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In This Week’s Podcast
For the week ending October 21, 2022, John Mandrola, MD comments on the following news and features stories.
This week, the new New England Journal of Medicine (NEJM) Evidence journal has published a very important trial of atrial fibrillation (AF) ablation. The ERASE-AF trial, first author Yan Huo, senior author, Christopher Piorkowski, set out to answer the decades-old question of how best to ablate AF in patients with persistent AF. The technique tested was the targeting of low-voltage areas in the left atrium (LA), in addition to pulmonary vein isolation (PVI).
Some brief and oversimplified background:
Persistent AF is different from paroxysmal AF in that when AF is persistent it often (but not always) means there is structural atrial disease, for example, areas of scar in the LA that can act as geographic and electrical barriers to conduction. Think rocks in a stream.
By contrast, patients with paroxysmal AF or early AF often have little structural disease, which makes the current approach of PVI reasonably effective, because PVI eliminates the triggers.
But when there is structural disease in the LA, electrophysiology (EP) docs have always felt that targeting only the triggers would not be enough to reduce AF. That’s because, in a patient with atrial scar, a premature atrial contraction (PAC) from anywhere could initiate AF, which could then be sustained because of disordered conduction. Scar in the atrium is like rocks in a stream causing turbulence.
It makes total sense that PVI alone would underperform in patients with persistent AF. (Pause there; whenever you hear the phrase it makes sense be on the alert for a surprise.) Yet, before ERASE AF, there was scant evidence that additional ablation beyond PVI made any difference.
STAR-AF-2 found that PVI performed as well as two strategies of PVI plus additional ablation.
DECAAF 2 found the MRI-guided ablation of scar plus PVI did no better than PVI alone.
STABLE-SR-II, published only 3 months ago in JACC-Clinical Electrophysiology, found that additional low voltage area (LVA) ablation did not improve successful rates of circumferential PVI in persistent AF.
The only two trials that hinted at better results from additional ablation beyond PVI were the VENUS trial of alcohol-based Vein of Marshall ablation and the CONVERGE trial of hybrid surgical and EP ablation of the LA. Both trials were small in numbers and had fragile results.
So, basically, the Bayesian priors before ERASE AF set out to target low-voltage areas is extremely pessimistic. It would take strong evidence to move these priors.
Now to ERASE AF: 324 patients with persistent AF were randomly assigned to PVI alone or PVI plus substrate modification (PVI + SM) — ablation that isolates any areas of low-voltage. Modern 3-dimensional mapping systems now allows a voltage map of the LA, and areas of low voltage are believed to indicate structural substrate capable of perpetuating AF.
The primary endpoint was typical: first recurrence of AF lasting more than 30 seconds.
The surprising result was that the endpoint occurred in 50% of the control arm (PVI alone) vs 35% in the PVI + SM group. This resulted in a hazard ratio (HR) of 0.62 or a 38% reduction, which was highly statistically significant.
This result was bolstered by the fact that 75% of patients had implanted loop recorders (ILRs) and an analysis of only patients who had an ILR (the most sensitive AF detection monitor) also found significantly less AF in the PVI + SM group.
There was a cost, however. The rate of adverse events was 1.8% in the PVI alone group vs 3.7% in the PVI + SM group. The only two pericardial effusions and tamponade events were in the PVI + SM group.
The authors concluded that their approach of electrically isolating areas of low-voltage improved AF suppression.
Comments. I love this trial. For decades, we have argued about the best approach to persistent AF. If there are five EPs on a panel discussing persistent AF, there will be five different approaches.
Instead of single-center studies and eminence-based approaches, the authors did what is needed. They randomly assigned patients to two strategies. Their trial was investigator initiated and self-funded. This alone is reason to honor their efforts. Self-funded trials are hard. I know this firsthand.
I also like their approach to low voltage ablation. They kept to a systematic approach wherein they isolated the area and confirmed block. If the LVA was on the posterior wall they isolated the posterior wall. They used anatomic boundaries to create lines that isolated the area and then checked for block. The supplement offers a clear road map on how to do this, and it’s likely reproducible.
But here’s the thing: the results are counter to a huge evidence-base wherein additional ablation beyond PVI adds nothing. So, we have to explain how it works, especially since a similar trial, the STABLE-SR-II trial also targeted LVA and found no benefit.
Curious to me is that only a third of patients in either arm had LVA at all. That means that the third of patients with LVA in the active arm (N=54) had to drive the results. That would be like a drug trial in which only one-third of those in the drug arm took the drug. It would have to be a special drug to move the overall results.
This makes me think there is a strong possibility of performance bias — totally unintentional and not nefarious, but bias. Specifically, it’s possible that there was better PVI in the active arm group. One logistical reason is that it takes longer to do SM and that leaves time to go back and check the PVs and touch up PVI, thus ensuring better PVI.
One way to test whether PVI was better in the active arm would be to observe the results of patients who only received PVI in both groups. See Figure S5 panel C. When they present results of patients who had no LVA and hence only got PVI in both arms, there was a strong trend towards less AF in the active arm. That at least suggests that operators did better quality PVI in the active arm.
There was also a bit of a balance issue. Table S2 shows more areas of LVA in those assigned to the PVI-only group. And in all defined areas, except the septum, the extent of LVA was greater in the PVI group. This could occur simply because there were small numbers of patients in the trial.
But if LVA are predictive of more structural disease, the PVI alone strategy could have included sicker patients who were more likely to recur.
This is a good first step. A hearty thank-you to the ERASE AF authors. Your data informs the next trial, which I would definitely require before changing to a more aggressive ablation strategy, especially with the doubling of the rate of complications.
In the next trial of LVA ablation, we could include more patients, more centers, and importantly, randomly assign patients further along the pathway. The problem with ERASE AF is that early randomization dilutes the groups with patients without LVA.
If you randomize a) only patients who had LVA and b) after PVI, you would isolate the effect of LVA ablation. I would also want to see ILRs in all patients and include AF burden rather than 30-seconds of AF.
LBB Area Pacing
The US Food and Drug Administration (FDA) has labeled a special lumenless pacing lead made by Medtronic specifically for left bundle branch (LBB) area pacing. I highlight this story for two reasons — one regulatory and one specific to the procedure itself. Regulatory wise: the FDA approval highlights an important concept regarding use of approved devices.
The 3830 lead has been on the market for years. It was first used in pediatrics. We then used it in His-bundle pacing. Now, LBB area pacing has nearly completely eliminated His-bundle pacing.
The approval was based on observational and randomized controlled trial (RCT) data from multiple countries. I covered the largest of these, the MELOS study, presented and published by Marek Yastrzemski, on the April 21, 2022 #TWICPodcast.
The most recent RCT data came from a Chinese group, first author, Yao Wang, published in the Journal of the American College of Cardiology (JACC) in September. This was a 40-patient trial that found that LBB area pacing compared favorably to cardiac resynchronization therapy for surrogate endpoints such as left ventricular ejection fraction and BNP.
I felt good about the use of this device outside of approved indications. With each step, His-bundle pacing and then LBB pacing, we generated reasonable evidence of safety.
The LARIAT device, which epicardially closes the left atrial appendage, was approved the laxer 510(K) clearance pathways predicated on demonstration of “substantial equivalence” with existing devices used for suture placement during other types of surgery.” The LARIAT is far from a suture device.
The only real implications for the FDA stamp of approval means that Medtronic can launch educational materials and programs on LBB area pacing. The United States is different from Europe. I just got back from Italy and Poland, and there, industry sends LBB experts to visit centers to help get operators up to speed.
Another important reason to highlight this approval is the 3830 is a low-profile, (thin) pacing lead without a lumen and without the need for a stylet to place. This may be important.
Heart Rhythm Case Reports published a case report of conductor fracture of a standard stylet-driven pacing lead in the LBB area.
The Journal of Cardiovascular Electrophysiology also has a report of two cases of fracture of standard leads in the LBB area site.
There’s also plausibility here: to do LBB pacing, you bury the tip of the lead in the septum to capture fibers of the LBB. That creates a bit of hinge point, which can even be seen on fluoroscopy.
The 3830 lead may — emphasis on may — be more suitable for this approach. Thing is that now that there is intense excitement among implanters for these narrow-paced QRS complexes, other pacing companies have been intensely interested in promoting their leads for the procedure. Yet all the data come from the 3830 lead, which is substantially different from standard pacing leads.
I am a medical conservative for all things, but I am a religious-level medical conservative when it comes to pacing and defibrillator leads, having been burned so badly with adapting “new” and “improved” leads.
The entire space of conduction system pacing (CSP) needs more data. I spoke to a number of CSP docs in Poland, an epicenter for the procedure, and none were using standard pacing leads. Only the 3830 leads. I have no financial conflict of interest with Medtronic, and I plan to keep it that way.
Finerenone Is Back in the News Again
JACC- Heart Failure has published yet another post-hoc analysis of the seminal trials of finerenone, which is a selective, nonsteroidal mineralocorticoid antagonist that was approved in 2021 by the US FDA to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, myocardial infarction, and hospitalizations for heart failure (HHF) in patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D).
FDA approval was supported by two placebo-controlled trials of finerenone. FIDELIO DKD found a significant 18% reduction in CKD progression events and a 14% reduction in cardiovascular events with finerenone treatment compared with placebo in patients with CKD and T2D.
FIGARO-DKD demonstrated a 13% reduction in the risk of the primary cardiovascular composite end point with finerenone vs placebo in patients with CKD and T2D.
Before I tell you about the recent meta-analysis of the two trials, I want to make two important points regarding these trials.
First, both compared finerenone with placebo and did not have a spironolactone arm. This is crucial because the mineralocorticoid (MRA) spironolactone costs pennies compared with finerenone, which is listed at about $600 per month.
Yes, finerenone is a nonsteroidal MRA and may be better tolerated, but gosh darn it, it would have been good to know how it compared with spironolatone.
Second point to make is that FIGARO DKD, which had cardiovascular (CV) outcomes as a primary outcome, was technically positive, but the 13% reduction in the composite endpoint was driven by a 1.2% absolute risk reduction (ARR) in HHF. But HHF represented only 7% of total hospitalizations. There were no differences in total hospitalizations.
The authors of the two trials have already done one pooled analysis. The European Heart Journal published the combined analysis of 6500 patients in each group and found modest reductions in both a cardiac and renal composite. The big point from this meta-analysis was the mixture in baseline eGFR (nearly all > 25 mL/min/1.73 m2), and urinary albumin to creatine ratio (UACR). The authors called this pooled analysis FIDELITY.
The UACR was a talking point here: first, we have to do it to identify finerenone-eligible patients. CKD was an entry criterion for FIGARO-DKD and it was defined using both GFR and UACR. Either you had increased albuminuria (UACR ≥ 30 to < 300 mg/g) with an eGFR of ≥ 25 to ≤ 90 mL/min/1.73 m2, or you could have severely increased albuminuria (UACR ≥ 300 to ≤ 5000 mg/g) and an eGFR ≥ 60 mL/min/1.73 m2.
The results of the pooled meta-analysis were the same as the original trials — a modest (less than 2% ARR) in the combined CV endpoint of CV death, myocardial infarction (MI), stroke, and HHF, driven by a 1.1% ARR in HHF, but this was still less than 10% of total hospitalizations.
The new analysis in JACC HF was very similar. This time they looked at slightly different endpoints: say CV death and first HHF, recurrent HHF, and CV death and recurrent HHF. They are all positive. Of course they are because they include HHF.
They then looked at the HF-related effects of finerenone on subgroups by eGFR and UACR. The modest effects of finerenone looked similar in all categories of eGFR and UACR.
The authors note the early separation of the curves. And they cite this as a reason to use the drug early. They also spend a few hundred words in the discussion speculating on mechanisms of HHF reductions. I can do it in four words: finerenone is a diuretic.
My friends, if finerenone was superior to spironolactone, a drug with huge effects in patients with HF with reduced ejection fraction (EF) and probably beneficial effects in HF with preserved EF (Topcat) in these lower risk patients, we would then have to discuss cost efficacy. Proponents of finerenone would say I am comparing different patients, and that is true. My point is merely that spironolactone is a highly effective drug.
These pooled analyses, especially the one with post-hoc endpoints, led to publications in big journals, will make great Power Point presentations for drug reps to show unsuspecting doctors, but they do nothing to change the fact that finerenone is a costly diuretic that may be either no better than or marginally better than spironolactone.
Perceptions of Cardiology
JAMA Cardiology has published results of a survey of IM residents that looked at their professional preferences and perceptions of cardiology. First author is Dr. Meghan York.
The survey of 840 internal medicine residents had two neat twists: they could compare answers of this survey with those of 2010 and second, there were near equal number of males and females. That’s cool.
Using the 1-5 Likert scale, not important to extremely important, residents rated 38 professional development preferences (things like stable hours, family friendly, positive role models, financial benefits, professional challenges) and 20 cardiology perceptions (like not diverse, CV role model, compensation, and adverse job conditions in fellowship).
The most important professional development preferences by descending Likert score were as follows: positive role models (4.56), stimulating career (3.81), and family friendly (3.78).
The cardiology perception statements with the highest agreement were: interferes with family life during training (3.93) and having met positive role models or having positive views of cardiovascular disease as a topic (3.85).
The authors then did a correlation or multivariable analysis of factors that would predict choosing cardiology as a career.
Compared with the 2010 survey, the findings of this survey indicated increased importance of work-life balance components for both male and female residents, with a greater change in male residents. Contemporary residents were more likely than their predecessors to agree with negative perceptions of cardiology.
Comments. You might think this is a soft topic for an evidence-translation podcast, but it really isn’t it. Heart disease remains a leading killer of humans and leading cause of ill health. We need a well-trained, available, and empathic workforce.
First it is a great thing that more women are coming into the field. As I’ve said, nearly half of my partners here in private practice are women.
This means systems must change. The old way is not going to work. Not long ago, female cardiologists who got pregnant took extra call, during pregnancy sometimes, to make up for the call they would miss during maternity leave. This was egregious. Atrocious.
Of the many things I have learned from visiting Europe relatively often is the practical way they approach training: trainees are paid a reasonable wage, and there is generous family leave for children. In Denmark, it is expected that you will be done and have time for family every day.
I will ask—wait, how do you give physician-moms one year maternity leave? “Well, John, we plan for it.”
The trade-off is that training may last longer, but that is not a major issue, because of systems. Trainees are paid well and not over-worked, so there is less rush to get out of training.
That young people in the United States increasingly emphasize work-life balance is a hugely positive sign. As my friend Dr. Dennis Lau once told me: John, there is more to life than work.
Again, systems can help. A positive development is the idea of hiring people to cover nights and weekends as their primary job, rather than having people share the burden of working 2 days straight without rest. The barrier in the United States is that it costs money and can diminish profits.
I push back strongly against the notion that we must overwork young people to make good physicians. That said, the time in fellowship, where you are exposed to experienced clinicians is absolutely crucial to learn the basics of cardiology. This is the time to focus on getting the foundation of being a doctor. Sure, you keep learning in practice, but the exposure to experienced doctors is unmatched in training — never waste it. A final comment on work-life balance. Some people think this ratio is simply about having a job that gets out at 5 PM and requires no thought after the shift. That is short-sighted. No matter how good your work-life balance is, you will be at work a lot, and you want it to have meaning. Am I contributing to the greater good?
This is where cardiology and doctoring, in general shines. Your job is to take people who ask for help, and use your hard-won skills to help them. Every patient. Every day. This is what you do: you help people.
To me, the meaning part of work is an under-appreciated factor in work-life balance. Of course, you don’t want to be run ragged. But what I love so much about cardiology is how our job is to help people who are sick.
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Cite this: Oct 21, 2022 This Week in Cardiology Podcast - Medscape - Oct 21, 2022.