Jan 14, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD


January 14, 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 US health professionals only.

In This Week’s Podcast

For the week ending January 14, 2022, John Mandrola, MD comments on the following news and features stories.


Wow. I don’t know what to say. Previous attempts at xenotransplantation failed due to rejection. This time, the pig heart was seriously genetically modified to help prevent rejection.

Get this: Three genes associated with antibody-mediated rejection had been knocked out in the pig supplying the transplanted heart, and six human genes associated with immune acceptance of the organ had been inserted into the pig's genome. If this works — even over the short-term — it seems more a story about molecular biology and gene modification therapy than transplant.

I know it sounds crazy, and perhaps it is, but I always like to remind my younger listeners that when I was in training, biventricular pacing and atrial fibrillation (AF) ablation were not invented and, indeed, had not yet been conceived.

So, we shall see.

Weight Loss Drugs

As many of you know, I led off my best stories of 2021 with the fact that semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, produced significant weight loss in patients with obesity. JAMA has published a randomized controlled trial (RCT) comparing semaglutide — a once weekly injection — with liraglutide — which is once daily.

The trial enrolled about 340 patients: one group received semaglutide, the other received liraglutide and each had their own placebo. That was necessary because semaglutide is once weekly and liraglutide is once daily, so it would have been somewhat open label otherwise. The primary end point was percentage change in body weight.

  • The bottom line was that semaglutide produced a 15.8% decrease in weight from baseline vs placebo vs 6.4% with liraglutide.

  • Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide.

  • Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide.

We have to be careful here: As the authors lay out in the limitations section, patients knew their group assignment because liraglutide is once daily and semaglutide is once weekly. They didn’t know if they got placebo but it’s possible that those in the once weekly group knew they were in the semaglutide arm and if they had done any homework, would know that drug seemed more effective in previous studies. With this knowledge, they could have eaten less food. To overcome this open label problem the investigators would have had to use a double-dummy approach which would have meant giving patients in the semaglutide group dummy shots 6 days per week.

The other limitation is that the higher discontinuation rate with liraglutide may have been dose related, as it was used at a higher starting dose, which is according to prescribing information. Finally, data were missing for nine participants in the semaglutide group, ten in the liraglutide group, and seven in the placebo group. Recall that only a little more than 100 patients participated in the study, so this is not a small amount of missing data.

Comments. While the GI side effects are an issue, obesity is a major problem and these drugs hold great potential. As for dosing, which we discussed last week regarding once daily vs twice daily, a medication given by injection once weekly is going to outperform a medication injected once daily. Novo Nordisk, the makers of semaglutide, is studying an oral form of semaglutide for weight loss. This drug was originally approved for the treatment of type 2 diabetes in 2019. With GLP drugs and SGLT2 inhibitors, the world of cardiology and diabetology are continuing to merge. We cardiologists are going to have to get more comfortable in the diabetes space.

DOAC Coverage

In the United States, a large insurer, CVS CareMark, has excluded apixaban from its formulary. This is a huge move because oodles of American patients who take apixaban will need to switch to rivaroxaban or pay full cost for apixaban, and for the vast majority, perhaps 99% of the population, this is not feasible.

The layers of bureaucracy and the rent-seeking groups that our American healthcare system encourages defies easy explanation, but this is an especially egregious move by third party payers.

I know, I know, last week, regular listeners heard me criticize a flawed observational study that purported to show superior outcomes with apixaban compared with rivaroxaban.

  • My opposition to this move, which is clearly driven by profit motives, is not because I think apixaban is the superior direct oral anticoagulant (DOAC). It may be, but we simply don’t know that.

  • My opposition to this move is that the two drugs are different enough that this sort of non-medical switching is an overstep.

It is one thing to prefer one ACE or ARB or statin or beta blocker, but there are only two DOACs, and we ought not be forcing patients doing well on apixaban to switch. There’s too much uncertainty and differences in the medicines. Journalist Patrice Wendling has nice coverage of the details; do read her news coverage.

This story makes the podcast not just because it exposes the terribleness of non-medical rent-seeking entities into the doctor-patient relationship but also because it exposes the problems inherent in a healthcare system driven by profit motive.

To be sure, CVS CareMark is not evil. They are simply responding to incentives. The problem is almost never with industry, insurers, hospitals, or doctors. The problem is with a system that has broken incentives.

Of course, I don’t have policy solutions for American Healthcare, I only take this opportunity to remind listeners of the matter of tradeoffs. As the great Thomas Sowell famously said about policy: There are no solutions, there are only tradeoffs.

Having visited many cost-constrained healthcare systems in Canada, in the UK, in Poland, I like the tradeoffs in these systems better than those here in the United States, where corporations like CVS can cause millions of people to switch DOACS. There are no perfect healthcare systems; there are simply healthcare systems with different tradeoffs.

Vitamin D

Two more RCTs of vitamin D supplementation came out this week. Both studies looked at supplementing vitamin D in people without vitamin D deficiency.

  • In the study published in the Lancet, with 21,000 Australians and over 5 years of follow-up, there was no difference in the primary endpoint of all-cause mortality, nor any differences in cancer deaths or cardiovascular (CV) death.

  • The American Journal of Clinical Nutrition published a smaller Finnish study of older adults without vitamin D deficiency and also found that over 5 years, vitamin D supplements did not lower the incidence of major CV events or invasive cancer among older adults.

  • In 2019, the BMJ published a massive meta-analysis of 50 trials and 75,000 patients looking at vitamin D and found no reduction in all-cause mortality.

  • You also have the null findings from the 25,000-patient VITAL trial that I have covered previously.

My only question is why in the world are we still burning money on vitamin D supplement research? What I tell patients—about vitamin D is to go outside and play as much as possible. This is good for your health, and I don’t need to spend millions on an RCT to know it.

LAAC and Frailty

I have debated left atrial appendage closure (LAAC) as the antagonist, on four continents, and the first time, against Professor Horst Sievert from Germany, who is one of the world’s foremost proponents. He said in the question-and-answer session that the least likely patient to benefit from this procedure is the old and frail.

Now to an important paper published in Heart Rhythm by the Beth Israel group of Robert Yeh, Dan Kramer, and first author Allen Wang. They used Medicare fee-for-service claims to study patients older than 65 who had LAAC from 2016-2019. Patients were identified as frail based on the Hospital Frailty Risk Score (HFRS), a previously validated way to measure frailty. They simplified the groups into patients with low, intermediate, and high frailty based on this score.

  • The observational study included nearly 22,000 patients, nearly half of whom were considered frail, including 15% in the highest frailty group.

  • Mortality rates at up to 3 years were 16% for low-risk group, 27% for the intermediate risk group, and 41% for the high-risk group.

  • After adjusting for age, sex, and comorbidities, the highest frailty group (compared to the lowest frailty group) had an 8 times higher risk of prolonged hospital stay, 6 times higher rate of death at 30 day, and 3 times higher rate of death at 1 year.

  • The authors also note the observed a high prevalence of dementia—in one-fifth of the overall cohort and in nearly half the highest frailty group.

The authors concluded that “Frailty is common in patients undergoing LAAC and is associated with increased risks of long hospital stay, readmissions, and short-term mortality.”

Comments. This is yet another example of procedures approved via trials that recruit younger, healthy patients being used in older, sicker, and frailer patients. LAAC is not alone here: implantable cardioverter-defibrillators, AF ablation, percutaneous coronary intervention, and transcatheter aortic valve replacement are often done in patients who are not like those in clinical trials.

This is an important use of registry observational data, as it is not being used to make nonrandomized flawed comparisons, but rather to tell us what we are actually doing in real-world practice. The specific findings here are:

  • Almost half the patients who had LAAC in this series were frail.

  • Frailty confers a super high risk of poor outcomes including short survival.

Why is that important? It’s important because LAAC is a strategy that trades a higher upfront risk of problems, including procedural complications and bleeding complications related to the need for short term anti-thrombotic medications for longer-term benefits from being off anticoagulants. (That is, if you believe there are any long-term benefits. I do not believe that, but for the sake of argument, let’s say there are benefits, these would accrue over years.)

In fact, the Watchman authors have published a post hoc PROTECT and PREVAIL study looking at “net clinical benefit” and found that early on, the net clinical benefit favors warfarin, but the net positives for the device take 3-5 years to be seen. So, if you are implanting this device in patients with high frailty scores who have poor 1–3-year survival, you may actually be creating a net harm due to exposing them to the upfront risk.

I am particularly troubled, and you should be as well, that nearly half of the patients in the highest frailty group had dementia. Not only does dementia confer a poor long-term prognosis, it also raises the possibility that these patients could not possibly meaningfully participate in the shared decision-making that is mandated before having this preventive procedure.

I want to commend the authors for doing this research and publishing it in a very clear paper, as it forces our community to reflect on what appears to be extremely dubious patient selection of an already dubious procedure.

I have long held that many preventive interventions help doctors and hospitals more than patients. When we put these foreign bodies into older frail individuals, it seems extremely likely that we benefit ourselves and our employers far more than we help our patients. This is a sad and sobering paper, on many levels.

LVAD Device Recall | Medscape Cardiology published a ProPublica news piece on the regulatory failure of the Medtronic HVAD left ventricular assist device (LVAD). In June of last year, Medtronic ended sales and implants of this brand of LVAD, but here’s the thing: That was in 2021, but in 2014, the US Food and Drug Administration (FDA) had published a warning letter describing serious problems with the pump.

This is a complicated story and I want to learn more about it before covering it further. Look for more on this coming in future podcasts.

I know post-marketing device surveillance needs improvement, but there must be some explanation for why it took 5 years to halt implants of a faulty device.

If you have any references or know about this issue please let me know.


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