Five Trials to Look for at ESC 2024

If you go to meetings to see presentations of major clinical trials, this year’s European Society of Cardiology (ESC) Congress will make you happy. There are 12 “hotline” sessions over 4 days. 
I will highlight five of these trials. 
Cardiology has mysteries. One of the biggest is how transcatheter edge-to-edge repair (TEER) of functional mitral regurgitation (MR) worked so well in the COAPT trial and failed in the MITRA-FR trial. 
Some experts point to a difference in patients, but that argument relies heavily on precise measurements taken from echocardiograms, which, when it comes to grading regurgitant lesions, falls short of precise. Some point to the funding of the divergent trials as an interesting association: the positive one funded by industry; the negative one funded by government. 
The RESHAPE-HF trial may act as tiebreaker. Investigators randomly assigned patients with functional MR and left ventricular dysfunction to TEER or medical therapy. The authors have published a baseline characteristics paper that included detailed comparison to patients in COAPT and MITRA-FR. RESHAPE-HF patients match up well to those in the other trials in regard to age, comorbidities, use of cardiac resynchronization therapy, and left ventricular ejection fraction (LVEF). But RESHAPE-HF patients may have had less severe functional MR. For instance, the RESHAPE-HF patients had lower mean B-type natriuretic peptide values, slightly better kidney function, less severe MR, and a lower mean effective regurgitant orifice than patients in COAPT and MITRA-FR. Use of guideline-directed medical therapy was also substantially more robust in the RESHAPE-HF trial. 
The authors of RESHAPE-HF argue that their trial enrolls a third unique cohort of patients. Their patients had mostly moderate to severe functional MR instead of the severe MR seen in the COAPT trial, and had less severe LV dilation than was observed in MITRA-FR.
Excuse me for even thinking this — I wish I didn’t — but the vigor of their argument in the rationale paper makes me wonder whether this is a set-up to preserve use of TEER for functional MR if RESHAPE (like MITRA-FR) finds no benefit. 
Another critical aspect of interpreting RESHAPE-HF is consideration of the primary outcome. The trial has not one but three primary endpoints. The first is total hospitalizations due to heart failure and cardiovascular death (similar to COAPT and MITRA-FR). But there are also two more primary endpoints: the rate of total (ie, first and recurrent) HF hospitalizations within 24 months, and the change in the overall Kansas City Cardiomyopathy Questionnaire score from baseline to 12 months.
This is a curious way to evaluate the device. First is the matter of blinding. TEER cannot be a blinded procedure because the clip is obvious on any imaging of the heart. A heart failure hospitalization requires a judgement from a clinician, so I worry about performance bias — as we should in all non–sham-controlled procedure trials. The third endpoint is even more at risk for bias because it measures patient-assessed quality of life in an unblinded trial. 
Another issue with the three endpoints is the statistical assessment. The authors write that they will use a hierarchical method that preserves statistical thresholds. But the possibility for spin is high when you have two softer primary endpoints. For me, the most important endpoint will be death and cardiovascular death. 
I don’t understand the design of the single-center MATTERHORN trial in Cologne, Germany, that will compare percutaneous edge-to-edge repair vs surgical repair in patients with functional mitral regurgitation, LV systolic dysfunction, and New York Heart Association Class II-IV heart failure. 
My question surrounds the lack of a medical treatment arm. By not having a medical therapy arm, the authors make the assumption that some intervention is superior to none. I trained a long time ago, when we learned that patients with severe functional MR and LV systolic dysfunction do terribly with surgery. I don’t think that lesson has changed. The conflicting results of MITRA-FR and COAPT argue strongly for having a nonprocedural arm in any functional MR trial. 
In the past three decades, nearly every strategy to prevent atrial fibrillation (AF) after cardiac surgery has been tried. Nothing has (definitively) worked. I now believe that the only way to avoid post–cardiac surgery AF is to avoid surgery.
German authors will present the results of a noninferiority trial, called TIGHT-K, which tests the maintenance of different levels of potassium after cardiac surgery. This trial makes my list because doctors’ infatuation with plausibility makes me smile. The thinking is that because potassium exerts electrophysiologic effects and low potassium associates with arrhythmia, we should keep potassium levels in the high-normal range after cardiac surgery. I know — it’s funny. 
The authors of TIGHT-K will test two strategies: keeping potassium levels in the normal range (above 3.6 mEq/L) vs more aggressive supplementation to keep the level > 4.5 mEq/L. My only hope is that when, as I predict, this trial shows no significant difference, doctors will be slightly less drawn to the Cartesian model of the human body being like a machine that can be tweaked. 
Finerenone is a novel mineralocorticoid receptor antagonist without steroidal side effects and with less propensity to raise potassium. The drug reduced hard outcomes (by modest amounts) in two phase 3 placebo-controlled trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and diabetes. These led to FDA approval of finerenone in July 2021. I have never seen the drug used in practice. That may change after ESC. 
The makers of finerenone have announced positive topline results of the FINEARTS-HF trial in patients with heart failure and a LVEF > 40%. The mean LVEF in the trial was 53%, similar to that in other trials of heart failure with preserved EF. The trial had fewer-than-expected events and the sample size was increased to 6000 patients. 
At ESC, we will need to assess the clinical significance and statistical robustness of this “positive” reduction of the primary endpoint of CV death or total heart failure events. It’s not clear how big the win is — relative to the cost of this brand-name drug. 
Finding breakthrough medical options for patients with HFpEF has proven difficult. Having any positive result in this patient population is notable, especially because patients in FINEARTS-HF were already on a substantial number of drugs at trial entry. 
The authors will follow this presentation with a meta-analysis of multiple trials using finerenone. Be cautious. I tend to favor individual trial results more so than complicated combinations of multiple trials. 
Millions of patients with AF have undergone ablation over the past 24 years. The CABANA trial of AF ablation vs drugs failed to show that ablation reduces hard outcomes. Outside of a highly selected group of patients with heart failure, the procedure has been done to improve quality of life. 
We have had no proof that the quality-of-life improvement after ablation of AF is resistant to placebo effects. My colleagues in EP (and I, too) think that AF ablation has more than a placebo effect. We think this because many postablation studies have correlated reduction of AF with improvement in quality of life. We also thought that coronary stents had a placebo-resistant effect on top of antianginal meds, but the first ORBITA trial humbled us. 
Rajdip Dulai, MBBS, will present results of the SHAM-PVI trial done in multiple centers in the United Kingdom. Investigators will enroll 140 patients with paroxysmal or persistent AF to either pulmonary vein isolation (with cryoballoon ablation) or a sham procedure (with phrenic nerve pacing and cardioversion if persistent AF). All patients receive an implantable loop recorder, which will provide the primary endpoint of AF burden at 6 months. Key secondary endpoints include to time to symptomatic and asymptomatic AF, total atrial tachyarrhythmia episodes, and patient-reported outcome measures.
This is a bold study, and I congratulate the authors for having the courage to design and conduct such a trial. I wish the primary endpoint was quality of life. I expect AF burden to be reduced in the ablation arm as this has been shown in many previous trials; the question the EP community wants to know is whether less AF burden leads to better quality of life. That said, SHAM-PVI is a great start. More placebo-controlled trials of AF ablation are ongoing. 
In addition to the 12 hotline sessions, there will be four new ESC Clinical Practice Guidelines released and 26 late-breaking science sessions. So, needless to say, these are just a few of the trials that drew my initial attention. 
John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.