Dec 15, 2023 This Week in Cardiology Podcast

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In This Week’s Podcast

For the week ending December 15, 2023, John Mandrola, MD comments on the following news and features stories.

Three Announcements

First, I made another mistake. In my post-Brazil podcast I said that we do not have Chagas disease in the United States.

Well, Dr Rachel Marcus, a cardiologist in Washington, DC, and medical director of the Latin American Society of Chagas, wrote to tell me that there are nearly 300,000 individuals living with Chagas disease in the United States, 57,000 of whom are estimated to have Chagas cardiomyopathy.

While I wish that I did not make errors, I am happy to receive comments such as these. I learn from them, and I am proud that people listen and take the time to correct me.

The second announcement is that it’s holiday time. This Week in Cardiology will take a Christmas and New Years break. We return on Friday January 5. I wish you all a peaceful time at the holidays.

I will have my Top Ten stories column coming soon on theHeart.org | Medscape Cardiology. In total, it’s about 2300 words, which is way too long. But I separate it into 200-word blocks. So, worry not. I hope you leave a comment and tell me about the stories that I missed.

FDA Approves PFA System for AF

• FDA Approves First Pulsed Field Ablation System for AF

The US Food and Drug Administration (FDA) has approved a pulsed field ablation (PFA) system for atrial fibrillation (AF) ablation.

PFA ablates cardiac tissue by delivering electricity to myocytes. Think shocks. People call them PFA “applications” but each application is actually a shock. The shock electroporates or creates pores in the cell membranes, and that is how myocytes are ablated. That is also why PFA is cardio selective. Namely, a cell has to have ion channels to be susceptible to PFA.

The system approved was the Medtronic system called PulseSelect. This is curious because nearly all of my European colleagues use a different system called Farapulse. The approval was based on a study called PULSED AF, which was reported at the American College of Cardiology (ACC) meeting last spring and was simultaneously published in Circulation.

• PULSED AF was a single-arm study of 300 patients.

• The primary efficacy endpoint was freedom from acute procedural failure, arrhythmia recurrence, or antiarrhythmic drug AAD escalation.

• The primary safety endpoint was freedom from a composite of serious procedure and or device related adverse events.

• Pulsed field ablation was shown to be effective at 1 year in 66.2% (95% confidence interval [CI], 57.9 to 73.2) of patients with paroxysmal AF and 55.1% (95% CI, 46.7 to 62.7) of patients with persistent AF.

• The primary safety end point occurred in two patients. One had a stroke and one a pericardial effusion.

• The procedural characteristics were not impressive, especially compared with European operators who are online bragging about 30-minute total procedure time. In PULSED AF, the procedure time was 134 minutes, left atrial dwell time 65 minutes, Xray time 26 minutes. General anesthesia was used in about 90%.

I realize this was a regulatory trial and this was a new system for the operators. And surely these times will improve, though I am not sure we will ever be as fast as the Europeans. Two other notable mentions:

• Success in eliminating AF was about the same as all other studies of AF ablation. That was also seen in ADVENT, a randomized controlled trial (RCT) comparing another PFA system and thermal ablation. I covered that study on the September 29 #TWICpodcast.

• The other notable is that there were two serious complications — one stroke and one tamponade. I note this because one of the selling points of PFA is safety.  PFA proponents point to its cardioselectivity which means PFA is less likely to damage the esophagus. That’s a good thing, but since esophageal injury is so rare, it would be hard to show any difference.

I have a Google alert set for “AF ablation” and it went crazy with news of this approval. PFA has created serious buzz in my field of electrophysiology (EP). I don’t know with certainty, but I expect other systems will gain approval. This will be followed by marketing blitzes. Maybe even on TV or YouTube.

I am always open to new technology, especially safer technology, but I am skeptical of PFA.

I recently gave a talk at the Brazilian EP Society titled “Is PFA a Game Changer?” My answer was, not so much. Here were my arguments:

• Efficacy is not any better than conventional thermal ablation.

• Efficiency: PFA may be a little faster than thermal ablation, though the empirical data do not suggest it’s much faster than thermal ablation. I do point-to-point radiofrequency AF ablation. It takes me about 70 to 80 minutes skin to skin. If PFA lowers that by 10 to 20 or even 30 minutes, how big an advance is that, really? I mean if you go from a 3 hour to a 30-minute procedure, that is big. But going from a 70 to a 50-minute procedure hardly seems like an advance.

Safety:  Yes, there are proposed benefits in avoidance of esophageal thermal injury.

• In the recently reported MANIFEST trial, a 17,000 patient observational study from Europe, with a different PFA system, there were no esophageal injuries. No pulmonary vein (PV) stenoses. And no permanent phrenic nerve injuries.

• Regarding phrenic nerve injury, however, in the ADVENT Trial, which was Farapulse PFA vs thermal, there were a number of transient phrenic nerve injuries in the PFA group.

• But in ADVENT, there was one death related to tamponade.

• There were strokes – albeit at a low rate.

• And, of course, there were also cases of tamponade.

To sum up the safety equation. We may (and it is a big may) be able to avoid esophageal injury, but there does not appear to be a reduction in the more common complications of stroke and tamponade.

• Another proposed benefit of PFA is left atrial posterior wall (LAPW) isolation. The LAPW is the area between the left and right PVs. Some experts believe that it should be ablated as well as the PVs, because the PV muscle bundles actually extend into the PW. The problem is that the recent CAPLA study found no benefit to thermal ablation of the PW.

• So PFA may be better able to ablate the PW — better because the esophagus limits how aggressive we can be with thermal ablation. But there is no data that convincingly shows the PW is an important target.

• Another reason I felt that PFA would not be a game-changer is cost. We don’t have the costs set out yet, but I’ve spoken with friends in Europe, and one of the main reasons why some have not started with PFA is high costs.

My final issue with PFA is that it is simply another way to destroy myocardial cells. The core problem with AF ablation, the reason why success rates remain similar to those reported 20 years ago, are that we don’t understand the underlying causes of AF. PFA does nothing to further our understanding of AF.

Possible Pulmonary Artery Hypertension Breakthrough

A couple of colleagues have called me out for not discussing sotatercept for pulmonary artery hypertension (HTN; PAH). One of them is an insider in the PAH space and says this is going to be a big deal. It’s not my area, so I report here as more of a journalist than expert.

As I was doing my year-end review, I came across the STELLAR trial, published in the New England Journal of Medicine in April.

• PAH is a rare and progressive proliferative disease of the pulmonary vessels. This results in narrowing of the distal vessels and subsequent pulmonary HTN. It’s not caused by pulmonary disease.

• The most common causes are idiopathic PAH, heritable PAH, PAH associated with a connective tissue disorder, or exposure to drugs such as methamphetamine.

• Recent research has highlighted the role of altered signal transduction by members of the transforming growth factor β (TGF-β) superfamily.

Sotatercept is a first in class fusion protein. I am way out on a limb here, but the idea is that the drug slows the proliferative process in the distal vessels.

I read the intro to the STELLAR trial and the biology is about 100 times more complicated than AF ablation.

The point is that subcutaneous sotatercept seems to work, on top of baseline therapy, such as prostacyclin infusion therapy. I also learned that there are 10 FDA approved drugs for PAH.

• STELLAR randomized about 320 patients; 47 years old; 80% female.

• The primary endpoint was change from baseline at week 24 in the 6-minute walk test.  There were nine secondary endpoints tested in hierarchical fashion.

• The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% C], 33.0 to 35.5 m) in the sotatercept group and 1.0 m (95% CI, −0.3 to 3.5 m) in the placebo group. 

• An increase in 30 meters is considered clinically important.

• The first eight secondary end points were significantly improved with sotatercept as compared with placebo. 

• Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.

The editorial was good. Quite good. Surprisingly critical actually.

The trial was enriched for patients with idiopathic and heritable pulmonary arterial hypertension (59% and 18% of patients, respectively), groups that commonly harbor disease-causing mutations ⁸; these findings potentially increase the likelihood of a favorable response to sotatercept.

“Only 15% of participants had connective-tissue disease–associated pulmonary arterial hypertension, less than half that typically encountered in clinical practice.

That last comment has meta-applicability, doesn’t it? Meaning, trials enroll ideal patients; those most likely to respond to therapy. It is not nefarious. It is what is done. Especially early on in development, you try to sort out ‘a’ population, some population for which a therapy works.

There was also a nice discussion on mechanisms and patient selection. Sotatercept works on the balance between proliferative and anti-proliferative signaling. But benefits may also come via non-PAH means, such as increasing hemoglobin concentrations or skeletal muscle efficiencies.

Merck noted in a press release that it has received priority review from FDA for a New Biologics License Application for Sotatercept. So we will learn soon whether this makes it to market.

Device Related Leaks in Percutaneous LAAO

A bunch of Greek authors have published a big meta-analysis of studies looking at the presence of and complications of peri-device leak after percutaneous left atrial appendage (LAA) occlusion. The first author is Athanasios Samaras. The European Heart Journal published the study. This paper was making the rounds on Twitter because its topline finding was that:

• Peri device leaks (PDL), when found by transesophageal echocardiography (TEE) were common and clearly associated with future bad events, such as stroke, and bleeding, and even death.

• But when PDL were found with CT scan, a) they were more common; but b) they were not statistically associated with future stroke events.

• The message therefore was, don’t worry about that recent SWISS APERO, Watchman vs Amulet study, which found that about 50% of LAA closures had patency (aka leaks) when assessed by CT.

I found some nuance here, and it doesn’t reassure us about the lack of full closure. Let’s look at their results.

• They take 48 studies, most of which were observational, and include nearly 62,000 patients. That’s a lot of patients.

• About one in four patients (26%) had a PDL by TEE. It was worse with CT imaging.

• CT-based LAA patency and PDL were present in 54.9% and 57.3% of patients, respectively.

• TEE-based PDL (i.e. any reported PDL regardless of its size) was significantly associated with a higher risk of thromboembolism (pooled odds ratio [pOR] 2.04, 95% confidence interval [CI]: 1.52–2.74), all-cause mortality (pOR 1.16, 95% CI: 1.08–1.24), and major bleeding (pOR 1.12, 95% CI: 1.03–1.22), compared with no reported PDL.

• A positive graded association between PDL size and risk of thromboembolism was noted across TEE cut-offs. For any PDL of >0, >1, >3, and >5 mm, the pORs for thromboembolism just go up: 1.82 (95% CI: 1.35–2.47), 2.13 (95% CI: 1.04–4.35), 4.14 (95% CI: 2.07–8.27), and 4.44 (95% CI: 2.09–9.43), respectively, compared with either no PDL or PDL smaller than each cut-off.

None of this is very new. The new stuff came in the analysis of studies that used CT scan. Here they found that neither LAA patency nor PDL by CT was associated with future thromboembolism.  The adjusted OR was 1.45 (95% CI 0.84-2.50)

They concluded: “Residual leaks detected by CT were more frequent but lacked prognostic significance.”

My comments. The proponents want a free pass. In other words, CT scans are too sensitive. They don’t predict events.

I don’t think so. Let’s go to the actual numbers.

• When you calculate the odds of future events with TEE guided leaks, you have tens of thousands of patients in the denominator. You also have many more events. This gives you tighter CIs and more confidence in the signal.

• When you calculate risk with CT, you have only a fraction of the patients. I counted. On Figure 4, there were only a few hundred patients exposed compared with tens of thousands.

• The hazard ratio for stroke for patency by CT scan was 1.45, or 45% higher. The CIs were wider because of the small numbers, but the signal of increased harm is there.

I think there is an extreme likelihood that there is a false negative here. But I do agree that future studies are needed, looking at the association between lack of patency on CT scan and future events.

Stroke Rates and Anticoagulation Decisions in Patients at Low to Intermediate Risk

The toughest patients are those with AF and non sex related CHADSVASC 1 scores. Persons with hypertension, with diabetes, person who are 66 years old.

Anticoagulation decisions with low or high risk are clear:

• CHADSVASC 0, don’t use oral anticoagulants (OAC).

• CHADSVAC ≥ 2, use OAC.

• It’s the intermediate-risk patients who are tricky.

A Norwegian group, one that I visited in the Fall, had a very nice database analysis looking at the questions of:

• Stroke and bleeding risk in AF patients with and without OAC who are in that CHADSVASC 1 group.

• Risk of stroke in non-anticoagulated patients with and without AF.

Their methods included a big Norwegian database, with one million plus individuals and 34,000 patients with AF.

They followed these patients for 8 years, or until an ischemic stroke, intracranial hemorrhage (ICH), increased CHADSVASC, or study end.

The authors calculated 1-year incidence rates in events per 100 person years. They then did Cox regression to provide adjusted HRs (aHR).

Results:

• Among those with AF, the Ischemic stroke incidence rate was 0.51%/person year in OAC users but 1.05%/person year in non-users. (aHR of 0.47, 95% CI 0.37-0.59)

• ICH incidence rate was 0.28%/person year in OAC users and 0.19%/person year in non-users (aHR 1.23 [0.88–1.72]). Not much difference there.

• OAC use was associated with an increased risk of major bleeding (aHR 1.37 [1.16–1.63]) but lower risk of the combined outcome of ischemic stroke, major bleeding, and mortality (aHR 0.57 [0.51–0.63])

• Non-anticoagulated individuals with AF had higher risk of ischemic stroke compared with individuals without AF but with the same CHADSVASC risk profile (aHR 2.47 [2.17–2.81]).

Take Home. Databases like those in the Northern European countries really help. Yes, they are still observational, and a clinician has to make a choice to treat or not treat.

In this case, they studied the most vexing population of AF patients – those with CHADVASC scores of 1. These are tough decisions because you don’t want a devastating stroke, but you also don’t want to commit a relatively young person to decades of OAC. Mean age of patients in this database study was only 61 years,

The main findings:

• The yearly stroke rate was 1% with AF and no OAC. Patients on OAC had a 0.5% risk. Or 53% HR reduction.

• And there was not much cost in terms of ICH; both were super low at less than 3/1000.

• Major bleeding was up by 37% but when compared with a composite net benefit type of endpoint, the higher rate of nuisance bleeding is swamped by lower rates of stroke.

• Finally, the rate of stroke on those CHADVASC 1 patients not on OAC was 2.5 times greater than for those similar risk patients without AF. So AF is a big risk in these patients.

This makes sense when we think about Andrew Foy’s four circles of domains on treatment effect. At age 61, with one risk factor, AF will substantially increase the risk of stroke, because there are so few competing risks of stroke. This is much different than for the older patients, say 85 years old, where AF may not change the stroke risk equation as much because there are many other reasons to have stroke.