May 01 2026 This Week in Cardiology

School's out today because it is Kentucky Oaks, the day before the Kentucky Derby, and tomorrow our city is electric. Okay, time to quadruple therapy in Hefref.

Jamal Cardiology has an interesting observational study taken from the Veterans Database. Joshua Jacobs is the first author of the study and is designed to characterize something I have not yet heard about. The TTQ. or time to quadruple therapy in patients with hefref. Now the background here is obvious. Patients with hefref do better if they can take to four drug classes.

Hard fire experts want us to move fast and get these drugs on board as soon as possible. Of course, this is easier said than done in the real world. Now the idea of this look back study was to look at the use of quadruple therapy, RAS inhibition with ACE inhibitor RBRNI, beta blockers, MRAs, and SGLT two inhibitors. TTQ was defined as the first date that the four medicine classes overlapped. VA data is good enough to know these things. The main findings had an interesting twist.

First, the total cohort was just about fifty two thousand veterans, mostly men who Slightly more than one in five patients, so twenty-one percent, achieved quadruple therapy at a mean of two point nine years. The median TTQ was 197 days, so about six months, but there was a huge spread from 49 days to 528 days. Here's the twist of the study. Black patients, Hispanic patients, and those from racial or ethnic groups had higher rates of quadruple therapy than white patients.

Uh black patients were 22% more likely to have quadruple therapy, Hispanic patients 21% more likely to have quadruple therapy than white patients. Now, a not surprise finding was that prescription copace made a difference. Compared to veterans in the most service connected status, so-called priority one, who have no copay, those with copayes had an eight percent lower rate of achieving quadruple status.

Rates of quadruple therapy were higher among veterans with an outpatient Hefref diagnosis, higher with those with diabetes, and those with out chronic kidney disease. Okay, the comments about this. The first thing to say is that this is a decent use of observational studies, right? It's not comparing outcomes, it's not trying to emulate an RCT, it's descriptive. And I would have never guessed that black and Hispanic patients would have higher rates of quadruple therapy.

This goes against the common theme that these patients gets wor gets worse care based on race. Now maybe it's the VA system, maybe these patients have better blood pressures. I don't know, but it's a really interesting observation nonetheless. Now I want to say a word on this TTQ, time to quadruple therapy measure. The author is right, enthusiastically I might say that quote, TTQ represents a potential

novel benchmark for policies, institutions, clinicians, and patients, end quote. And I could not disagree more strongly with that sentence. we must always remember the all important Goodhart's Law. Goodhart, an economist, famously wrote that once a measure becomes a target, it ceases to be a good measure. We should have learned this lesson with hospital readmission penalties, which are as likely to increase mortality as improve it.

Now, I am a proponent of quadruple therapy. I do it, but I am also a realist and I push back on the key opinion leaders who push this as if it is always possible. I think proponents are too quick to cite inertia as the cause of low rates of quadruple therapy. Doctors aren't just lazy about it. Sometimes patients don't want to take all these pills. Sometimes doctors don't want to risk side effects. Sometimes cost get in the way.

When possible I s prescribe the four drugs, but I think it is important to do it correctly. What drives me absolutely bonkers. Bonkers is when a patient with new severe left ventricular dysfunctions comes in with soft blood pressure, evidence of low perfusion and volume overload, and a doctor's start beta blocker. This is totally wrong. Totally. These patients who have a failing heart should have gentle titration of ACE inhibitors first. Rub some captapril on their tongue, if you wish, but

Just get them started on afterload reduction. The failing heart needs afterload reduction. Save the beta blockers. for the outpatient clinic where the trials were actually done, uh in ambulatory outpatients. All right, next topic is the avant garde trial. At Heart Rhythm Society meeting in Chicago,

We heard results of the Avantgarde trial of PFA versus antirhythmic drugs as first line therapy in patients with persistent, persistent AF. At first glance when I thought saw this trial in the New England Journal of Medicine, I thought, Here we go with another marketing trial designed to sell more products. I thought this because Oodles of trials have already clearly established that AF ablation is better at suppressing AF episodes than drugs.

Further, we already know from at least five trials that PFA produces similar or better results compared thermal ablation with either RF or cryo. So my thinking was that this would be a slam dunk for PFA. New England Journal published the trial and the company would have yet another reason to bring free burritos to doctors' offices. Yet, yet when you look under the hood of the results, I think you find extremely disappointing results from the Boston Scientific PFA system.

The trial had pretty standard procedures, right? Two hundred patients randomized to PFA, a hundred to antiarrhythmic drugs. The primary end point was short term and long term success through twelve months, only one year. Short term success was defined as procedural success in the PFA group and the absence of ablation during the blanking period, which is ninety days after treatment initiation in the drug group.

Long-term success was defined very typically as freedom from recurrence of atrial arrhythmias, freedom from repeat ablation, freedom from the need for antiarrhythmic drugs in the PFA group, and then freedom from ammiodorone use at any time in either group. The primary safety endpoint was device and procedure related serious adverse events. In the PFA arm, all patients had successful pulmonary vein isolation and posterior wall isolation.

By the way, posterior isolation is done with PFA because it's easy. Right? The two circles around the PVs come so close to each other on the posterior wall you just have to do a few more deliveries in the middle of the circle so that That's enough to take out the posterior wall. Now we know no studies have shown it that it's beneficial, but like I said, it's convenient.

It's totally different from trying to isolate the posterior wall with RF, which is difficult and dangerous due to esophageal thermal injury. PFA does not heat the esophagus enough to do thermal damage, at least that's the thinking so far. Now, one more rub in the trial procedures. The drugs that were used were flaconide in just about half, and sodolol in twenty eight percent.

Only seven percent of patients received opetolide. The mean number of drugs per patient was usually just one. One point two was actually the mean number. About two-thirds of patients in the drug group had cardioversion, and I mentioned the drugs because phleconide is terrible for persistent AF. Dolphetolide is our most common drug and amiodorone, the most effective drug, was not allowed in the trial, so the drug arm was highly disadvantaged in the avant-garde trial.

The results at twelve months the primary endpoint occurred in fifty-six percent of the PFA group versus thirty percent in the drug group, that hazard ratio zero point four six, highly statistically significant. But The main driver of the composite primary endpoint was a lower occurrence of asymptomatic AF of more than one hour. Notably, all these patients had loop recorders.

Symptomatic AF, the AF that patients care about, occurred at the same rate in both arms, 2% versus 3%. Median AF burden was very low in both groups, 0% in the PFA arm and 0.3% in the drug arm. The mean AF burden was three point four percent versus six versus nine point nine percent, respectively. Now the most notable result came in safety. Six strokes occurred. Pause there. Six strokes. And this led to a pause in the trial for consultation with neurologists.

They then modify the trial, which is disallowing anyone with a Chadsvas greater than four to They required TEEs, they required uninterrupted anticoagulation, and they required an ACT greater than 350. They then did 74 more patients without stroke, but that's only 74 patients. The other strange thing with the safety analysis is that they did not simply compare the two arms.

They just said that safety had to be less than twelve percent. Why twelve percent? I have no idea, but that is a ridiculously high safety margin. In fact, their point estimate for safety was five point one percent complication rate, but the upper bound of that was nearly nine percent. So my comments. The authors wrote a positive conclusion in the New England Journal of Medicine and news coverage was mostly positive.

PFA beats drugs as first line therapy went the message, but these results are not only not good, they border on the terrible for this brand of PFA system. A safety event of 5% is nearly five times what we would expect from modern AF ablation. We usually quote about a 1% risk.

that there were six strokes is far more than five times what we see in practice. In our practice at at Baptist in Louisville, we have not seen a stroke in our center in a decade or more, like zero strokes in thousands of cases. I've now received three private messages from colleagues in North America and Europe who have told me about strokes with their PFA systems. Each one noted the same thing. They just said we've never had strokes until now.

And it's not just opinion. Uh in in the article that I wrote on the Heart.org on avant garde, I cited a meta-analysis of fifty-six ablation trials, and they found a periprocedural stroke rate of zero point seven percent. Now the efficacy in Avant Garde was also disappointing. While the top line composite primary efficacy endpoint made superiority, so it's positive, it was on the basis of asymptomatic AF of more than one hour noted on a loop recorder.

Symptomatic AFib was very low in both arms and not significantly different, and this was despite using largely ineffective antiarrhythmic drugs. Now in support of the disappointing efficacy results of AF suppression were five quality of life surveys, none of which showed a statistically significant improvement with PFA, and remember this is an unblinded trial. So

In the column that I wrote, I proposed another antiarrhythmic drug-friendly framing. Here's what I thought. Only thirty-two percent of the patients in the drug arm had crossover to ablation due to recurrent symptoms. So an anti arrhythmic drug first strategy. Even with inferior drug choices, delivered similar results for symptomatic AF, no difference in quality of life, no strokes, with nearly half having an AF burden below point three percent.

And more than two thirds of the patients achieve these results without without undergoing an invasive procedure. And my conclusion differs from the authors. I think this is bad news for this PFA system. Strokes are bad. Strokes should not occur with AF ablation. The efficacy in avant-garde was bad compared to ineffective drugs, and there was no difference in quality of life.

My question is whether this is a problem with the Boston Scientific Brand of PFA system or whether we as a profession are getting over our skis about PFA. We often throw around the three letters PFA if they are the same, but they are not the same, right? Catheters, she's delivery systems differ quite a bit. Also different are the electrical algorithms that the pulses deliver. I think we need far more study, including head to head comparisons of PFA systems.

I remain strongly optimistic about PFA as a technology. It's faster, it's easier on the patient, and we are seeing excellent results with our chosen system. It's not the Boston system, but honestly, studies like this give me a lot of caution.

All right, next topic. Speaking of scary news on PFA, I want to tell you about the Tiffany study. Professor Roland Tills from Lubeck, along with a list of highly prominent European electrophysiology professors, presented the Tiffany study at HRS. Right now it's an abstract, but it's uh the paper is written up and will be published. You had better sit down or stop riding your bike for this topic.

This was an investigation using three sources of data: the FDA's MOD database, procedural volumes from public sources or manufacturers. And the relative rates of ablation procedures from the global EMBOL AF registry. The authors found four hundred twenty seven reports in Maud with death as an adverse outcome from ablation.

Over the entire study period, a total of one hundred seventy eight death reports were noted following RF ablation, one hundred and thirty four following cryo ablation, one hundred and thirteen following PFA. and two following laser ablation. After the introduction of PFA technology in 2021, a total of 292 fatal cases were reported, including 36% after RF, 25% after cryo, and 38% after PFA.

Cardiac tamponade remained the most common cause of death. The second most common was atrial esophageal fistula following thermal ablation, whereas arrhythmic events represented the second most frequent cause of death after PFA. The next part of their study was to use the total number of procedures as a denominator. So for cryoballoon mortality was zero point zero zero eight six percent. For PFA it was zero point zero one seven eight percent.

If you divide those, it's almost exactly two times higher rate of death from PFA than cryoballoon. Now the authors could not reliably find the total number of RF ablations, but in the MBOL AF registry of three hundred thirty five ablations, RF was used seventy percent of the time. So by imputation, RF seemed to have the lowest mortality, whereas cryobalone, PFA, and lasers were 2.6, 3.7, and 3.5 times higher. So the comments on this.

The authors were careful to note that the limitations of the MOD database, which is voluntary and it's hardly systematic. They also found very low mortality rates with all ablation systems and whether PFA is actually worse is hard to say from this study. But we also must not forget the important study from the German group led by doctor Gunnarwardin et al. This was in circulation and they just recently described a series of eleven patients who had

who had both myocurial ischema and fatal arrhythmias due to uh PFA ablation. Uh I talked about this in the February twenty-seventh podcast. But this particular MOD study study is an important study. It's also a brave study because the enthusiasm among our professional leaders and societies about PFA is massive. Young operators may have had patients with PFA complications, but they may be reluctant to speak up. They may be especially worried about singling out a specific PFA system.

I want to add one more quote. This is from doctor Alberto Alfi, a prominent EP in Argentina, who posted on X quote. After twenty years in EP, I've never seen hype like PFA. Point by point RF, when done properly, delivers excellent results with no clear superiority of PFA. Are we driven by better outcomes or by speed, simplicity, and industry momentum? Time to refocus on science over marketing. He adds, PFA offers a meaningful safety advantage, particularly regarding esophageal injury.

But superiority in durable outcomes versus optimized RF remains unproven. Early adoption is inevitable, but it should be thoughtful, evidence-based, and patient-centered. Balance over hype. Again, I remain a PFA proponent, but we need to slow down and think, gather data, analyze it humbly, and be transparent about our findings.

Alright, next topic is a the treat PVC trial. Jack EP has published this week a wonderful sham-controlled RCT. of low level tragus stimulation of the auricular branch of the vagus nerve for patients with PVCs. And again, I love this trial, but before I tell you about the elegant, simple trial, let's say a word about Uh low level tragous stimulation. This is a novel, non-invasive way to modulate activity of the autonomic nervous system.

by stimulating the auricular blanch of the vagus nerve, which are afferent fibers, at the tragus of the ear, LLTS modulates the activity of multiple brain stem nuclei. It leads to enhanced peripheral vagal activity and reduced sympathetic outflow. Previous studies have shown that LTS may suppress AF. It may attenuate inflammatory responses and improve ventricular remodeling and endothelial function, as well as improve diastolic function in patients with HEFPEF.

For the treat PVC trial, patients had to have symptomatic PVCs with a greater than ten percent burden. They were randomized to low level tragos stimulation versus sham stimulation with stimulation to the ear lobe, right below the discomfort threshold for one hour daily. The active stimulation group participants received LLTS via a transcutaneous electrical nerve stimulation device.

and it used a tragus detached ear clips, targeting vagal innervation and sham received identical electrical stimulation parameters, but to the earlobe where there is no vagus nerve branch. The primary outcome, of course, was reduction of P V C burden at six months and was assessed by using ten day ECG monitoring.

About 100 patients were enrolled. The baseline characteristics included a PV sir uh PV burden of about 18%. Adherence to the stimulation protocol was high at 86% in both groups, and the main result. At six months, both groups showed reduced PVC burden assessed by the ten day monitoring. In the active arm, burden went from 18.7 to 11%. The sham went from 16.7 to 12.6%, and that delta was no statistical difference between the two groups.

One very interesting finding was that the parameters of heart rate variability did not differ between the two groups, but both groups showed signs of higher heart rate variability. So my comments, the negative results of the treat PVC study had different results than the treat AF study where low level tragus stimulation versus sham stimulation was

reduced AF burden in patients with PAF, and I'll cite that study. It was in twenty twenty. Why did trigger stimulation seem to work for AF burden but not PVCs is unknown. But what is most fascinating about this study is that both groups had substantially lower PVC burden over time.

It was slightly more reduction in the active arm, but it was not statistically different. And get this, both groups had more markers of parasympathetic stimulation, Sham not only affected PVCs, but it seemed to modulate the autonomics nervous system to a similar degree. So the sham worked either by exposing the natural history of PVCs or it worked via modulation of the autonomics nervous system.

Now, what I mean by exposing the natural history of PVCs is much of the time PVCs improve if we give peace a chance. I cannot emphasize this enough. In the same way that I oppose very early ablation of AF because it might go away, I am even more against early ablation of PVCs because as was shown in this trial. PVCs tend to improve over time.

Now whether this is regression to the mean or simply that PVCs come and go like thunderstorms, I do not know. But I would resist the urge to intervene in low level PVCs unless they persist. Then I would resist some more, resist, especially with left ventricular PVCs.

The other thing to say is that to really sort out the true placebo effect The authors and the editorialists suggest, rightly, I think, that a third arm where there was no treatment would have helped a lot, because then you could quantify what actually is happening with the placebo effect. That third arm would have been especially valuable here because the sham stimulation may have worked not only by regression to the mean, but also by modulating the autonomic sur sys nervous system.

Finally though, I really like this in a sea of industry sponsored marketing studies. It's a pleasure to read about a true experiment, as it really sought to answer an important question.

All right, next topic is non-STEMI and frail older patients. A couple of years ago in 2024, New England Journal of Medicine published a senior Rita RCT of patients older than age seventy-five. who had non-STEMI. In this large trial of 1,500 patients done in the UK, an early invasive strategy was compared with a conservative approach. There were no differences in a mace endpoint over four years of follow up. CV death was numerically higher in the invasive arm.

Oh senior Rita allowed enrollment of patients with frailty, and last week the JAMA Network Open Journal published a pre-specified subgroup analysis. Of about a third of the patients, four hundred and sixty eight patients who had frailty, they basically just looked at outcomes in this subgroup. So the primary outcome of CV death or MI was twenty one percent higher, higher in the invasive arm, thirty eight percent versus twenty nine percent.

The hazard ratio did not m meet criteria for statistical significance. It was 1.21, 95% conference of 0.88 to 1.67. So the potential for a 67% worse. CVDAT or MI endpoint. However, when frailty was analyzed as a continuous variable, there was a significant interaction with treatment patients. At the highest levels of frailty had a potential signal for harm with a routine invasive strategy.

Frail patients showed a numerically higher rate of procedural complications compared with prefail and robust patients, although this did not read statistical significance, but the numbers are s the numbers are substantial, right? eight point three percent versus Three point nine percent frail and three point four percent robust. So my comments. I put this study and this substudy in the quote resist the urge to help too much category of medical practice.

It reminds me of my friend Andrew Foy's work on treatment effect heterogeneity, that is, the fact that while a treatment may be found beneficial overall in a clinical trial, there may be groups within that trial that benefit more or less. The paradox here is that patients with the highest risk and lowest risk may be least likely to benefit from a treatment.

I mean low risk patients can be thought of having the same outcome no matter what treatment they receive because they're so low risk. They do well basically with nothing. High risk patients have more competing causes of bad outcomes and they have higher procedural risk. The absolute classic example here is statin drugs, which clearly reduce outcomes.

in both primary and secondary prevention, but have a null effect in patients with advanced heart failure. This is the GCHF in corona studies. And they have a null effect in patients with end-stage renal disease. That's the 4D and Aurora trial. Now in Signorita, the overall effect of the invasive strategy was null, but in the group with frailty there was even a modest signal of harm.

Now you might be thinking, wait a minute, John, hold on. I thought the early invasive trials were mostly negative, but in high risk patients there may be a signal of benefit. So I went back and I looked at the jobs at all meta-analysis of eight RCTs for non-STEMI. This was published in Lancet. And the overall death and MI signal are negative. That is early invasive and conservative overall negative. Null, no difference.

But when looking at higher risk cardiac signals like elevated enzymes, a diabetes, or a higher gray score, there were trends to better outcomes with early invasive. Interesting was that the subgroup on age was no benefit in early invasive in age greater than 75, but a hazard ratio of 0.65 in younger patients.

But I would remind everybody these are cardiac risk factors. What emerges from that meta-analysis is that younger patients with higher cardiac risk may benefit from an early invasive strategy. I say may because these are subgroup findings and subgroup comparisons. always have a greater chance of type one error, false positive. But it's at least plausible that a young person with isolated cardiac risk factors stands to benefit more from early revascarization.

That's totally different from a frail older person who has A higher procedural risk and B more competing causes of bad outcomes. So the bottom line and I think the message from this senior reader's study and the senior reader's sub analysis. is that we shouldn't apply evidence from sixty year old trial patients to eighty year olds with frailty. In these patients, a conservative approach is surely the better strategy. Again, I repeat, resist the urge to help too much.

So that's uh this week in cardiology, but I wanted to say that if you are in Connecticut this coming week I'm speaking at the sixty second annual Jarasadi Symposium This is the oldest annual cardiovascular symposium in the US and it's at Saint Francis Hospital in Hartford on Wednesday. It's a special thing for me because I was a medical student at the University of Connecticut and I rotated through these hospitals as a young person.

My talk is titled Anticoagulation in the Era of Left Atrial Occlusion Devices. So that's it for this week in cardiology. As always, I'm grateful that you listened. Thank you. And remember, if you like the podcast, take the time to give us a rating, write us a review. These things help others find us. Until next week, this is John Mandrola from the Heart.org Metscape Cardiology.