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In This Week’s Podcast
For the week ending July 18, 2025, John Mandrola, MD, comments on the following topics: Finerenone, what not to consider when choosing treatment of AS, brain health after atrial fibrillation ablation, early rhythm control for AF, and Watchman reimbursement cuts.
Listener Feedback
I received an email from an academic EP who is involved with regulation, regarding my coverage of pulmonary embolism (PE) devices two shows back.
He clarified my thoughts on the 510(k) approval pathway where devices get approved by being similar to an already approved device. I called it extremely problematic and called for FDA to reform it.
My colleague writes that it’s not up to FDA to reform the program. The 510(k) pathway and the rules around substantial equivalence are in federal law and Congress would need to change these rules.
Speaking of 510(k) pathway, he agrees it can be problematic. It works well for devices like blood pressure (BP) cuffs and diagnostic EP catheters, in which the underlying technology is well established. It’s harder in things like artificial intelligence or machine learning-based devices or anything that is sort of—but not completely—new.
He said we spend a lot of time on these, often focused on whether the intended use is the same, whether we have enough bench and clinical data, etc. And, he writes, “substantial equivalence” means we need to be assured that the device performs as well as the predicate and that often requires clinical data.
I have come to really appreciate listener feedback because it is so instructional. I did not know that Congress has to change the 510(k) pathway. Keep coming with the listener feedback.
Finerenone
Medscape news has a good summary of the FDA approval of finerenone. It’s actually an expansion of the indication of the nonsteroidal mineralocorticoid receptor antagonist (MRA).
The FDA initially approved finerenone in 2021 to reduce the risk for cardiovascular death heart failure hospitalization (HHF), myocardial infarction (MI), and kidney complications in adults with chronic kidney disease (CKD) associated with type 2 diabetes—a rather specific indication.
The new expansion will be for patients with heart failure (HF) and left ventricular ejection fraction (LVEF) of at least 40%. This is based on the FINEARTS-HF trial published in New England Journal of Medicine in 2024.
This was a big 6000+ patient trial comparing finerenone to placebo in patients with heart failure with preserved ejection fraction (HFpEF). Mean age 72, LVEF 53%, most with NYHA Class 2 and 3 HF.
The primary endpoint was a composite of total worsening HF events (HHF or urgent visit) and CV death.
Follow-up was 2.5 years. There was a 16% reduction in the primary endpoint. The hazard ratio was 0.84 and confidence intervals were significant. The absolute risk reduction (ARR) was 2.8%, or a number needed to treat (NNT) of 35. The primary composite was driven almost completely by HF events as there was no statistical difference in CV death or all-cause death.
This came at a cost of more increases in creatinine and potassium. High potassium more than 6 was 3.0% vs 1.4%.
FINEARTS-HF is fine. It was a positive trial. My criticism of the trial and finerenone use in HFpEF centers on three main issues.
First issue: Wrong comparator. Finerenone should have had to beat spironolactone. I say that because the Americas part (US, Canada, Brazil, Argentina) of the TOPCAT trial clearly show that spironolactone improved outcomes in HFpEF. Of course it does. MRA drugs as a class help in HFrEF and likely do in HFpEF. The question facing clinicians is which MRA to start—one that costs pennies, spironolactone, or one that will surely cost bunches, finerenone. The lack of head-to-head comparison is what we get when we let industry control regulatory trials. If I were at FDA, I would have pushed for a spironolactone arm.
The second issue was that the benefit from finerenone was modest. Despite enrolling 6,000 patients, there were only 200 fewer events in the finerenone arm, and no difference was seen in cardiovascular death. The 16% reduction in the primary endpoint was driven solely by heart failure events, not mortality. Finerenone is a diuretic after all. HFrEF patients have 4 classes of “disease-modifying” drugs. Finerenone cannot be called disease-modifying.
The third issue I have with FINEARTS is that the authors surely have — but don’t share — the effect on total hospitalizations. As I have shown in other HFpEF trials, most hospitalizations in these patients is not HF. So, if a drug or device reduces one type of hospitalizations (here for HF), but this type is only a small fraction of the total burden of hospitalizations, the patient does not win. HHF are a reasonable surrogate in HFrEF, because in those patients a weak LV is the primary issue. But in HFpEF, these patients are older and burdened with much higher co-morbidity, so HHF becomes a weak surrogate measure.
I don’t have a problem with FDA approving the drug for this indication. But they should have been stronger in the regulatory input regarding the seminal trial. Drug companies will jump over the bar we set for them. We help them when we set the bar low.
For clinicians, we shall see what the cost of this drug is. I still believe we start with spironolactone and keep finerenone in the bullpen for relief when the first line fails.
Choosing TAVI or SAVR
One of the most common decisions in the field of valvular HD is whether to do transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis (AS). There are obvious cases when patients are clearly poor surgical candidates. TAVI is the choice. There are also obvious surgical choices when the patient is very young or has the need for concomitant surgical procedures, such as left atrial (LA) ablation, mitral disease, or coronary artery disease (CAD) requiring revascularization. Then SAVR.
For the large number in the middle, patients and doctors have to translate the nuances of the PARTNER, EVOLUT, Notion 1 and 2, DEDICATE, and UK-TAVI trials. You could have day-long conferences on sorting through the details of these trials.
Ultimately, there is a tension between the much lower burden of TAVI vs its long-term durability relative to SAVR.
Editors of the European Heart Journal and authors, mostly from Columbia University, tempt us to consider another factor in the decision: the carbon footprint of the two procedures.
I kid you not. EHJ has the top impact factor of all cardiology journals, and it has now published a comparison of the carbon footprint of 10 patients who had SAVRs and 20 patients who had TAVIs (10 in the OR and 10 in the cath lab). They used a model that measured the kilograms of CO2 equivalents based on the primary data, such as the materials, procedures, energies, in the preoperative, operative, and postoperative setting.
TAVI used less CO2 equivalents than SAVR (about half less). The numbers were 300 kg of CO2 equivalents in TAVI vs 600 kg of CO2 equivalents in SAVR.
Postoperative intensive care unit and floor care accounted for the largest portion of the carbon footprint. The intraoperative footprint of SAVR was driven by biological waste, postoperative length of stay, and inhaled anesthetic gases.
The authors concluded:
The carbon footprint of SAVR is about twice as high as those from OR–TAVI or CATH–TAVI. These findings should potentially be considered when making population level decisions and guidelines moving into the future.
Comments
I don’t know what is happening to us as a field. The authors write this in the discussion:
While carbon emissions should not be the deciding factor in the treatment strategy for individual patients, relative emissions should play a role in the future when deciding between different treatment options.
I did a simple Google search on carbon emissions. Even if we accept their calculations, the difference was about 300 kg of CO2 equivalents.
To fly across the US is 1000 kg of CO2 equivalents per passenger. So if you take your family of 4 that’s like 13x more than the difference in these two procedures.
Walk through Atlanta, Dulles, Newark, or LAX airports and just eyeball the number of people flying. I am all for climate stewardship. I ride a bike to work. I live close to everything in town. I don’t litter. I like European hotels that minimize wasteful energy use.
But my friends, the role of carbon footprint should have exactly zero influence on medical decisions such as TAVI vs SAVR. Number 1, it is miniscule relative to other human activities, and number 2, we take care of patients not the environment. Public health should have no bearing on individual decisions.
Finally, I used to think coffee, blueberry, and quinoa studies were the most wasteful of time and effort. Now I think studying the carbon footprint of two medical procedures may have earned top honors in the most useless and wasteful studies.
Come on you all.
Brain Lesions and Visual Migraine After Left-Sided Ablations
The group of Dr Greg Marcus at UCSF continue to do interesting work in EP. Their latest, led by fellow Adi Elias, investigated the possible association of a transseptal puncture during catheter ablation for ventricular arrhythmias with post-procedural visual auras. As well as to assess the relationship between occipital and parietal lobes acute brain emboli and migraine-related visual auras.
The questions are important because it goes to the health of the brain during left-sided ablation, which is undergoing a massive increase due to the use of pulsed-field ablation (PFA) in the left atrium (LA).
This work is actually an observational substudy of a recent randomized controlled trial called TRAVERSE. I will discuss both because both papers are making the rounds in the EP. Note also that this isn’t just an EP topic because visual auras and micro-emboli to the brain also occur with coronary angiography, percutaneous coronary intervention (PCI) and valvular procedures.
Let’s talk first about the TRAVERSE trial, published in Circulation, in February 2025, first author Greg Marcus. TRAVERSE randomized only 146 patients who were to have a left sided ventricular tachycardia (VT) ablation to either retrograde aortic (RA) approach vs transseptal approach. The primary endpoint was an acute brain lesion on MRI.
The main result: in the retrograde aortic approach, 28 of 62 (45%) exhibited an acute brain lesion compared with 19 of the 69 (28%) of those randomized to a transseptal puncture (P = .036).
No differences in clinically manifest complications or procedural efficacy were observed. No patient had a clinical stroke.
Notable in the study was 10% of patients did not get an MRI—which means that they did not have a primary endpoint measured.
The authors conclude from this data that:
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A transseptal approach may be the more favored strategy over a retrograde aortic approach for catheter ablation of endocardial left ventricular arrhythmias to reduce brain injury.
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The heightened risk of new brain lesions detected using MRI without overt clinical manifestations in the retrograde aortic arm may suggest a higher risk of other organ damage that is not immediately clinically occult.
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It is possible other procedures conventionally performed through a retrograde aortic approach might incur similar harms, and that novel transseptal approaches may yet prove beneficial.
Comments
The first thing to say is that they have convinced many in the EP world that transseptal is the preferred approach to the LV. I sent a message to private EP group about access for a VT case and the overwhelming answer was transseptal and [quote] “I am impressed by the UCSF data.”
Well, my friends, I like many of the authors of this multicenter trial, but the trial is a mess, and it does not tell us the best approach.
The first thing to say is that there were only 47 primary outcome events, and the primary outcome events were white spots on an MRI that disappear and have no know permanent sequalae. So even if there were a statistically robust difference, would it be clinically significant? I am not sure, and likely neither are you.
I put the numbers into a Fragility Index calculator, which tells us how many non-events or events in each group would have been required to make the results nonsignificant or greater than P value of .05. The Fragility Index is 1. If one more patient in the transseptal group had a white spot, then the trial is negative.
That is not a statistically robust finding. Not at all.
What’s even worse is that 10% of patients did not have an MRI. So the missing data is 10x the Fragility Index. The authors acknowledge this limitation but soft roll it. The academic editorialists don’t mention the fragility of the data, nor the massive missingness.
I think it is an existential problem with this study. We simply do not know. Imagine a drug or device outcome trial where 10% of the patients did not have a primary outcome measured.
My final take of this study is that EP doctors might spend less time destroying LA during AF ablation and more time learning to look at evidence. TRAVERSE was a good effort, but its internal validity issues, small differences in a surrogate outcome and no difference in stroke tells us near zero about what approach to use when ablating LV sources of arrhythmia.
To me, the doctor should choose the approach most likely to achieve success. Retrograde aortic access is clearly superior to transseptal for some areas of the V. TRAVERSE should not discourage them from using it.
In the meantime, the question of best approach is an answerable question: it simply requires a larger study with more primary outcome events and less loss to follow-up.
The second paper, first author fellow Adi Elias, was published in Heart Rhythm last week. This observational study asked two questions: (a) did the access site (RA vs transseptal) affect visual auras and (b) was there an association between occipital and parietal white spots and migraine-related visual auras.
In total, 121 patients of the 146 had assessment of visual auras. A total of 18 reported a visual aura in the first month after the procedure and 103 did not. Pause there. Because the authors will soon be making conclusions about 18 reported visual auras.
This paper also suffers from serious missingness, as 15% of those in the transseptal arm and 21% of those in the RA arm did not complete the 1-month questionnaire about having a visual aura, which was the primary endpoint.
The first main result was that there was no difference between post-ablation visual auras observed between transseptal (16% of 63) and retrograde aortic approaches (14% of 57; P = .78).
The second main result was that more participants with acute brain emboli in the occipital or parietal lobes experienced migraine-related visual auras (38% vs. 11%; P = .014). The actual numbers are 7 of 18 of those with occipital/parietal lesions vs 12 of 103 patients without parietal/occipital lesions.
I calculated the Fragility Index on this difference, and it was 2. If 2 of the 103 without a white spot in the occipital/parietal area had a visual aura, then the association is non-significant. And again, recall that loss to follow-up was more than 15% in both groups.
The authors make positive conclusions from this fragile data.
Transseptal puncture was not associated with visual auras, however acute brain emboli involving the visual cortex was associated with such symptoms. These data suggest that transseptal punctures are not causal in migraine-related visual auras and that post-procedure acute brain emboli are apparently not always clinically silent.
They then double down in their interviews on Medscape.
Marcus says, “These findings demonstrate that, contrary to a long-held belief that these post-ablation MRI-detected small brain lesions are asymptomatic — in fact, they are often referred to as ‘asymptomatic cerebral emboli’ or ‘ACEs’ — these small acute brain lesions actually can, and perhaps often do, manifest in clinical symptoms.”
Dr Elias, too, is too strong. He says, “The data show that these post-ablation brain lesions are not clinically silent. It may be the case that we haven’t known what to look for and assessed for symptoms immediately without enough time for the subsequent visual auras that would occur.”
Comments
Again, maybe they are correct, but the data is not statistically robust. They’re making big conclusions based on 18 MRI scans and nearly 1 in 10 patients did not have an MRI and 1 in 5 patients did not have an assessment for visual auras. Only 2 events would change the conclusions. The data, therefore, do not support their conclusions.
I would conclude only that there may be a signal, but we need more data to understand the relationship of postprocedure brain emboli and visual auras.
Finally, my criticism of these studies is not meant to downplay the issue of brain emboli after procedures. These are potentially quite serious because even if the effect size on cognition is small, the large numbers of procedures being done means there could be a huge public health crisis in the future.
As it is in all of medicine: everything turns on patient selection. When we do TAVI in an older person who has less than 6 months to live due to severe AS, and he or she gets asymptomatic brain emboli, we worry a little.
In contrast, when we blast a 50-year-old with persistent AF with PFA, ablating the pulmonary veins, posterior wall and God knows what else, creating oodles of microbubbles that then cause multiple brain lesions, we should worry a lot.
The best way to avoid brain emboli is to avoid procedures. That’s not happening now. The reverse is. Early AF ablation is a money maker for doctors and hospitals. PFA lowers the threshold for doing AF ablation because it’s faster and less likely to cause catastrophic complications.
But our profession should be wise enough to be concerned about these observations. We should demand better data on brain MRIs as well as cognitive testing, especially with the advent of PFA. A small harm could turn into a huge problem.
Early Rhythm Control for AF
European Heart Journal has published a rapid communication from EAST-AFNET authors, regarding the short-term benefit of early rhythm control (ERC) vs rate control.
To briefly review, NEJM published EAST-AFNET 5 years ago in 2020. About 2800 patients with newish AF were randomized to two strategies: early rhythm control (mostly with antiarrhythmic drugs) vs rate control. The primary endpoint was a composite of CVD, stroke, heart failure hospitalization, or acute coronary syndrome.
The 5-year trial found a 21% statistically significant reduction in the primary endpoint. The primary safety endpoint did not differ. However, the authors combined death and stroke as both primary efficacy and safety endpoints. If you don’t double count stroke and death, there were nearly 3x more safety events (68 vs 19) in the early rhythm control group (ERC) vs rate control.
A couple notables: EAST-AFNET was not an ablation trial. Less than 1 in 5 patients in the ERC had ablation. So you have to posit that antiarrhythmic drugs (AAD) reduced hard outcomes—a first for sure. Another notable, there was only a 20% difference in the presence of sinus rhythm (80% vs 60%) at 2 years. So you also have to posit that a difference in sinus rhythm of only 20% drove hard outcomes.
I am pretty sure — no, highly sure — that the better outcomes in EAST-AFNET were just performance bias, in that the ERC transmitted ECGs with symptoms had many, many more interactions with their clinicians.
I am not against ERC, and do it often, but I oppose the use of EAST-AFNET to foster lucrative early AF ablations. I believe strongly that patients with AF who do not have HF or decompensation should be treated slowly and given a chance to let nature (or natural history) or risk factor modification help with their AF.
One more thing about EAST-AFNET: the Kaplan-Meier curves for the primary endpoint do not separate for about 1.5 to 2 years, which is what you expect with patients with new AF. If there is a benefit of SR or enhanced medical interactions, it should take time to reduce cardiac outcomes.
Now to the rapid communication of a post-hoc study. Here the EAST-AFNET authors look specifically at outcomes in the first 30 days both in the overall population and in the subset with HF.
First result: A primary outcome event occurred in 9 of the 1400 patients randomized to early rhythm control and in 21 of the 1400 patients in the usual care group hazard ratio (HR) 0.43, 95% CI, 0.20–0.93).
Second result: Deaths in first 30 days were observed in 1 of 1400 patient randomized to early rhythm control and in 4 of the 1400 patients randomized to usual care (HR 0.25, 95% CI, 0.03–2.24).
The third result involved HF patients in EAST-AFNET 4. Slightly less than one third of all patients had prevalent heart failure, of which 400 patients were randomized to early rhythm control therapy and 400 to usual care.
Within 30 days after randomization, a primary outcome occurred in 3 vs 14 patients with prevalent heart failure randomized to early rhythm control vs rate control, respectively (HR 0.22, 95% CI, 0.06–0.77; Figure 1).
The authors concluded that:
This exploratory analysis suggests immediate beneficial effects of early rhythm control therapy within 30 days after randomization, including a lower incidence of the primary outcome, fewer deaths, and a reduced composite of death or heart failure hospitalization—in both the overall population and in those who have HF at baseline.
This supports its early implementation in patients at risk of heart failure or with acute and advanced heart failure.
Comments
Again, I offer no malice to the authors, but this is a really problematic study. The numbers are tiny. I don’t care what the P value or confidence interval say. EAST-AFNET was powered to tell differences over many years, not 30 days. So small are the differences in the first year, the Kaplan-Meier curves do not separate at all in the main paper.
I am not sure why the authors set out to look at a comparison with so few events, or why the EHJ published something so unhelpful. But it depresses me to see stuff like this.
Not only does it not help us, the small numbers of events (9 vs 21, for instance, in a study of 3000 patients) is more likely to deceive us.
EAST-AFNET was a great effort. Strategy trials are hard; they are noisy. Performance bias was likely. But looking at 30 days with its few events only adds more noise to a noisy piece of evidence.
Watchman Reimbursement Cuts
I will close on a positive note. Our government, and likely yours too, makes a lot of mistakes. We should celebrate when government does something smart.
This week, the Centers for Medicare & Medicaid Services announced that reimbursement will be cut by 27% for percutaneous LAAO. Since I strongly believe there is little to no benefit for these procedures—perhaps even a net harm—I consider this a positive. Better would have been zero reimbursement unless the patient is in a trial. Then we would have an idea of whether this procedure works.
Keep in mind, my friends, that the PROTECT AF trial of warfarin vs Watchman did not pass FDA scrutiny due to internal validity issues. PREVAIL missed its first primary endpoint of stroke, systemic embolism, or CV death. Watchman did not meet noninferiority vs warfarin. Most patients having left atrial appendage occlusion (LAAO) would not have been included in the regulatory trials. And no clear data exist comparing LAAO to direct oral anticoagulants or no anticoagulation.
Also, a note to my enthusiastic EP colleagues. Go ahead. Keep posting on Twitter that you can do LAAO or AF ablation in 6.5 minutes. We get that you are fast. Do you think that payers don’t follow you on social media?
Finally, I am still trying to understand the new National Coverage Determinations (NCD) criteria for tricuspid transcatheter edge-to-edge repair (T-TEER). The matter in question is the coverage with evidence criteria wherein patients having T-TEER have to be enrolled in a proper study. I don’t know of one of those but will continue searching.
