Nov 17, 2023 This Week in Cardiology Podcast

John M. Mandrola, MD


November 17, 2023

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In This Week’s Podcast

For the week ending November 17, 2023, John Mandrola, MD comments on the following news and features stories.

Comments and Announcements

A couple of comments before the evidence review: First, I want to thank those of you who came up to thank me at the American Heart Association (AHA) meeting to say you liked the podcast. This means a lot to me. Thank you. Really. Thank you.

Second, every time I get home from a big meeting like AHA, I am reminded how valuable it is to take the trouble to be there in person. Why? To be with people. To meet people. Medicine and medical science are people professions. And then there is the Italian food in South Philly.

Third, I am not sure how AHA did it, but few recent meetings have garnered this much important medical science. In fact, today’s podcast will include all positive and important studies.

Finally, next week This Week in Cardiology takes a rare week off for Thanksgiving. In the coming weeks this winter, there will be plenty of AHA studies to discuss. Today I do the big ones.

Semaglutide and the SELECT Trials

The glucagon-like peptide (GLP-1) agonist semaglutide has been shown to reduce outcomes in patients with diabetes. It reduces weight in patients with obesity.

The placebo-controlled SELECT trial tested it as a disease-modifying agent in patients with obesity and established atherosclerotic cardiovascular disease (ASCVD). It worked. Clearly it worked.

17,000 patients. The most common qualifying vascular disease was being post myocardial infarction (MI); mean age 62 years, mostly male, and all patients were on baseline guideline directed medical therapy (GDMT). The mean body mass index was 33. So, the trial included overweight patients as well.

The primary endpoint was major adverse cardiac events (MACE): CV death, MI, stroke.

The trial was positive. Results:

  • In the semaglutide arm, 6.5% of patients experienced a first primary outcome event vs 8.0% in the placebo arm.

  • This 1.5% absolute risk reduction (ARR) translates to a 20% relative risk reduction (RRR); hazard ratio (HR)  was 0.80; 95% confidence interval (CI), 0.72 - 0.90; P < .001.

  • Other notable and positive findings for semaglutide included:

  • Patients lost about 8.5% more body weight than those in the placebo arm.

  • The Kaplan-Meier (KM) curves for the primary endpoint began to separate early, well before weight loss took effect, suggesting multiple ways the drug may confer its benefit.

  • Each component of the primary endpoint was lower.

  • Overall death was nearly 1% lower.

  • These positive findings occurred in the setting of robust baseline care, including statins and antiplatelet agents in approximately 90% of patients.

  • The onset of prediabetes was reduced by 75% and levels of C-reactive protein and systolic blood pressure (BP) were lowered.

  • Adverse events leading to stopping the drug occurred in 16.6% of those taking semaglutide (weekly dose of 2.4 mg) vs 8.2% on placebo.

My Comments.  I don’t know how else to feel about this trial other than positive. The degree of RRR and ARR are similar to statins, except patients with overweight and obesity also get the benefit of weight loss and likely better quality of life.

Because I am positive on SELECT, maybe a counter may be that it is only one trial. For a new indication, we should have two trials. And I would normally agree, but it’s not like GLP-1 agonists don’t have priors on being CV event-reducing drug.

SUSTAIN-6 showed that semaglutide reduced MACE in patients with diabetes. Plus, it is plausible that inducing nearly a 10% weight loss would improve BP, glucose, and inflammation, all factors that likely lower rates of recurrent MI or stroke.

  • SELECT is likely going to change practice. For patients with established vascular disease who are overweight or obese, semaglutide is a disease-modifying drug. We will be using it.

  • The other thing SELECT may change, I hope, is the framing of obesity. Since a drug that induces weight loss improves outcomes, the next logical idea would be that obesity is not healthy. Right now, one of the headwinds of treating obesity is the tension created by a cultural sense that all body types are ok.

  • I hope that SELECT and GLP-1 agonists in general change norms around obesity as a serious medical condition.

  • Another discussion point at AHA was that the KM curves separated early, and that implicated mechanisms of benefit beyond weight loss. I believe that is right, too. I don’t know what it is exactly. Perhaps, simply eating less. But the thing about trials that make them so important is the why answer is less important. Trials show us whether things work or do not. And semaglutide sure looks like it works.

  • Finally, there is cost. I don’t have the answer, but we will have to find a way to get a disease modifying drug to people in an equitable fashion. I know health economics isn’t simple, but my mind is. Mandrola thinking holds that if we stopped burning money on low-value care, wink, left atrial appendage occlusion, excess atrial fibrillation (AF) ablation, coronary artery calcium screening, we’d have more for proven therapies.

Congratulations to the researchers. And to Novo Nordisk, the makers of this drug. Here is an example where industry has improved society.


In 2017, Imperial College London investigators nearly killed interventional cardiology with their ORBITA 1 trial. At AHA, they presented ORBITA-2, and interventional cardiology, which was nearly lost, is now found. And saved. Thank goodness.

Before I say anything else, I want to point out how special Imperial College must be. Darrell Francis and Rasha Al-Lamee must be much more than incredibly smart scientists, they seem to be wonderful leaders as well. Because the Imperial College team not only puts out unique research (the SAMSON trial with statins), but they also seem like a big happy family when you meet them. Another clue on leadership — in 2017, Darrell Francis had Rasha Al-Lamee present and take first authorship of ORBITA-1. In 2023, Rasha Al-Lamee had Christopher Rajkumar present ORBITA-2 and take first authorship.

As many of you know ORBITA 1 shocked the interventional community when it studied a placebo percutaneous coronary intervention (PCI; we used to call this a sham procedure, but don’t anymore, because sham as a word doesn’t fit) against a real PCI. Just pause for a second. Picture a patient with angina and a 90% proximal stenosis somewhere. Imagine the boldness to put a pressure wire across the stenosis and leave it unfixed.

  • And in ORBITA 1, when patients with these single-vessel lesions were first maximized on anti-angina therapy, fixing the lesion made no significant difference on exercise time or angina scores. ORBITA-1 showed that PCI as an add-on in this setting did little more than placebo.

  • ORBITA 2 was different. Patients with single or multivessel disease and chronic stable angina were recruited. They then had their angina meds stopped 2 weeks before the procedure.

  • Then they went to the lab and were randomly assigned to a real PCI or a placebo procedure. Blinding was extensive, which is critical.

  • ORBITA 2 investigators also designed an app wherein patients would report daily angina episodes and the number of anti-anginal drugs. This allowed the investigators to create an ordinal score, which they used for their primary endpoint.

  • They also measured treadmill time and other typical angina questionnaires.

  • With this new design, one that isolates the effect of PCI-alone, not as an add-on, PCI worked to improve the angina symptom score.

  • The odds ratio was 2.2 for a better angina score. Which was highly positive.

  • Angina frequency was also 3.4 times less in the PCI arm.

  • PCI also improved the Canadian Cardiovascular Class angina scales.

  • Treadmill walk time was now a statistically significant 59 seconds better, rather than 16 seconds in ORBITA-1.

My Comments. Some may wonder about the ethics of stopping pills 2 weeks before randomization. It was totally ethical because, in patients with chronic stable angina, angina meds are not disease modifiers, they are like acetaminophen in arthritis. All patients in ORBITA 2 remained on GDMT such as statins and aspirin.

  • The main interpretation of these two trials, is that the current recommendation to start tablets first and then do PCI if symptoms continue may systematically select patients for whom PCI works poorly.

  • Instead, two trials provocatively suggest that if angina relief is the goal, patients could rationally choose either tablets or PCI. Both seem to work.

  • I worry, of course, that in our American sea of overuse, ORBITA-2 will be used to further increase the amount of PCI in stable disease. But if that happens, it is not the fault of PCI or the Imperial College team.

  • My perspective on PCI for stable disease is one in which I see patients with AF, who require both antiplatelet and anticoagulant drugs (OACs) if they’ve had a prior stent. I also see stent thrombosis when these drugs are held for bleeding.

  • So, if this were to happen to me, I would likely try tablets so as to avoid having a metal cage in my coronary that requires long-term dependence on antiplatelet drugs and always looms as a site of neo-atherosclerosis or stent thrombosis.

Finally, I want to remind new listeners, that no matter the degree of stenosis or number of lesions, there is no compelling evidence that PCI reduces hard outcomes over medical therapy. The rate of heart attack or death is the same if you treat stable coronary artery disease (CAD) with tablets or PCI.

PCI for stable CAD is done to relieve symptoms. ORBITA-2 shows that it works well as a first-line therapy. ORBITA-1 shows that it works hardly at all when added to maximal medical therapy.

Look for guidelines to change.


One of the most common questions in cardiology today is what to do when a device (usually a pacer or implantable cardioverter defibrillator [ICD]) finds asymptomatic short duration AF, say 1 hour, maybe 2 hours, maybe even 8 hours.

This patient has CHADSVASC of 4 and if this were clinical AF, that is, they came into the office for symptoms and an electrocardiogram (ECG) showed AF, you would definitely put them on an OAC. Because there are oodles of trials showing that warfarin was better than placebo or aspirin, and direct OACs are similar or better than warfarin.

  • So-called subclinical AF (SCAF) is different. It’s shorter in duration and only discovered because of technology. We don’t even know whether it is an actual disease or a condition of aging.

  • SCAF looks like AF. The atrial channel shows fibrillatory activity. The V channel is usually irregularly irregular (when there is an intact atrio-ventricular node), but the duration is shorter, and patients rarely feel it.

  • At the European Society of Cardiology meeting 2 months ago the NOAH AFNET 6 trial of edoxaban vs placebo for patients with SCAF found surprising results: The DOAC drug edoxaban did not significantly reduce the primary endpoint of stroke, systemic embolism, or CV death but it did increase the rate of major bleeding by a statistically significant 31%.

  • NOAH was stopped prematurely for both perceived futility of efficacy and harm from bleeding.

  • The explanation for NOAH was that SCAF conferred a very low stroke rate of only 1% per year. I know, sometimes my eyes glaze over talking about yearly stroke rates, but it’s important and we use this concept every day with the CHADSVASC score when treating clinical AF.

  • The idea is simple: OACs are not free. The reduce stroke but also increase bleeding. If the CHADSVASC is high enough, then we use an OAC because a higher CHADSVASC means a higher yearly stroke rate. For instance, we estimate, emphasis on estimate, that a CHADSVASC of 2 means a 2.2% yearly stroke risk. And at that level, we feel that the absolute risk reduction of stroke from OACs is outweighed by the bleeding rate increase. And we say there is now a net benefit.

  • Well, if the yearly stroke risk is low, the absolute risk decrease with OACs will not outweigh the bleeding increase. That is exactly what happened in NOAH.

ARTESIA was different. This apixaban vs aspirin trial enrolled more patients — 4000 instead of 2500. ARTESIA followed patients longer. And they had an endpoint of only stroke and systemic embolism. That’s more focused than NOAH with its stroke, systemic embolism and CV death as an endpoint.

So, ARTESIA was set up to have more stroke events. Using aspirin in the control arm would also mitigate the delta in bleeding events, right? Because in AVERROES, aspirin and apixaban had very similar bleeding rates.

  • In ARTESIA, the average age was 77 years, and slightly more than one-third of the patients were female. The mean CHADSVASC score was 3.9. The median duration of AF was 1.5 hours. Only 20% of patients had AF duration longer than 6 hours.

  • A primary endpoint occurred in 55 of 2015 patients in the apixaban arm vs 86 of 1997 patients in the aspirin arm (0.78% vs 1.24% per patient-year). This difference of only 31 stroke events in a trial of more than 4000 patients yielded, however, a statistically significant RRR of 37% (HR, 0.63; 95% CI, 0.45- 0.88; P = .007).

  • The authors assessed stroke severity and reported that 18 of 55 strokes in the apixaban group were disabling or fatal vs 36 of 84 strokes in the aspirin group (33% vs 43%, respectively). The RRR for these severe strokes, with a modified Rankin scale score of 3 to 6, was greater, at 49%.

  • The safety endpoint of major bleeding occurred in 86 of 1989 (4.3%) patients in the apixaban arm and 47 of 1972 (2.3%) patients in the aspirin arm. This difference of 39 excess major bleeding events yielded a relative risk increase of 80% (HR, 1.80; 95% CI, 1.26-2.57; P = .001).

The investigators also subdivided the bleeding events, noting that most bleeding events were handled with supportive care. Fatal bleeding and intracranial bleeding events were actually numerically lower in the apixaban arm.

Significant reductions in stroke and increase in bleeding led the authors to two conclusions. The basic one, in the abstract of the New England Journal of Medicine paper:

Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding.

But at the meeting and in the final conclusion, the authors asked us to consider that a) strokes are worse than bleeds; b) apixaban reduced all strokes but also disabling strokes; c) most bleeding events could be managed without disability; and d) the worst bleeds, fatal or intracranial hemorrhage, were not increased with apixaban.

This led them to write:

Simply counting strokes as compared with bleeding events might suggest a neutral overall effect…strokes involve permanent loss of brain tissue whereas major bleeding is usually reversible with most patients having a complete recovery.
In this trial involving patients with risk factors for stroke who were found to have subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin. This effect included a substantial between-group difference in disabling or fatal stroke. The risk of major bleeding was higher with apixaban than with aspirin; most cases responded readily to supportive care.

In my opinion column, I differed a bit from this preference for apixaban. I totally get the fact that net benefit leans that way.

But the ARR in stroke and bleeding was small. The risk reduction was about 1.6% over 3.5 years. The number needed to treat is about 67. The risk increase was roughly 2% or a number needed to harm of 50.

  • So, it’s a tough call. When you present options to patients, different people will feel differently about it. Patients more fearful of stroke might take an OAC. Patients more fearful of bleeding will hold off. Keep in mind too that it’s not just the calculus of stroke and bleeding.

  • Patients also must factor in the burden of taking a twice-daily pill and its costs.

  • The thing is that this data — both trials combined — doesn’t allow an algorithm or quality measure. There will be no correct answers. I sort of like that. You have to talk with patients.

  • One thing to look forward to is a patient-level meta-analysis. Bill McIntyre and colleagues including authors of both trials have published a trial level meta-analysis. Circulation published the study, which shows that NOAH and ARTESIA results are consistent.

  • But what we really need is a patient-level meta-analysis where they can graph duration of SCAF with treatment effect. I suspect that graph will show that treatment effect of OACs will reach net benefit with the longer duration episodes.

Recall that in the TRENDS observational study, it took 5.5 hours to see an elevated stroke risk, and in ASSERT, it took 24 hours.

Okay, I’ve gone on for a good while. In the coming weeks, I will review the many other papers from AHA. 


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