Sep 26, 2025 This Week in Cardiology Podcast

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In This Week’s Podcast

For the week ending September 26, 2025, John Mandrola, MD, comments on the following topics: A bold trial in valvular heart disease, a CV prevention trial whose message is humility, VTE dogma challenged, more news on oral GLP-1 agonists, and a few public service announcements.

DOUBLE-CHOICE Trial

• DOUBLE-CHOICE: Minimalist Approach to TAVI May Be as Good as Standard of Care

The last couple of weeks, I’ve had tough criticisms of trials. This week I will start with a very nice example of evidence-based medicine.

A German team, led by Holger Thiele, presented results of their DOUBLE-CHOICE trial comparing a minimalist approach to transcatheter aortic valve implantation (TAVI) sedation to standard of care.

The clinical question surrounded the use of just local anesthesia — and nothing else — to do a TAVI vs standard of care, including conscious sedation and local anesthesia. In Germany, SOC had long progressed to CS from general anesthesia.

I find the fact that my German colleagues would do — and German patients would accept — a major operation without sedation quite remarkable. It speaks to the different cultures of medical practice. Because, here in the southeastern United States, and likely most places in the US, sedation is used for about everything. I try to hold the line on wide-awake loop recorder insertion but some patients demand sedation.

But nonetheless, the ability to do TAVI with nothing but a bit of local anesthesia is worthy of study. So that’s what the Leipzig-led team did. They did not do 700 cases and then report retrospectivevely that everything went fine. No, they did it properly: they randomized half to the minimalist approach (MA) and half to standard of care (SOC). The primary endpoint was a composite of bad things: death, vascular and bleeding complications, infections, and neuro events at 30 days. They used a non-inferiority test, which is totally appropriate. In fact, this is a classic case for non-inferiority design, because the MA is clearly less aggressive.

The cohorts studied look to be typical for TAVI—age 83 years, 58% female, and an STS score of 4.6%.

The primary endpoint occurred in 22.9% in the MA vs 25.8% in the SOC group. The absolute difference was 2.9% better. And the upper bound or worst case scenario of 2.4% worse for MA was rate was well within the non-inferiority margin.

Other important findings:

Delirium, technical success, Kansas City Cardiomyopathy Questionnaire (KCCQ) at 30 days, were all similar in the two groups. As were rates of moderate or severe aortic insufficiency and mean aortic valve gradients.

One notable finding: only 79% of the MA stayed in the MA arm — 21% crossed over to the SOC. Most often due to pain. And in the as treated arm, results were even better for MA.

Self-reported anxiety and stress during the procedure were higher in the MA approach.

The authors concluded that a minimalist approach is feasible and noninferior to SOC. Though they note that the high cross-over and self-reported anxiety and stress require careful patient selection, structured monitoring, and interdisciplinary collaboration between cardiology and anesthesiology.

Circulation published their paper. And I congratulate the authors for staying true to evidence-based medicine (EBM) principles and studying this bold and novel approach in the proper way—with an RCT. This is the way forward for new innovations. 

KP Vaccinate Trial

ESC offered another good example of using EBM the proper way. That is the study of electronic nudges for treatments that we want to increase patient uptake.

Authors from Kaiser Permanente evaluated the effect of cardiovascular-focused messaging on influenza vaccination uptake using an RCT.

First the background: while influenza vaccine is known to vary in efficacy, and data on its value in a general population can be debated, there is strong data supporting its use in patients with established heart disease.

Most impressive was the IAMI trial, a German RCT, published in JAMA in 2021, which found that early flu vaccine after myocardial infarction (MI) vs a saline placebo led to a statistically significant 28% reduction in a major adverse cardiovascular event (MACE) composite endpoint. All-cause and CV death were also reduced in the flu vaccine group. There are also meta-analyses of trials suggesting flu vaccine can be considered a disease modifying therapy for patients with CV disease.

So we want our cardiac patients to take the flu vaccine. One way to do that is with nudge messaging. In fact, Danish researchers have shown that in their system, letter-based nudges seem to increase flu vaccine uptake.

But what can be accomplished in high-trust Denmark may not be scalable in other systems.

Enter the KP Vaccinate study. Kaiser Permanente is a great place for studies like this because it’s like a health system within a health system. The trial included 4 million people. Four million were enrolled into four groups

All eligible participants were randomly assigned in a 1:1:1:1 ratio to receive combinations of two different messages promoting influenza vaccination (ie, a cardiovascular-focused message and a usual care message) across two timepoints of messaging. These were not just cardiac patients. It was general population.

This yielded four trial groups, corresponding to the messaging received at “Trial Touch Point 1” and “Trial Touch Point 2”. And, respectively, these were:

• CV focused nudge communication at each time point;

• CV focused nudge communication and usual care communication;

• usual care communication and CV-focused nudge communication; and

• usual care communication at each time point.

So there were about 1 million per the four groups. The primary endpoint was receiving flu vaccine.

Overall vaccination rate at the end of the trial was 32.46%.

Compared with participants who received two rounds of usual care communication, those receiving cardiovascular-focused messaging at any timepoint had similar vaccination rates (32.41% vs. 32.60%; absolute change, −0.19 percentage points; 99.2% CI, −0.34 to −0.04). Time to vaccination did not differ.

Subgroup analysis found no heterogeneity.

The authors spend a great deal of time discussing the negative results relative to the positive results in Denmark.

One of the factors is trust. Trust figures in the differences. In Denmark, messaging came from a national email system and in Denmark, people trust public health authorities.

In KP, email came from the health system, which I am sure looks similar to the oodles of emails patients receive from their health systems. If your health system is anything like mine, I receive tons of worthless emails. Mostly I hit delete.

So the impact of nudges in the KP study may have been diluted by the usual e-spam sent out by systems.

My experiences in Denmark highlight the extreme difference in trust in public health. The authors write that trust in US public health is low. This is the understatement of the year.

But I have another reason why KP vaccinate did not work. It goes back to Andrew Foy’s minimizer/maximizer frame. Minimizers are not going to care about nudges. Maximizers are signing up for flu vaccine when first available. These large groups are not affected by nudges (nor PCE risk calculators or CAC scans).

This reminds me of one of the most important policy papers ever published in cardiology. This is 2011, New England Journal of Medicine. The MI FREEE trial studied two groups of patients discharged after MI. One group got full prescription coverage with no copayments vs usual prescription coverage.

Adherence to meds was barely any higher in the free group (36% vs 49%) and there were no significant differences in MACE.

This reinforces my feeling that preventive healthcare is burdensome to patients. Why? Because people are busy living their lives.

While we clinicians sometimes tend to think patients are like robots, who, if they took every single thing we want them to, they would live forever, free of MACE or CV hospitalizations. But, in reality, most people don’t live to be patients. Most people sense the smallness of our preventive therapies. Most people sense that the most likely result of not taking oral anticoagulants (OAC) for atrial fibrillation (AF) is not having a stroke.

Ironically, the better we get at acute treatment, the less important screening and prevention become, right? MIs are fixed in a matter of minutes. The next day the patient has a band-aid on their wrist and a normal ejection fraction and goes home mostly unfazed.

Make no mistake, I am not arguing against preventive therapies. I encourage my patients with AF to take OAC, and my patients with heart failure to take guideline-directed medical therapies, and my patients with coronary artery disease to take statins, but the simpler we make things, the more likely we are to maximize adherence to the most important things.

As for nudges in the KP Vaccinate trial, I would argue for de-implementing these. The less we bother people the more likely they are to respond to important things.

The biggest gain from KP Vaccinate is its monster dose of humility.

HI-PRO Trial

I am still doing ESC trials. Gosh there were a lot of great trials this year. HI-PRO was conducted at Brigham and Women’s Hospital in Boston. The question was the duration of OAC after a provoked venous thromboembolism (VTE).

The key modifier here will be provoked. Dogma has long been that if your VTE is provoked (surgery, long travel, etc) then treatment need only be 3-6 months.

The Boston team, led by Dr Gregory Piazza, challenged that dogma by randomizing 600 patients with provoked VTE and one risk factor to apixaban 2.5 twice a day or placebo for 12 months. Randomization occurred after 3 months of OAC.

The primary efficacy endpoint was recurrent VTE, and primary safety endpoint was major bleeding.

The most common provoking factors were surgery, immobility, trauma and acute medical illness, as you’d expect. The most common risk factors for thrombosis were chronic inflammatory disease, obesity, atherosclerotic vascular disease, or COPD.

The results were clear;

Efficacy was 1.3% recurrent VTE in apixaban group vs 10% in the placebo arm. That’s a hazard ratio of 0.13, or an 87% reduction. It’s obviously statistically significant. MACE endpoints were low and not different.

Safety as measured by major bleeding was 0.3% (one of 300 patients) vs 0%. Non-major bleeding was slightly higher in apixaban group, 14 vs 5 patients.

Subgroups were similar. No heterogeneity of effect.

Conclusions were that 2.5 mg twice daily of apixaban for patients with provoked VTE and one risk factor do better with low dose OAC for a year. They have a dramatically lower rate of recurrence VTE and no substantial difference in bleeding.

And this upsets standard practice, which held that provoked VTE only requires 3 months of treatment.

It also makes us think about the dichotomous provoked vs unprovoked framing. In this trial, the recurrence rate in the provoked arm was 10%, similar to studies of unprovoked VTE.

The trial has limitations. It was single center. Two doctors recruited patients and one doctor recruited more than half the patients. This is not a major problem for internal validity, but it might make us cautious about external validity or generalizing results — especially since the placebo VTE recurrence rate of 10% is so much higher than the expected rate of about 5.8%.

Another limitation was that nonmajor bleeding was higher in the apixaban group. While major bleeding was very low, non-major bleeding is not nothing.

Yet, I think this trial should open up further studies in this space. A) we should have a replication trial, preferably a multicenter trial. B) we should further study patient characteristics in whom longer duration treatment is wise. C) What about after 12 months? Should we not know if even longer duration AC is better than no treatment? I don’t know. I am asking.

Finally, I think this data strongly supports the remarkable safety of direct oral anticoagulant (DOAC) drugs. Only 1 of 300 patients had a major bleeding episode. Always remember, my friends, that in AVERROES (full dose apixaban vs aspirin in patients with AF who had a reason not to take OACs) bleeding rates with apixaban were similar to aspirin. Pause there. Apixaban and low-dose aspirin had similar rates of major bleeding, at least in the intention-to-treat population.

I think we overestimate the risk of DOACs.

Oral GLP-1 Agonists

Two weeks ago, NEJM published results of the ATTAIN-1 trial of the oral GLP-1 agonists orforglipron. Eli Lilly makes the drug and sponsored the trial.

This was a four-arm trial of 6,12, 36 mg doses vs placebo. And the results were good.

About 3100 patients were randomized. Mean age 45, 65% female, and mean BMI 37.

The primary endpoint of percent change in body weight at week 72 was significantly lower than placebo for all doses:

• -7.5% for 6 mg

• -8.4% for 12 mg

• -11.2% for 36 mg

• -2.1% for placebo

Among the patients in the orforglipron 36-mg group, 55% had a reduction of 10% or more, 36% had a reduction of 15% or more, and 18% had a reduction of 20% or more.

Markers of metabolic health all improved. Safety was as expected. Adverse events resulted in treatment discontinuation in 5.3%–10.3% of the patients in the orforglipron groups and in 2.7% of those in the placebo group. 

The degree of weight loss is less than of injectable semaglutide and tirzepatide.

But it is a pill rather than an injection.

I don’t have much critical to say about GLP-1 drugs. They are clearly a huge advance. No, we should not need them. We should be like Norway or Denmark or Sicily. But we are not like those places. I increasingly see patients in my AF clinic who have shed 20, 30, 50 lb on these drugs. And if you do that, AF gets better. In some cases, AF is vanquished.

Metabolic health is probably our number-one public health problem today. And here are drugs that help those who have metabolic disease.

Recall that in the SELECT trial of semaglutide vs placebo in patients with established CV disease, the MACE reduction was 20%. And this was on top of 90% use of lipid-lowering therapy. That degree of risk reduction is similar to statins, which are considered disease modifying.

Whether an oral GLP-1 will be better than injection remains to be seen. Certainly a pill may be easier to take than an injection. I am happy to hear your opinion on this drug class. And if you have a way to get Americans to eat like Sicilians, I’m all ears. I am happy to learn.

Three Public Service Announcements from Clinical Practice this Summer

As many of you know, I practice clinical electrophysiology in a medium-sized hospital in a medium sized American city.

Three observations:

1. Pulsed field ablation has changed everything when it comes to AF ablation. Its efficacy may be similar to thermal ablation, but it’s faster, better tolerated by patients and does not have the worry of death from AE fistula. It is shockingly good. One company is clearly in the lead. I have not done a thermal AF ablation in nearly a year.

2. If you don’t have the Queen of Hearts app yet, you should get it. I covered a study of accuracy of cath lab activation on the August 1 podcast. The AI app was far better than EM docs and cardiologists. I’ve seen it correctly identify borderline ST-elevation myocardial infarction (STEMI) cases. STEMI care is also amazing but there remains a group of patients with STEMI mimics or subtle cases that are missed — and for these poor souls, myocardium is lost when it did not have to be.

3. If you are called to see a patient with ventricular tachycardia, please have in your mind to look for pause-dependent polymorphic VT related to QT prolongation. So-called torsades de pointes is common, and it is often incorrectly treated. The incorrect treatment is antiarrhythmic drugs (eg, amiodarone). The correct treatment is to increase the heart rate, usually with temporary pacing, and correction of the QT interval, usually by replacing electrolytes and/or stopping QT prolonging drugs. You can save a life by learning to recognize and treat torsades de pointes.

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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: Sep 26, 2025 This Week in Cardiology Podcast - Medscape - Sep 26, 2025.