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For the week ending Oct 4, 2024, John Mandrola, MD, comments on the following news and features stories: Reader feedback on late gadolinium enhancement (LGE) pre-implantable cardioverter-defibrillators (ICDs), pulsed field ablation (PFA) for atrial fibrillation (AF), chronic total coronary occlusion-percutaneous coronary intervention (CTO-PCI), endovascular ablation of the greater splanchnic nerve in patients with heart failure with reserved ejection fraction (HFpEF), and data sharing.

Last week I reported on a meta-analysis of observational studies of LGE in patients with nonischemic cardiomyopathy (NICM). At issue was the concept of risk stratification. Electrophysiology (EP) doctors care about predicting risk because we are asked to consider ICD placement in these patients.

At this moment, and for the past two decades, we base our ICD decision solely on left ventricular (LV) EF, as LVEF was an entry criterion for the seminal ICD trials. When the seminal ICD trials were done, LVEF was the best risk stratifier we had. Times have changed and now, many patients with newly diagnosed NICM get a cardiac magnetic resonance (CMR) imaging. CMR detects LGE, or scar.

The JAMA meta-analysis of more than 100 smaller observational studies reported a strong correlation between scar and ventricular arrhythmia, sudden death, HF, and overall mortality.

It's a compelling association because epidemiologic data comports with biologic plausibility. Namely, scar can act as a nidus for reentry.

Regarding the meta-analysis that found strong associations of LGE and risk, I spoke in optimistic tones about the possibility of using LGE on CMR to guide ICD recommendations. Of course, an ICD recommendation is basically a surrogate marker for arrhythmic risk.

The failure of the 2016 DANISH trial of ICD vs no ICD in patients with NICM to confirm an ICD benefit could possibly be explained by the fact that modern-day NICM patients have a lower arrhythmic risk compared with 20 years ago. The lower rates of arrhythmic death may be because medical therapy is better, or it may be because LVEF is not the best risk stratifier. Had we used scar burden as measured by LGE on CMR, we may have enrolled higher risk patients and given an ICD a better chance at lowering mortality. In fact, there are at least two ongoing randomized controlled trials (RCTs) using LGE to guide ICD decision making.

That was a bunch of words to say I was swayed by the meta-analysis and the idea of risk-stratifying with LGE.

However, an expert in imaging and an artificial intelligence (AI) researcher sent me a note of caution. He argued that, a) LGE tracks with LVEF, so, even with adjustments, many of the observational studies included in the meta-analysis could be confounded, and b) LGE is difficult to quantify.

My expert writer noted that the precision (or intraclass correlation coefficient for LGE is not so great. Perhaps even more variation than LVEF. (The reliability of measurement is important; I make fun all the time when patients worry about an LVEF measure. Say, it was 43% and now it's 41%. I tell them this is much like the data showing judges give harsher sentences before lunch.) The reason why I share this reader feedback is that I did not know there were reliability issues with LGE reporting.

I will share my colleague's conclusion because it so good:

A central thesis of medical imaging is that in the current state, variations in medical impressions is much more driven by human variation than image quality. I don't think one can say scar is better just because it's a more expensive or 'fancier' technology.

I could not agree more. The thing with ICDs is there is room for improvement in patient selection. The vast majority of ICDs placed for prevention are never used. And the vast majority of sudden arrhythmic death occurs in patients with EFs greater than 35%. Prediction is tough, but I hope technology can help us do better with patient selection.

I have an announcement to make: I may have been overly skeptical of a new technology. I know, it's hard to believe.

The journal Circulation has published the ADMIRE pivotal trial of PFA to treat paroxysmal AF. It's a great name for a trial, but it's not really a trial. It's merely a non-controlled study of 277 patients who had ablation using a novel catheter made by one company.

While this sounds like a highly specific EP topic, there are general medical lessons.

First. PFA is a new way to destroy myocytes. Instead of thermal energy (radiofrequency (RF) or cryoballoon), PFA uses electrical energy. Think shocks. The electrical energy creates pores in myocardial cell membranes, leading to cell death. We call this electroporation. In fact, the first ever ablation used DC shock to ablate the AV node.

The chief putative advantage of PFA is cardioselectivity. You can ablate the atria without causing pulmonary vein (PV) stenosis, or damage to the esophagus or phrenic nerve.

Proponents of PFA argue that avoiding these three complications makes PFA safer than thermal ablation.

Here comes the first lesson, an evidence-based medicine-type lesson. The proponent's safety argument is likely true, but evidence does not directly support it.

But these are not the most worrisome adverse effects (AEs) of AF ablation. The thing that keeps EP docs up at night is the roughly 1 in 5000 to 1 to10,000 risk of atrial-esophageal fistula, which usually happens weeks after the ablation and results in death in most cases. The worst part: most ablation folks, including me, believe the risk of damage to the esophagus is stochastic. Meaning it's mostly due to bad luck.

Bench studies show that PFA does not cause esophageal damage. But, given its rarity, trials of a few hundred patients could never sort out that signal.

Therefore, on paper, the "safety" of PFA looks similar. Yet not having to worry about a rare but devastating AE confers a major safety advantage.

Consider the probability of esophageal injury and death from the point of view of the operator. Using thermal ablation, if the risk of causing death is 1 in 5000, and you do 250 AF ablations per year, then it would take 20 years to cause one death. That might sound like a long time, but I can testify that it happens quickly. Remember, we often ablate middle-aged people.

For hospitals, and somewhat for docs, AF ablation is one of the most lucrative cardiac procedures. Hence, there has been an arms race to get PFA catheters on the market.

The marketing message will be that the catheter is both a mapping and ablation catheter. Since Johnson & Johnson makes the most common mapping system, docs can create a map and ablate and then create a post-ablation map. This makes for great pictures to put on Twitter. (Which I don't recommend doing, but people do it anyways). And it reduces catheter exchanges through a stiff thick sheath that is in the left atrium.

The other marketing message will be that one in four patients in this study had ablation without fluoroscopy. Doing ablation without x-ray is a parlor trick. Doctors brag about it. But then the same doctor does a biventricular device and gets 30 minutes of direct x-ray exposure. A couple of minutes of x-ray at the leg with shields is nothing.

The problem with the marketing message of fewer sheath exchanges is that three patients had cerebrovascular events. That's way too many given that these were 61 year-old patients with paroxysmal AF.

The authors say that the stroke rate will improve as operators get more experience. Maybe they will, but these are experienced operators. And I suspect many have been doing PFA with other companies' devices.

That said, I am now 2 months into my experience using PFA and I like it. It's fast. The signals go away, and patients don't get a lot of chest pain afterwards. Not worrying about causing death from esophageal fistula at 3 weeks is nice -- even though the risk is very low.

I've spoken to European colleagues, who have more experience with PFA, and they say that durability is still an issue. Early studies have shown that PFA is no better than thermal ablation in durability of PV isolation.

In sum, I like PFA's ease of use and avoidance of esophageal injury. I am using it. But I don't think it is a revolutionary breakthrough. It's incremental. Which is ok.

I forgot to say it's more expensive. But in TAVR dollars, it's not that bad.

The up-and-coming journal EuroIntervention has published the 3-year outcomes of an RCT comparing revascularization and optimal medical therapy (OMT) for CTO.

It's called the EuroCTO trial. First author Gerald Werner. This includes about 400 patients with CTO randomized to OMT or OMT and PCI.

The study has two primary endpoints: a quality of life (QOL) Seattle Angina Questionnaire (SAQ) done at 12 months, and major adverse cardiac events (MACE) or composite of cardiovascular (CV) death or myocardial infarction (MI) at 3 years.

In 2018, the authors published the results of the SAQ part.

The 3-year results were reported last month. A couple of things about trial procedures. This was a 2:1 randomization, with more in the PCI arm. Also, all non-CTO lesions were treated before randomization. Crossover from OMT to PCI occurred in 7.3% at 1 year and in 17.5% by 3 years.

Results:

Comments. The authors of this study see it differently than me. They argue that PCI of the CTO improves QOL outcomes at 1 year but there is no worsening of outcomes at 3 years. So full speed ahead. Let's help our patients vanquish their angina.

I am not seeing it like that.

I would argue that the first-year results of EuroCTO can be discounted because it's procedure vs tablets in an unblinded group. The procedure group is faith healed and the medical group is PCI-subtracted. They have subtraction anxiety. By the way, this is exactly why ischemia-driven revascularization endpoints were higher in this trial and in FAME-2.

For the angina results, not only does a lack of placebo arm bias the results for PCI, so does looking at angina at 1 year. COURAGE was clear in this, showing that angina differences favoring PCI over medicines waned by 2 to 3 years.

Rather than saying MACE outcomes were not worse at 3 years, I would say that an aggressive PCI procedure did not improve MI or CV death over medical therapy. In fact, in the intent-to-treat at 3 years the rates of MI or CV death were 3.7% for meds and 6.2% for PCI. There's no hazard ratio (HR) given but it's substantially in favor of OMT, though not "statistically significant." I wonder where the HRs are in this paper or journal?

The results are also similar to DECISION CTO, which also found no outcome benefit to CTO-PCI

The EuroCTO authors do tell us of and cite the rationale and design paper of the ISCHEMIA-CTO trial, led by a team in Denmark and Sweden.

I must be riding my bike too much early in the morning because I missed the idea that RF ablation of the greater splanchnic nerve (GSN) could be a treatment for HFpEF.

JAMA-Cardiology has published the results of the REBALANCE-HF RCT, which is sham controlled.

90 patients with HFpEF, median age 71 were randomly assigned at 15 centers. The procedure is something like this: femoral venous access, inferior vena cava, through the right atrium, superior vena cava to azygous vein retrograde, down to T-10 or T-11 intercostal veins. Then ablate 3 minutes. Sham does all this without ablation.

The idea with GSN is that temporary blockade of the GSN in acute decompensated HF and chronic HF have demonstrated a reduction of cardiac filling pressures at rest and exercise, which is thought to be driven by a greater degree of vasodilation (especially splanchnic venodilation) with increased abdominal blood pooling and resultant reduction in stressed blood volume.

REBALANCE is a phase 2 study so the primary endpoint is a reduction in legs-up and exercise pulmonary capillary wedge pressure (PCWP)at 1 month.

Comments. There are some things to like here.

As for the overall results, it is negative. The authors give us a responder analysis, and the right answer here is not to make causal inferences because trials are not powered to sort out signal from subgroups. Instead, the right answer, if you think this is plausible, is to pursue another trial randomizing patients with these characteristics.

To those who have knowledge about this procedure, Iet me know if I screwed up. I covered this because I love seeing RCTs leading the way for new products.

Circulation Outcomes has published a cautionary note on data sharing. The two authors, Dan Kramer and Brahmajee Nallamothu, are academics I have great trust in.

I am not sure what the stimulus was to opine on data sharing, but they definitely make the case for caution.

I have been very much a pro-data-sharing person. Dan and Brahm make the case that data-sharing has its problems.

Let me first say why I believe data ought to be shared.

I strongly encourage reading Kramer and Nallamothu's piece. They make strong points.

I would even argue that debunking flawed papers has a positive social value. For example, the TIMI group was motivated to address a re-analysis of the FOURIER trial. While they may not have liked it; the public learned a lot about critical appraisal and trial conduct.

Finally, I am least moved by their argument that primary data collection is hard; people spent time and sweat doing it. Others -- the so-called data parasites (my word, not theirs) -- should not be able to come in and easily get data to use without doing the work. To me, the potential value in finding an important discovery trumps the personal goals of the researcher.