COMMENTARY

Jul 2, 2021 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

July 02, 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 July 2, 2021, John Mandrola, MD comments on the following news and features stories.

Note that This Week in Cardiology will take a break next week to celebrate America’s Independence from Britain.

New interns and fellows started yesterday. July 1 reminds me of why I love being a doctor—perhaps now more than ever. The greatest thing about this job is that we are paid to help people. Whenever I get down, I try to remember that. Helping people comes in many forms: You can help people with ablation, stents, valves, pacers, and medications. But the main way we can help people is even simpler: it is to care. Just by caring, we help. Congrats to the new doctors.

COVID

Another week has passed, and again, COVID-19 case counts in the United States remain super low. Some local areas, such as Springfield, Missouri, are seeing surges, however. These are areas with low vaccination rates and high obesity rates. This is exactly as my moonlighting pulmonology friends say: in rural areas, there are still folks in ICUs and they are all unvaccinated.

I led the podcast with a note about American independence. Well, sometimes, said rebelliousness is counterproductive. The story from Missouri depresses me because it would be awful to repeat the stress of 2020 in the hospitals and community. The good news is that I have seen no evidence that the Delta variant is escaping protection from vaccines.

COVID Vaccine-Induced Myocarditis

JAMA cardiology published two more case series of myocarditis. One was a case series of 23 male patients in the military who developed myocarditis within 4 days of receiving mRNA vaccines. 20 of 23 cases occurred after the second shot. All patients had significantly elevated cardiac troponin levels.

Duke University authors report on seven cases of myocarditis, four of whom had been given an mRNA vaccine in the days before. Three were young men, and one was a 71-year-old woman. All four had significant troponin elevations, severe chest pain, and positive MR scans.

I realize this a contentious issue and I’ve discussed it the last 3 weeks. But this week, I’ve put my thoughts into words, in a column on theHeart.org | Medscape Cardiology. I would be grateful if you all took a few minutes to read it. I discuss:

  • the nature and implication of myocarditis;

  • the stats of COVID-19 risk vs myocarditis risk in this age group;

  • the arguments for and against vaccination;

  • the role of shared decision-making among parents and teens;

  • implications of absolutism in vaccinating this segment of the population.

One of the things I worry about is whether the absolutism in discussion of vaccines (anyone asking questions gets tarred as antivax) and the downplaying of myocarditis in the young mixes with American rebelliousness and fierce independence to impede vaccine uptake. I work in Kentucky and I see all sorts of people; some respond to empiricism, others not so much. I am not saying I could do it better, but gosh, sometimes I think the public messaging in the pandemic could be humbler and more nuanced.

Type 2 Diabetes in Kids

Two studies presented at the American Diabetes Association meeting struck me as concerning. While I am not a public health doctor, a pediatrician, or diabetes specialist, my heart sank when I read the headline: 'Staggering' Doubling of Type 2 Diabetes in Kids During Pandemic.

I realize that type 2 diabetes (T2D) is one of those conditions, like hypertension, that is being broadened by a lower bar for normal, but an increasing incidence of metabolic disorders in kids is an obvious concern for those of us who treat lifestyle related heart disease, such as atrial fibrillation (AF) and coronary artery disease (CAD). The studies, one from a group in Washington, DC, the other from Louisiana, were both observational and ecological—ecological, meaning, they compared a chunk of time before and during the pandemic.

  • Both studies found that the rise in T2D during the pandemic wasn’t only in outpatients, both groups noted increases in hospitalizations for serious diabetic issues, such as diabetic ketoacidosis.

  • Both studies found disparities based on race, with African American kids more adversely affected.

Based on my estimate from my clinic, namely, that nine out of ten patients have gained weight and lost fitness during the last year, it seems highly unlikely that these were statistical aberrations. Why wouldn’t kids without in-person school, gym classes, sports, and time with friends eat more junk food and gain weight like my adult patients?

I highlight these sobering studies for two big reasons:

  • In the last year and a half, communicable diseases have rightly garnered most of our attention. But it’s not as if non-communicable diseases stopped. Any amount T2D in kids seems like an urgency to me; but when that incidence doubles, it seems like an emergency. What do public health experts think will happen in 10 to 20 years?

  • These studies underscore the harms of an intervention. A patient asked me this week: Doc, what if I didn’t do this procedure? What would happen? Before answering with the specifics, I told the patient that I loved this question because too few doctors consider the counterfactual of not intervening. That is largely because, we, me included, have an optimism about our healing powers. We have intervention bias.

The pandemic interventions are a shining example of harms from interventions. No doubt early in 2020, it was totally reasonable to err on the side of caution and shut down schools and day care facilities. But at some point, and we can argue about when that was, we learned that children were at substantially lower risk from the virus. Private schools opened; so, basically, for the rich, pandemic life was much less disrupted than for the less well off. Not only did pandemic interventions cause harm to children, in the matter of increasing diabetes, these two studies support something that should have been obvious: kids with less means were harmed more by interventions.

The point here is not so much the rightness or wrongness of lockdowns and school closures (it was a once and lifetime pandemic after all); it is simply to remember to always think about the harms of intervening and the counterfactual of not intervening—a perfect lesson for July 1 new doctors.

Optimal Medical Therapy in CAD

A study published recently addressed the question of optimal medical therapy (OMT) in patients with stable CAD. Stable CAD is another way of saying the person has atherosclerosis of the coronary arteries. That is, of course, a systemic disease.

I have a strong bias that systemic diseases do best when treated with systemic, not focal, therapies. In the case of stable CAD, oodles of properly run and powered RCTs have shown no advantage to revascularization of focal lesions when added to conservative approaches using OMT.

My question to you all is this: what shall I do when an utterly flawed study is published in a legit journal by well-known experts that supports my bias? Should I gloss over the methodologic flaws and say, see, I told you, OMT is great? Or should I take the opportunity to point out why the study cannot be used to say anything useful. I will choose the latter.

Authors of the SYNTAX trial, which was an RCT that the New England Journal of Medicine published in 2009, compared percutaneous coronary intervention (PCI) to coronary artery bypass graft (CABG) in 1800 patients with three-vessel CAD or left main coronary artery disease. This was a non-inferiority trial with a primary endpoint of death, stroke, myocardial infarction (MI), or repeat revascularization over 1-year.

  • The primary endpoint was way worse in the PCI arm -- 17.8% vs 12.4% in the CABG arm -- and SYNTAX therefore did not show noninferiority of PCI to CABG.

  • The negative result was driven mostly by repeat revascularization and the rates of death, stroke, or MI taken together were similar.

I looked on the clinicaltrials.gov site and counted 36 subsequent substudies of this trial. One noteworthy trial was the 10-year results of all-cause death. Published in the Lancet in 2019, 28% of patients had died in the PCI arm vs 24% in the CABG arm, hazard ratio (HR) 1.19 (0.99-1.43). The authors concluded no difference but the bulk of the HR was well above 1 and went as high as 43% worse for PCI.

The current study sought to assess the impact of the status of OMT at 5 years on 10-year mortality after PCI or CABG—did patients in either arm do better if their OMT was optimized?

The degree of OMT was defined as how many of the big four classes of medication a patient was on: antiplatelet, statin, ACE/ARB, and beta blocker. The authors stratified the available patients (about 1400) at 5 years by number of drugs and then did a landmark analysis out to 10 years.

  • Patients on ideal OMT at 5 years had a significantly lower mortality at 10 years compared with those on ≤ two types of medications (13.1% vs 19.9%; adjusted HR: 0.470; 95% CI: 0.292-0.757; P = 0.002)

  • Patients on three drugs had mortality close to those on four drugs, at about 12.9%. So, it was really those on less than two drugs that did worse.

  • Antiplatelets and statins seem to be the most important drugs, especially in those randomized to the CABG arm.

The authors concluded: In patients with three-vessel and/or left main disease undergoing percutaneous coronary intervention or CABG, medication status at 5 years had a significant impact on 10-year mortality. Patients on OMT with guideline-recommended pharmacologic therapy at 5 years had a survival benefit.

The editorialists said: These observations are extremely important in reaffirming the synergistic and beneficial effect of OMT on long-term mortality in patients undergoing revascularization with either CABG or PCI.

Do you see the problem? These are causal verbs. Good OMT had a significant impact. Patients on good OMT had a survival benefit. These observations reaffirm the beneficial effect of OMT. But this is a huge problem: my friends, whenever, authors do a post-hoc study and use patients from an RCT, mixing groups and looking at something other than the endpoint, it is a nonrandomized observational analysis. And you can’t easily make causal conclusions from this.

  • OMT in this trial was not mandated by a protocol; it was left up to the doctors taking care of these patients. That means a clinician had to decide to prescribe one, two, three or four drug classes. Patients on fewer meds may have been on fewer meds because they were sicker and that is why they did worse.

  • Another sign of worry: patients receiving an antiplatelet drug and statin who underwent CABG showed a significant mortality reduction, though this benefit did not extend to PCI-treated patients. Conversely, beta-blocker use was associated with a reduced mortality in those undergoing PCI.

  • These are strange and counter intuitive observations because there are no trials in stable CAD that have demonstrated a benefit from beta blockers. And why would statins and antiplatelet drugs not help those with severe CAD who had PCI but beta-blockers would? Likely answer: play of chance.

  • Finally, there was a lack of precise data on the extent of OMT use after 5 years. Did the OMT at 5 years continue for 10 years? You’d think that if you were going to propose the importance of medical therapy, you’d want to know not what they started on at 5 years but what they took from years 5 to 10. At most, you could say that there was an association between patients well enough to be on three or four classes of drug at 5 years and death rates at 10 years. But that is it.

Thus, there was incomplete data, medical decisions left to discretion (with likely confounding) and other evidence of spurious findings.

Yes, I still believe OMT is important, along with lifestyle modifications, but I will not cite this paper due to its methodologic flaws. I would go so far as to say that the citation and promotion of flawed analyses to support a point of view may actually reduce trust in any future points one tries to make.

Alcohol

Canadian cardiologist Christopher Labos has an excellent blog debunking the myth that alcohol is cardioprotective. As an AF doc, I field a lot of questions about alcohol intake. For AF, three sets of observations seem clear:

  • In populations studies, any amount of alcohol associates with an increase in AF.

  • In an elegant recent RCT, alcohol cessation in patients with AF reduces AF burden.

  • In basic physiology studies from the University of California San Francisco group, acute alcohol intake promotes pro-fibrillatory changes and increases the odds of AF episodes.

What I like about Labos’ take is how he debunks the French paradox about red wine. The French Paradox, he writes, like most medical paradoxes, is a statistical anomaly and is most certainly not true. The French may have lower rates of cardiovascular disease and the French may drink lots of red wine, but they are unlikely to be causally linked.

  • If you have been to a France, one confounder is obvious: the French walk and cycle a lot more than Americans.

  • Labos notes other issues with red wine: it is in fact grape juice and full up with simple carbohydrates. Reducing alcohol means reducing calories, which is a good thing.

  • Another paradox he writes about are the observational studies that find nondrinkers tend have higher risk than moderate drinkers. Again, you have to think about collider biases—many nondrinkers were former drinkers who have other reasons for not drinking, say liver disease, AF, diabetes, etc.

  • When you mix nondrinkers with never drinkers you are at risk for sick-quitter effect—people don't get sick because they abstain from alcohol; they abstain from alcohol because they got sick.

I agree with Labos’ main conclusion that alcohol should not be considered a health food. It is an indulgence, one with negative health effects, especially when taken in excess. Don’t get me wrong, indulgences are fine; they make life more fun.

I will see you all in two weeks. For my American listeners, have a great and not too rebellious Independence Day holiday.

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