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In This Week’s Podcast
For the week ending June 12, 2026, John Mandrola, MD, comments on the following news and features stories: Listener feedback, transcatheter tricuspid valve replacement, a new metabolic disease called CKM, the ARISE-FLUIDS Trial, the BIHCA trial, and temporal trends in ICD therapies.
Listener Feedback on LOSE-AF Trial
A listener emailed me this week to let me know how much I missed in speaking last week about weight loss in atrial fibrillation (AF). I covered the LOSE-AF study from two groups in the UK. The trial found that an intensive behavioral weight loss program induced weight loss but had no effect on any other AF-related outcomes.
The listener alerted me to three other studies that I should have mentioned — which were either not mentioned in the LOSE-AF manuscript or mentioned only superficially. It turns out that there are strong signals of benefit from behavioral-guided risk factor intervention. Let me briefly review:
The ARREST-AF trial was published in JAMA Cardiology in 2025. A total of 122 patients with obesity and atrial fibrillation AF undergoing initial ablation, randomized to lifestyle and risk factor management (LRFM) program vs standard of care in Adelaide. The active arm lost 9 kg (20 lb) more weight, and had a 47% significant reduction in the primary endpoint of freedom from AF at 12 months after ablation. Secondary measures were also improved including symptom severity and a 10 mm Hg decrease in blood pressure (BP).
European Heart Journal published the Dutch POP-AF trial. A total of 145 patients with persistent AF referred for pulmonary vein isolation (PVI) were randomized to a nurse-led integrated lifestyle treatment (ILT) before ablation vs normal care. The intervention arm lost 6 kg (13 lb) more and had a significant 51% reduction in the primary endpoint of repeat ablation or cardioversion in the first year. As in the Australian trial, BP was also reduced in the active arm.
JACC published the PRAGUE-25 trial in 2025. A total of 200 patients with obesity and AF were randomized to lifestyle modification (diet + exercise) + antiarrhythmic drugs vs catheter ablation. The intervention arm lost 6.7 kg (15 lb) more but catheter ablation did better at reduction of the primary endpoint of being AF-free: 73% (ablation) vs 35% (lifestyle+AAD); non-inferiority not met (P < .001 for superiority of ablation). I actually covered this trial last summer and my take was that even though it sits in JACC as a negative trial for lifestyle management, the AF burden and quality of life scores were similar, and the lifestyle management group lost more weight, had better A1c and VO2 max. So, I considered it a positive trial.
Now, all of these positive trials have serious limitations in that they are small, mostly single-center, and obviously unblinded. They are at risk for the normal performance bias seen in pragmatic trials. That said, though, regardless of AF outcomes, the lifestyle interventions resulted in superior metabolic health — and that may be as important as AF outcomes.
Imagine a future where these interventions are combined with GLP-1s. Honestly, the AF epidemic might be slowed.
Listener Feedback on FLECA-ED Trial
Dr John Rozich from South Carolina writes that my enthusiasm for IV flecainide’s superiority of amiodarone in patients with stable coronary artery disease (CAD) without ischemia is [quote] “at odds with the reality that you yourself highlighted in that many hemodynamically stable patients with PAF, self-convert with beta-blockers and time, and providing them with an anticoagulant may be all that is needed.”
Dr Rozich worries that if IV flecainide were let loose in the real world where many ED’s have no cardiology support, safety may be an issue. I always agree with safety concerns.
I went back and looked at my comments and yes, maybe I was a bit too muddy on the matter. I was indeed positive about the trial. IV flecainide was clearly better than amiodarone, which is a lousy cardioversion drug. But then I noted the RACE 7 Dutch trial showing clear benefits of delaying cardioversion. I guess I would clarify by saying that the vast majority of patients with new, early AF can be managed with time, reassurance and follow-up. But when we think cardioversion may be useful — say, in a more symptomatic patient who really wants out of the AF — IV flecainide is a lot better than amiodarone.
Feedback on ALLEVIATE-HF trial
Finally, feedback on my comments on the negative ALLEVIATE-HF trial of implantable loop recorder (ILR)-guided management of heart failure (HF). This from Dr Marc Louis Baker.
I offer his comments with a direct quote that is so good that I really have nothing more intelligent to add. He nails the human nature part of caring for people in medicine:
The problem with heart failure is really a social one. When there’s a disconnect between the alert and the intervention as mentioned in this recent trial, it is because there aren’t enough people to care for heart failure. The failure of CardioMEMS and complaints from the FDA about company nurses display this problem. The company nurses offered good interventions not thought of by the burned-out staff in the trial.
Doctors want to fix things; it’s why we do ablations and stents, and heart failure doesn’t offer that immediate gratification. A device monitor can help alleviate the strain of the chronic care team, and very bluntly can help with funding for a problem that nobody wants to pay for. It’s not a “sexy” problem identified with celebrities and youth.
Humans want to help other humans, but they also want to “see” their interventions have effect in a short attention span time period. That doesn’t happen with heart failure. Someone has a heart attack, you open that artery, and YOU feel good about what you did. As silly as this sounds, until heart failure and other chronic medical issues are made to satisfy the mental health of their caregivers, this problem will persist. If we continue to ignore the mental health of our caregivers who treat these chronic conditions, these problems persist.
Transcatheter Tricuspid Valve Replacement
The TRISCEND II trialists have published a paper on the costs of adverse events after transcatheter tricuspid valve (TCV) replacement with the Edwards Lifesciences EVOQUE valve. They analyzed 155 patients who had the valve as part of the TRISCEND II study. The main reason I highlight this cost-of-adverse-events study is that the frequency and severity of adverse shocked me. Truly.
I think it’s worth going back to the TRISCEND II trial and think about this intervention.
As always, the three tenets of tricuspid regurgitation (TR) hold true: a) TR is common and contributes to serious morbidity in patients with HF; b) TR is almost always secondary to the maladaptive process of right ventricular/left ventricular adaptation in HF, and c) surgical intervention for isolated TR is a highly morbid operation.
Percutaneous strategies, therefore, hold great promise. But since there are so many patients with TR, and doctors make money from procedures, the risk of indication creep and overuse is substantial.
As you all know, I look at this problem as a Neutral Martian. I don’t do these procedures, though I often get involved after the patient has heart block and then needs a pacemaker.
NEJM published the TRISCEND II trial in October 2024. About 400 patients with severe symptomatic TR in a 2:1 ratio to TCV replacement with EVOQUE or medical therapy alone. A hierarchical composite endpoint of death, right ventricular (RV) assist device, post-index tricuspid valve intervention, heart failure hospitalization (HHF), improvement in KCCQ, improvement in NYHA functional class, and 30 seconds gained on 6-minute walk test favored the valve replacement group. Of course it did.
The win-ratio analysis however was driven by valve interventions, KCCQ and NYHA improvement — all subjective endpoints vulnerable to the bias of an open-label trial done at centers that love doing interventions. More objective endpoints, such as death, HHF, and 6-minute walk tests were not different.
As for safety, severe bleeding occurred in 15.4% of patients in the valve-replacement group and in 5.3% of those in the control group (P = .003) and permanent placement of a pacemaker occurred in 17.8% of patients in the TCV arm vs 2.3% of those in the control group.
In the follow-up study, where only 155 patients of the 259 total had available cost data, the authors report that complications occurred in 20% of patients, most commonly new pacemaker or cardiac implantable electronic device (CIED) implantation (9.7%) and severe bleeding (9.0%).
Pause there: 1 in 5 patients had severe adverse events. Not surprising is that these add substantial costs to the procedure. The paper did not tally extra costs in the control arm, likely because there were so few compared with the valve replacement arm.
The new paper doesn’t really add much to our knowledge. Rather, it brought my attention to how bad this procedure is. I mean, what are we doing? The seminal trial, TRISCEND II, finds no difference in objective endpoints, such as death. There wasn’t even a reduction in HHF — which is remarkable, because this endpoint is highly susceptible to bias.
If you have this valve vs medical therapy you are 9x more likely to need a pacemaker (and not an easy one because we don’t put standard pacers through valve replacements) and are 3x more likely to suffer severe bleeding, and for that you get no reduction in death or HHF.
In my opinion, this is failure of both regulation and critical appraisal. Looking back at this trial, TRISCEND II might be worse than TRILUMINATE (the tricuspid transcatheter edge-to-edge repair trial). And I did not think it was possible to get worse than TRILUMINATE.
More Disease Creation — the CKM Syndrome
Journalist Crystal Phend has nice coverage of the first-ever guideline for CKM syndrome. This reads like a comic tragedy repeated since the creation of prediabetes and pre-hypertension.
That is, we now have three branded drug classes (SGLT2 inhibitors, GLP-1 receptor agonists, and the always positive nonsteroidal mineralocorticoid antagonist finerenone). So, we must have a disease for these to treat.
Enter CKM, or cardiovascular-kidney-metabolic syndrome. I kid you not. No longer, my friends, should cardiovascular health be separated from metabolic and kidney health. It’s all one now.
CKM comes with four stages. Stage 1: A person is just obese. Stage 2 is being obese with high blood pressure, high triglycerides, or diabetes. Stage 3: CKM is subclinical CV disease and CKM risk factors such as a high PREVENT score or very-high kidney disease risk by being, get this…and I quote: “stages G3a with A3, G3b with A2-A3, or G4-G5 range).” I swear that I read that as written. That’s not me having a TIA.
Only Stage 4 includes having ASCVD, or HF, or stroke, or peripheral artery disease or even AF with obesity.
Figure 4 in the Circ paper is a “ CPR framework — calculate, personalize, reclassify” for primary prevention of CV disease. It has 7 rows, 10 columns and 20 decision arrows, at least.
My criticism of this is similar to the lipid guidelines. It’s too complex and too self-evident. I mean, you can have three stages of this new syndrome and not have any disease — just abnormal lab values. You can be obese, minimally mobile, a smoker and if all your labs are ok, you barely have CKM.
Do we really need a many-thousand-word document, and a new disease name, to counsel patients on weight loss and treat them with SGLT2 inhibitors when they have type 2 diabetes or chronic kidney disease (CKD), and GLP-1 when they have obesity, diabetes, sleep apnea, or ASCVD? And don’t get me started on finerenone, because every positive trial of this drug is marred by the fact that it’s compared against placebo instead of spironolactone.
Another problem with these new diseases is it scares patients. I can’t tell you how many patients I have seen who tell me they have stage 3 kidney disease. Which sounds terrible. Then I look and their creatinine is 1.5.
I simply think we could do with fewer disease categories and fewer treatment guidelines, and this is a classic example.
Two Trials That Teach Important EBM Lessons
I want to go over two trials that are peripherally involved with cardiology that teach super important evidence-based medicine lessons, one in NEJM and one in JAMA.
I, and maybe you, don’t treat patients with sepsis. But we have all seen the Surviving Sepsis Campaign (SSC) guidelines which give what some call weak recommendations for early, high-dose IV fluids. According to ICU doctor Josh Farkas these have often been weaponized as quality measures and resulted in doctors being pressured to prescribe arbitrary volumes to patients.
I have seen patients diagnosed with sepsis, then flooded with fluid who then developed worsening respiratory failure due to acute respiratory distress syndrome (ARDS) or even just pulmonary vascular congestion.
Another approach to early sepsis is a more-restrictive fluid resuscitation and earlier use of vasopressors. Previous trials of these two strategies have been inconclusive.
NEJM has published the large ARISE FLUIDS pragmatic trial of the two strategies. The primary outcome was “days alive and out of the hospital” from randomization to 90 days. That is a good endpoint.
Approximately 1000 patients were randomized. First thing: patients in the vasopressor groups received less fluids (about a liter less on average). And the percentage of patients who received vasopressors was 19% higher in the vasopressor arm. This speaks to trial procedures.
The primary endpoint was about as null as null can get: At day 90, the median number of days alive and out of the hospital was 76 (interquartile range, 55 to 83) in the vasopressor group and 76 (interquartile range, 55 to 82) in the fluids group (difference, 0.0 days; 95% CI, −2.7 to 2.7; P = 1.00). Other secondary outcomes were also no different.
One safety outcome was different. Only 0.6% in the vasopressor arm had pulmonary edema vs 5% in the fluids group. That’s a relative risk (RR) of 0.12 or an 88% reduction in the risk of pulmonary edema.
My Comments
This is a great example of the over-reach of guidelines and protocoled medicine. People get all upset about practice variation, so sometimes they try to stomp it out using guidelines and protocols. But these guidelines are highly fallible, so what may occur is that you standardize care in a way that harms everyone equally.
It’s also worth thinking about where these guidelines came from. Farkas also noted they were initially motivated by raging cases of toxic shock syndrome (eg, Rory Staunton, a 12-year-old from Queens who grazed his arm playing basketball back in 2012, was sent home with Band-Aids, and later died of sepsis.)
I mention this trial and story because it is yet another example of how well-intentioned guidance can run amok. This is a great trial, but it should have been done a long time ago.
You would hope that one of the role of our professional societies would be in preventing such medical reversals. Instead of cozying up with industry or promoting rent-seeking money extraction programs like the American Board of Internal Medicine (ABIM) testing initiative, our professional organizations should be beacons of science wherein academics prevent over-reaching guidance. They would promote proper trials before coercing doctors with ill-guided performance measures.
Note that the trial does not say to use high-dose fluids or earlier vasopressors. It merely says one is not superior to the other, and there should be no protocol for all patients with sepsis. Thus, the use of high dose fluids is no more a quality measure then the length of the review-of-systems in the note.
Sodium Bicarbonate for Inpatient Cardiac Arrest – The BIHCA trial
Despite the lack of evidence, many doctors give sodium bicarbonate as an acidic buffer to patients who have cardiac arrest. This is one of those old-school plausibility arguments: cardiac arrest causes low perfusion, which creates an acidosis, which then hampers cell function. Correction of the acidosis with bicarbonate creates a more favorable healing milieu.
It turns out that current guidelines do not recommend it, but no matter, doctors do it. I’ve seen it done since the 1990s. And it’s still done to this day.
Now we turn to Denmark, where nearly 3000 patients in 21 hospitals were screened, 913 determined eligible, of whom 779 were randomized to IV bicarbonate or placebo in the setting of in-hospital cardiac arrest.
The primary endpoint of return of spontaneous circulation occurred in 39% in the bicarb group and 37% in the placebo arm. You don’t need statistics but if you’d like, the risk ratio was 1.05 [95% CI, 0.88-1.24]; P = .62). Note the tight confidence intervals wherein the lower bound was 0.88 or 12%, which pretty much excludes a clinically meaningful benefit.
At 30 days, 12% in the sodium bicarbonate group and vs 9.1% in the placebo group were alive (risk ratio, 1.25 [95% CI, 0.84-1.88]). Favorable neurologic outcome was also not different.
Nor were there any signals in the subgroups, so for those doctors who think they can identify a specific sort of patient who will benefit from bicarb, there were surely no obvious signs of treatment effect heterogeneity.
My Comments
This is another example of a strong trial where a high percentage of eligible patients were included. It was placebo controlled and had a good primary outcome choice. Return of spontaneous circulation (ROSC) is a better endpoint for one dose of bicarb than, say, favorable neurologic outcome because obtaining a favorable neurologic outcome has many other factors on the causal pathway. If effective, bicarb is supposed to aid in immediate recovery, making ROSC a better outcome.
This reversal in medical practice is even stronger than the sepsis reversal because there was actually zero prior evidence that bicarb was effective. So now you have a terribly pessimistic prior distribution combined with very strong null data showing no benefit. Combining these for a posterior distribution would yield absolutely no reason to use this intervention in cardiac arrest.
In fact, the use of bicarb for in-hospital cardiac arrest may be a marker for a dumb clinician who does not use evidence.
The Decline of Ventricular Tachycardia in Heart Failure
EP Europace has published a super nice observational study from the EP group in Basel who consistently put out great work — both observational and trials.
The paper is titled, “Contemporary trends and outcomes in European ICD recipients: a 15-year analysis.”
The research idea is to understand temporal trends in how the implantable cardioverter-defibrillator (ICD) is functioning. It’s important because the seminal trials of ICD benefit in patients with HF were done more than 25 years ago, and HF therapy has changed quite a bit.
In two centers, Erasmus in the Netherlands and University Hospital Basel, they analyzed just under 2200 patients with ICD. About 60% had the ICD for primary prevention. The total time period was 2002 to 2017 broken into 4 time periods: 2002–05, 2006–09, 2010–13, 2014–17.
The primary outcome was first appropriate ICD therapy (anti-tachycardia pacing and/or shock) for ventricular tachycardia (VT) or ventricular fibrillation (VF), censored at 60 months.
Baseline characteristics yielded some expected findings: recipients had modestly higher left ventricular ejection fraction (LVEF) and better functional status, with higher guideline-directed medical therapy (GDMT) uptake.
The key finding was that at 60 months, appropriate ICD therapy declined from 35.7% (2002–05) to 20.2% (2014–17), driven by fewer VT events (29.8%–12.7%), whereas VF remained low and did not change materially.
Overall mortality did not differ significantly across eras, but the proportion of deaths classified as arrhythmic decreased.
In adjusted analyses, QRS duration independently predicted ICD therapy, whereas LVEF was not independently associated; later implantation eras had lower odds of therapy.
My Comments
The first thing to say is that this is an excellent use of observational data. It tells the important story that the amount of ventricular arrhythmia in HF is plummeting.
It confirms an important observation from the HF trialists who published in the NEJM in 2017, first author Li Shen, that when they looked at 40,000 patients in all HF trials from 1995 through 2014, the rate of sudden cardiac death has declined substantially.
Specifically, in the observational study of RCTs in HF, the cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial.
The cause of these declines is likely multifactorial, but surely better GDMT is the likely reason.
Both the Basel analysis and the NEJM analysis end in 2017, but I really wonder if we had a fifth time period from 2017 to now, I strongly suspect VT would be even lower. Though that is just a prediction.
The main teaching point is that declining rates of VT and sudden death set the stage for new trials testing the primary prevention ICD.
In an era when HF therapy was weak, the proportion of sudden death to HF death or all-cause death was high enough that the ICD lowering sudden death was enough to move all-cause death.
But now, if VT is occurring less, you’d expect the ICD benefit to be lower, and since the ICD comes with a fixed, finite risk, the harm/benefit calculus no longer favors the device. This is exactly what happened in the DANISH trial of non-ischemic cardiomyopathy, where there was no ICD benefit.
Data like this should strengthen the equipoise needed to enroll in the European PROFID EHRA trial of ICD use plus GDMT vs GDMT alone in ischemic cardiomyopathy patients.
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Cite this: Jun 12, 2026 This Week in Cardiology Podcast - Medscape - Jun 12, 2026.
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