Cardiology (ACC) meeting was that it was nice to be normal again.

The second to thing to say is that I was surprised by the crowd. During the poster sessions, which were held alongside posters taped on boards, as they should be, attendance was decent. The opening session was standing room only. The press room was sparsely attended but media have learned that they can cover the meeting remotely.

Sure, it was New Orleans, which is a good place to have meetings, but maybe I was a bit premature in worrying about the demise of big meetings. We shall see at the European Society of Cardiology (ESC) and the American Heart Association (AHA) meetings.

Finally, I am grateful for all those who came up to me to offer thanks on the podcast. Seriously, every Friday I talk into a microphone and hope folks are listening. So, thank you times 1000.

Three Studies in Sports Cardiology

I want to start with Sports Cardiology news. I like sports. One of my biases has always been against overly strict restrictions on returning to play. Well, two late-breaking studies presented at ACC suggest that patients with significant genetic heart disease can return to participate — that is, with proper evaluation and follow-up.

Professor Rachel Lampert, an electrophysiologist at Yale, presented results of LIVE-HCM, an observational study of 1600 patients with hypertrophic cardiomyopathy (HCM) who aimed to participate in vigorous sport. (Of note, 8% were gene positive but had no obvious disease).

The modifier ‘vigorous’ and HCM usually don’t go together. For as long as I can recall, docs have been fearful of letting patients with these thick stiff ventricles exercise vigorously. At baseline, HCM associates with a higher risk of ventricular tachycardia (VT). We’ve long felt this risk is even higher with exercise.

  • Lampert and her colleagues broke up the 1600 patients into three groups—vigorous exercisers, moderate exercisers, and sedentary.

  • They then looked at event rates in vigorous vs non-vigorous individuals. The non-vigorous group included both moderate exercisers and non-exercisers.

  • The primary endpoint was death, resuscitated cardiac arrest, syncope due to arrhythmia, or an appropriate shock with an implantable cardioverter-defibrillator.

  • These occurred at very low rates and were not substantially different between the two groups.

Lampert said these data “do not support universal restriction of vigorous exercise in patients with HCM.”

In the same session, undergraduate student Katherine Martinez presented an observational analysis of 76 elite athletes with genetic heart disease who gained a return-to-play approval from four expert centers in the United States.

The most common condition was HCM followed by long QT syndrome. They had a three-step protocol: initial evaluation; frank discussion on risks and harms of playing; and informing of coaching staff. Athletes had to purchase a personal automated external defibrillator (AED), avoided QT prolonging drugs, and kept their follow-up.

  • Similar to LIVE HCM, with this three-step process, event rates were tiny. Only three athletes had non-fatal events, none of which were directly related to intense exertion.

  • Their take home was similar to Professor Lampert: When there was careful evaluation by experts and shared decision-making, a specific plan to return to sport can be put into place for the highest-level athletes with genetic heart disease.

Masters@Heart. This is a good one, too — a Belgian study of about 600 middle-aged adults recruited from an online survey, about the effects of lifelong exercise on coronary atherosclerosis. These investigators were interested in studying the coronaries of long-term endurance athletes. And boy did they study them.

Core to their study is the paradox of endurance athletics. We know that exercise lowers the relative risk of cardiac events, yet numerous imaging studies have found high rates of coronary artery calcium (CAC) in endurance athletes, especially those who run marathons.

They made three groups — lifelong exercisers, late-onset exercisers, and normal exercisers. (Of note, the control group had minimal atherosclerotic cardiovascular disease (ASCVD) risk factors, took few meds, and had 122% of normal VO2 max.

The main findings were:

  • Lifelong exercisers had a significantly higher CAC burden than controls, which confirms previous work.

  • Lifelong exercisers had a higher percentage of multiple coronary plaques, plaques ≥ 50%, and proximal plaques.

  • There were no significant differences in the mixture of plaque types in the three groups. About two thirds of the plaques in each group were calcified and the remainder were deemed non-calcified or mixed.

  • When looking only at non-calcified plaques, lifelong exercisers tended to have a higher prevalence of multiple plaques, plaques ≥ 50%, and proximal plaques.

  • So named “vulnerable” plaques were extremely infrequent in all three groups.

  • The authors concluded that lifelong endurance sport relative to a generic healthy lifestyle was not associated with more favorable coronary plaque composition.

This is surprising, isn’t it? Two quick thoughts. When I was in training in Indianapolis– Indy was a hot bed of amateur sports — our cath lab conference frequently featured cases of runners and cyclists with bad disease. Now, decades later, I’ve known fellow racers Who have had myocardial infarctions (MI). The question in the group is always, how did that happen? Well, this data is at least somewhat supportive.

The main limitation, of course, is that images of coronary arteries are surrogate markers. It’s possible that more calcification is protective in that it creates more stable plaques. We definitely need more data on outcomes.

One final comment: the authors propose a J-curve wherein being sedentary or engaging in too little exercise increases risk, but at the other extreme, perhaps too much exercise also increases risk. That’s an attractive thesis, but it’s very speculative. I can cite at least one study that shows former Tour de France riders have great outcomes.

Another problem with this theory is that even if it’s true, I don’t think many lifelong endurance athletes like me would modify our behavior. Because for most of us, we do this because we can’t not do it. Almost no one I’ve raced with did it because it was a healthy endeavor.

Clear Outcomes

I realize that I have spoken about bempedoic acid (BA) for the last couple of episodes, but hear me out. We learned about outcomes of BA at ACC, and there is more to talk about than just the CLEAR-Outcomes trial results.

  • 14,000 patients with heart disease or high-risk for heart disease and statin intolerance and high LDL.

  • The mean LDL level was 139 mg/dL.

  • BA reduced LDL by about 20%.

  • The major adverse cardiac event (MACE) composite primary outcome of CV death, MI, stroke, or revascularization was reduced by 13% (0.79-0.96) with a P of 0.004. Definitely signal not noise.

  • But the absolute risk reduction (ARR) was only 1.6% over 4 years, nd, there were no differences in CV death or all-cause death. The drug reduced only non-fatal outcomes.

  • Notable was that in the figure in the NEJM there were 4 Kaplan Meier (KM) curves, the primary endpoint (PEP); the three-component MACE; MI; and coronary revascularization. Why did I note it? Because these were the components that were reduced. CV death and stroke, both components of the PEP, were not included in the main figure. Nor was all-cause death.

  • Another factor pointing to a modest effect was that the baseline LDL was high at 139 mg/dL. The risk reduction going from a high level is going to be greater at higher levels. (It’s why there is more bang for the buck treating very high blood pressure [BP] than milder hypertension [HTN].)

Another non-statin drug, ezetimibe significantly lowered a MACE endpoint in the IMPROVE-IT trial, but the reduction was measly at 6%, perhaps because the starting LDL was lower at 94 mg/dL.

These statements speak to the modest effect size of BA, one positive is that the KM curves did separate gradually over time, consistent with the notion that the longer exposure to low LDL cholesterol, the greater the benefit.

Safety was mostly ok. BA has no effects in muscles, so myalgia-like complaints did not differ, but there were more cases of gout and cholelithiasis in the BA group.

Now what should happen? BA is already approved for use in familial hypercholesterolemia. Here is one worry: statin drugs have a much more robust evidence base, and a larger effect size in reducing MACE outcomes. They should be preferred.

But then there is the matter of statin intolerance. My friend, Bogdan Enache, an EP in Monaco, captured the sentiment many of his worry about in a (tongue in cheek) Tweet:

After years in which we minimized almost every account of statin intolerance, starting today statin intolerance is a very serious matter, that afflicts our patients and is a huge public health issue.#ACC23

In blinded randomized controlled trials (RCTs), and in the elegant SAMSON trial, there is convincing, I mean super-convincing evidence that statin intolerance almost doesn’t exist. In SAMSON, more than 90% of the symptoms of statin intolerance occurred during the months, patients took placebo tablets.

But now, Bogdan and I and perhaps you, too, are afraid that statin intolerance will become a marketing campaign. (Kind of like the “forgotten valve” campaign of tricuspid regurgitation [TR]). This would be bad for patients because statins are better and far less expensive.

Now I want to tell you about observations I made. Just the observations. You make the conclusions.

The principal investigator of CLEAR-Outcomes made two references during the presentation to a packed house in the main ballroom of the possibility of the combination pill of BA and ezetimibe. This he said could accomplish up to a 40% reduction of LDL, which is big. I didn’t think much of it. Then he said it again in the press conference.

Later that day, I was walking through the expo, cutting corners, looking at my phone, and almost walked into a car. Not just any car — a NASCAR adorned with the label of a drug called Nexlivet, a combination drug of, you guessed it, BA and ezetimibe. The company is Esperion, the same company that makes BA and sponsored CLEAR-Outcomes.

That’s it, no more comments. Just the observations.

In conclusion, we ought to discuss the evidence or lack of evidence for statin intolerance with our patients. We should resist the urge to easily succumb to more expensive drugs with far less evidence for benefit.

What a great segue to another trial with interesting interpretations.


ACC also brought the results of the TRILUMINATE trial of transcatheter edge-to-edge repair (TEER) vs medical therapy in patients with symptomatic isolated tricuspid regurgitation (TR) who were poor candidates for surgery.

Gina Kolata of the New York Times covered the results and here was her lede:

For the first time, patients with damaged tricuspid valves in their hearts might have a safe treatment that actually helps.

I don’t think so. And this one really frustrates me. I will try to keep it professional but this one tempts you to cynicism.

  • TRILUMINATE randomly assigned 350 patients, median age 78 years, 55% female.

  • Investigators chose a hierarchical composite PEP of death, need for tricuspid surgery, hospitalization for heart failure, or quality of life (QOL) as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).

  • The trial duration was 12 months.

  • Multiple other secondary endpoints were measured; one that I will come back to is the 6-minute walk test.

  • The results were positive. But Gina Kolata was likely wrong about a helpful treatment.

You have to go look at the components of the primary endpoint. No difference in death, need for tricuspid valve surgery, and no difference in hospitalizations for heart failure (HHF). Of the first three hierarchal endpoints, we are negative. The only difference was a better KCCQ delta in the surgery group. KCCQ scores how a patient judges their own well-being.

The authors analyzed the data with a win-ratio. It’s a sort of new statistical technique that estimates the likelihood that one or the other treatment is "better," but the more serious events are given higher priority and are analyzed first. And it was positive in favor of TEER. But only because of the KCCQ. As I have said, none of the other endpoints were positive. Even the 6-minute walk test did not differ.

  • The fatal flaw here is that there was no placebo. Patients in the surgical arm knew they had an invasive procedure. Patients in the medical arm knew that they did not have one.

  • As a limitation, the authors cited the Hawthorne effect as a possible explanation. But I don’t agree. The Hawthorne effect occurs when people change their behavior because they know they are being observed. The KCCQ questionnaire asks people how they feel about their own well-being.

  • I’ve discussed the necessity of placebo effect many times. I mean we have the reversal of transmyocardial revascularization, internal mammary artery ligation, pacing for hypertrophy cardiomyopathy, and even percutaneous coronary intervention (PCI) of single vessel disease (ORBITA).

There was some discussion on Twitter about the difficulty or impossibility of doing a sham control. The PI of ORBITA, Dr Rasha Al-Lamee shut all of this down.

Of course we can do a placebo-controlled trial of a percutaneous procedure like this. We owe it to our patients to stop producing unblinded data that, in my humble opinion, does not inform clinical practice.

What really bothered me about this story is that the authors surely know the importance of placebo effects when including a QOL PEP but they still chose the design. The buzz from the conference and obviously in the New York Times was that TRILUMINATE was a positive trial. TEER offered hope to patients with TR.

But that’s not what I see. Not at all. The KCCQ difference could easily have been placebo effect.

The stakes here are super high because of the epidemiology of TR. It’s common in older patients. It’s often load-dependent and hard to grade.

TRILUMINATE is a pre-market approval study and the US Food and Drug Administration will have to decide on approval. If they accept these results and approve this device and Centers for Medicare and Medicaid Services creates a code for it, I am afraid there will be a deluge of low-value care. Sadly, and I don’t say this lightly, I really think regulators should say no.

Proponents might counter, but Mandrola, patients with TR feel terrible, we need to offer them something. To that I would say what I always say: the burden of proof is on the proponents to show me which patients benefit in a proper trial. Show me lower CV death, less HHF, or even a better 6-minute walk test against a placebo control.


Professor Divaka Perera from the REVIVED-BCIS trial presented a substudy of that important trial looking at the effect of myocardial viability, functional recovery, and PCI on clinical outcomes in the main trial.

Recall that REVIVED-BCIS is one of my picks for the most important trials of the decade. Of all the trials that showed the lack of benefit of PCI over optimal medical therapy (OMT) in chronic coronary artery disease (CAD), REVIVED-BCIS was the most definitive.

The main results were clear and totally upend the common practice of taking patients with new left ventricular (LV) dysfunction to the cath lab for assessment by coronary angiography.

Here is the main trial:

  • 700 patients were randomly assigned.

  • All had to have four things: A bad LV; multivessel severe CAD; the lesions had to be amenable to PCI; and there had to be large amounts of myocardial viability.

  • One group got PCI +OMT, the other group just OMT. Yes, they left these people untreated.

  • There was no difference in any outcome at 3.5 years. Not even LV ejection fraction. It was a shocker. Revascularizing large areas of viable myocardium did not improve LV function, on average.

This rocked the world of proponents of PCI. How could this be? One question: Within that trial, was there a subset of patients with just the right amount of viability that would benefit from PCI? That was the focus of this prespecified analysis of the main trial.

First, I will tell you how they did it, but then, please listen to the conclusions, which are disruptive to the status quo.

Viability was assessed in 3 ways: volume of hibernating myocardium, total volume of viable myocardium, and scar burden. They then correlated each of those three components of viability with outcomes:

  • Hibernating LV volume: No predictive effect on all-cause mortality or HHF.

  • Total Viable Myocardium: This was marginally significant for predicting the PEP.

  • Scar Burden: The adjusted composite-endpoint hazard ratio per 10% increment in scar burden was significantly increased at 1.18 (95% confidence interval, 1.04 - 1.33; P = .009). More scar meant worse outcomes. Scar burden seemed to be the best predictor.

Now for the Big Finding: Was there a treatment effect based on these viability parameters?

  • Answer: No. The extent of myocardial viability, regardless of viability definition, did not highlight any group with a reduced risk for death or HHF, or a group with better LV functional recovery, from OMT + PCI compared with OMT alone.

  • There was also no treatment effect on LV recovery. IOW no viability parameter affected PCI vs OMT.

Crazy, isn’t it? No group did better with PCI. Not those with tons of myocardial viability, not those with low scar burden.

Conclusion of the Authors: PCI did not improve prognosis or LV recovery in ischemic cardiomyopathy (ICM) compared with OMT regardless of viability characteristics at baseline.

Conclusion of me: the main trial results hold up. This study fails to find a HTE wherin you can select out ICM that will improve with PCI. No, you can’t.

What is more, this finding is similar to the STICH sub-analysis, in which they also found the presences of viable myocardium was not associated w long-term survival in a trial of CABG vs OMT in patients with ICM.

So, not only does this not disrupt the practice of bringing patients with LV dysfunction to the cath lab for angiography assessment, it also calls into question the whole notion of myocardial viability testing. Gosh, we have spent a lot of time and effort with viability for predictive purposes, and looks to be a heap of waste.


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