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In This Week’s Podcast
For the week ending January 13, 2023, John Mandrola, MD comments on the following news and features stories.
Last week I reported on a provocative paper in BMJOpen that re-analyzed death outcomes in the placebo-controlled FOURIER trial of the PCSK9 inhibitor, evolocumab.
The authors, who are part of a group called RIAT (restoring invisible and abandoned trials) got interested in FOURIER because the 27,000-patient trial showed massive reductions in LDL cholesterol in high-cardiovascular (CV)-risk patients that led to only a 15% reduction of a composite primary outcome, but CV deaths and overall deaths were actually higher in the evolocumab group. These investigators were also struck that most of the CV deaths were labeled as “other” CV deaths, not as myocardial infarction (MI) or congestive heart failure (CHF) related, which typically predominate the CV death category.
With much effort, the BMJOpen authors got hold of the clinical study reports (CSR), which included details on efficacy and safety events. They found substantial disagreement between how local investigators reported deaths vs how the clinical events committee (CEC) adjudicated them.
In their adjudication, using the CSR, they also found higher rates of CV death in the evolocumab group though this still missed significance. Their hazard ratio (HR) was 1.20 or 20% higher, and the upper bound was up to 50% higher.
In my opinion, they overreached in their conclusions by stating that their re-analysis should cause clinicians to be skeptical about prescribing evolocumab.
Last week, I offered some options:
One was that this was a much ado about nothing because the main trial results were upheld, and the CSR reports offered less info than what the CEC had.
The other was that there seemed a lot more flux in trial reporting than I had expected, and that it at least raised the possibility that this cholesterol-lowering drug may have off-target effects that reduce its CV protective actions.
What’s more, I thought, the re-analysis argued for more independent and transparent review of major studies.
Well, this week, the TIMI study group at Harvard, wrote a letter of response. The first author was Marc Sabatine, who was the principal investigator (PI) of FOURIER. It was a strongly worded response, with strong modifiers, in which they rebut the claims of the re-analysis. You all should read it. I found it a persuasive argument.
Some experts have called this a waste of time. The TIMI letter concludes by saying that this is a gross disservice to the medical literature, clinicians, and patients. That may be over-reach as well.
Sanjay Kaul had a worthy comment at the end of the theheart.org | Medscape Cardiology news piece. He said:
FDA's response not to provide the data was "rather curious" and that Sabatine and colleagues had the opportunity to address the RIAT group's concerns, but the paper notes they did not even bother to respond. "You can't be holier than thou in medicine. You have to treat every question with respect and humility and can't be dismissive.... He could have nipped the evil in the bud, so to speak."
I am drawn to Kaul’s comment because I see it as important that we move to a more open and transparent system of science adjudication. Here is a another example that may have flown under your radar. Neurologist Ravi Garg from Loyola University published two papers last year that called into question the validity of major thrombolytic trials for acute stroke.
One was a survey of missing data in the seminal meta-analysis of randomized controlled trials (RCTs) of alteplase for ischemic stroke. Garg found that “the number of participants lost to follow-up was greater than the fragility index in the chosen meta-analysis and individually positive component RCTs, suggesting that missing outcome data may impact the direction of the reported effect or effect size.”
Another of Garg’s re-analyses, this one of the seminal NINDS trial, which started the whole thrombolytic for acute stroke paradigm, found that the famous baseline imbalances in that trial were more likely related to randomization errors than chance. And that when he adjusted for these baseline imbalances, he found a reduction of treatment effects. These findings strongly suggest the possibility of selection bias.
I don’t want to get into the weeds of stroke care, I’ve already done that, and it’s quite scary how weak the evidentiary support is for such an established dogma. My point is that it’s a little late to be doing such independent re-analyses.
I’d propose a world where these sorts of things — questions on outcome adjudication, questions on randomization errors, or missing data -- are dealt with at the time of regulatory approval, before therapeutic fashions are established. You may disagree – let me know.
A Potential Practice-Changing Paper
A group from Israel, first author, Moris Topaz, senior author, Sami Viskin, has published their 14-year experience treating infected device pockets without extraction. That’s right, it’s not me misspeaking. The technique is called continuous in situ–targeted ultrahigh concentration of antibiotics (CITA).
Before I tell you about the study, I want to set out how shocking this is. It’s shocking because a solid dogma in electrophysiology (EP) has been that the only solution for infected devices is total system extraction.
This can become a serious problem because extraction is quite difficult in some patients. They may be frail, they may have old leads that get scarred in place, they may have many leads that are bound together, or the center may not be highly experienced.
The Journal of the American College of Cardiology (JACC) has published this important paper, which included two study types: the first was a descriptive case series and the second was a case control non-randomized comparison of CITA vs extraction.
The series included 80 patients and 85% were cured with CITA. Follow-up was a median of 3 years.
In the case control study, cure rates were higher after device/lead extraction than after CITA (96.2% vs 84.6%, P = 0.027).
However, rates of serious complications were also higher after extraction (14.8% vs 1.5%, P = 0.005).
A word on their technique of CITA:
They first got cultures from any dehisced wounds or at the time of surgery. Patients with Staphylococcus aureus were mostly excluded.
Patients with systemic infection were excluded (these were patients who presented with localized infections).
Then the patient had extensive debridement surgery with removal of the pacemaker capsule and wound edges.
Then they cleansed the pocket with hydrogen peroxide and povidine iodine.
Then an indwelling catheter was inserted into the pocket for high dose antibiotic infusions, the idea being that they get a standard full dose of antibiotics all in the pocket — enough so that you could measure levels in the body, but most of the drug is in the pocket.
Then a negative pressure vacuum system dressing was applied.
The cultures were negative in one-third, coagulation-negative staph in one-third, and a smattering of others in the rest.
Professor Anne Curtis, from the University of Buffalo, led the editorial. She wrote that this was a promising approach, one that offered patients a potential choice in therapy. She also noted the limitations – only 6% of the patients in their series had S aureus. That’s a big limitation because this is a common pathogen.
For now, she points out, cardiovasular implantable electronic device (CIED) extraction remains the only definitive treatment for device infections, but this study was a first step. She emphasized that identifying patients for whom this approach is not appropriate is going to be key. I totally agree with her.
Most hospitals in the United States do not have an expert extraction center. In such centers, there will be strong temptations to extend this therapy to patients who should be referred out for extraction.
These were a select group of people with localized infections. But for a patient with 25-year-old leads, the chance of cure without the potential of superior vena cava tearing and possible death is a huge advance.
Congratulations to the authors and to the JACC editors for publishing such an important paper.
One final note: device infections are one of the most catastrophic things that happens to us in EP. They most often occur during generator changes. Being older teaches you some tricks to avoid such infections during generator changes:
One is to debride the capsule and make sure the new device is sitting properly in a new pocket.
The other is to see the patient in the clinic beforehand and have an earnest discussion on the benefits and harms of not doing the surgery at all.
Yes, that’s right, some patients with pacers hardly pace at all. Many patients with implantable cardioverter defibrillators (ICDs) no longer garner significant net benefit from the device. If you can avoid replacing the generator, you avoid the risk of infection.
The ATLAS trial
I want all my listeners to bookmark this trial, a comparison of two defibrillators, as a classic example of doubtful choice of endpoints and the strong possibility that marketing played a role in study design.
At its core, this podcast aims to teach critical appraisal in a skeptical, not cynical, way. The ATLAS trial highlights the bias inherent in trial design. Stanford professor John Ioannidis famously wrote about how most bias in medical studies comes before the first patient is randomized.
We have a big debate in the EP world about the choice of ICDs in patients who are at high risk of ventricular fibrillation (VF) and sudden death.
The standard transvenous ICD (TV-ICD) involves placing a lead into the heart for sensing, pacing, and defibrillation. These devices are highly effective VF converters and have been shown in multiple clinical trials to extend life in high-risk patients. They are tried and true, but their Achilles heel is that there can be lead problems, especially over time. Lead problems that occur a decade later can be super problematic because extraction is hard and risky. And a 30-year-old with a standard ICD is facing many generator changes and possible lead revisions.
The subcutaneous ICD (S-ICD) has as its potential advantages because there is no hardware in the heart. The lead sits outside the ribs close enough to the heart to sense activity and defibrillate the heart. The device sits in the side of the chest under the axilla. The potential advantages all stem from not having a lead through the tricuspid valve and in the heart. The Achilles heel of the S-ICD is that not having a lead in the heart poses challenges for sensing and defibrillating the heart. It requires exquisite attention to detail regarding implant techniques. And the S-ICD has never been tested in long-term clinical trials that looked at mortality outcomes.
The ATLAS trial sought to compare the two devices. The outcome chosen was not long-term lead complications, was not mortality, but perioperative lead-related complications.
With zero surprise the S-ICD crushed the TV-ICD.
In the trial of 544 patients, only one patient in the S-ICD group had a primary outcome vs 12 patients in the TV-ICD arm. This 4.4% relative risk easily met statistical significance.
The S-ICD had 2.4 times more inappropriate shocks, a trend that nearly made significance.
There were slightly more reports of pain at the ICD site.
The authors concluded that the S-ICD reduces perioperative, lead-related complications without significantly compromising the effectiveness of ICD shocks.
The paper was published in the Annals of Internal Medicine, which is curious. Why not a cardiology or EP journal?
When this was presented last year, the very next day Boston Scientific, the maker of the S-ICD, had advertisements up on social media about the superiority of their S-ICD. So far, you’ve probably not detected anything interesting.
Now for the punchline. It’s the choice of primary endpoint:
The primary endpoint was a composite of pneumothorax, cardiac perforation and tamponade, lead dislodgement requiring revision, new tricuspid regurgitation, or upper extremity deep vein thrombosis.
This industry-funded trial had a composite primary outcome that included four of five components that could not occur in the S-ICD arm. By design, you don’t risk pneumothorax, tamponade, tricuspid regurgitation, or vein occlusion with the S-ICD.
I can find no better example of a trial designed to show that one arm will win.
The question remains as when to choose between these two devices. This RCT of 544 patients does not inform that question. I’ve previously discussed the PRAETORIAN trial of S-ICD vs TV-ICD, which was a non-inferior trial that found the S-ICD noninferior to TV-ICD. But that trial too was marred by biased adjudication of primary outcome events. I’ve co-authored a letter to the editor of the New England Journal of Medicine explaining these issues.
This week, the Journal of the American Medical Association published a very important trial in the atrial fibrillation (AF) ablation space. The CAPLA trial took patients with persistent AF (the tougher kind) who were going for ablation and randomly assigned them to standard pulmonary vein isolation (PVI) or PVI plus posterior left atrial wall (PW) isolation.
As background, we have established that electrically isolating the muscle bundles within the PV is the standard lesion set for AF ablation. We don’t really know why but, in general, PVI alone has been shown to work as well as PVI plus any other ablation strategy.
But there have been eminent experts who believe that extending the ablation so as to isolate the posterior wall of the left atrium, between the right and left PVs, is also important.
Their reasoning is that the PVs share an embryologic origin with the PW, and smaller, methodologically weaker studies have suggested PW isolation improves outcomes over PVI alone, especially in patients with persistent AF, who tend to have more advanced structural atrial disease (but not always).
What makes CAPLA so perfect for #TWICpodcast is the method the authors used to answer this question. They didn’t use eminence, they didn’t report case series or non-randomized observational comparisons, they conducted an RCT.
The choice of therapy was determined by random chance. This leads to balancing of confounders.
Unlike the ATLAS trialists, they measured a primary outcome that was relevant to both groups --- AF recurrences.
They found that there were absolutely no differences in AF recurrences. Procedural times were 20 minutes longer in the PVI plus PW group but there were no differences in safety outcomes.
They concluded that “these findings do not support the empirical inclusion of PW isolation for ablation of persistent AF.”
Comments. This is in line with the seminal trial called STAR-AF-2 which also found that in patients with persistent AF, PVI alone performed as well as PVI plus additional ablation outside the PVIs. These results add to the field because it tempers the natural tendency in doctors that more is better when dealing with patients with more advanced disease.
The idea for AF goes like this:
PVI basically stops premature atrial contractions from initiating AF. It’s a strategy for targeting drivers of AF. But in patients with persistent AF, that is unlikely to be enough because these patients may have structural or electrical disease that perpetuate AF. PVI alone won’t work.
But CAPLA along with STAR-AF-2 shows that less is as good as more. And that’s a great finding because I hate burning on the PW. That’s because the most feared complication of AF ablation is thermal injury to the esophagus, which can lead to death. Remember, these are often youngish people.
I will use CAPLA to not be tempted to use PW isolation on the first ablation.
Now for the nuance. Proponents of PW isolation have good points, and editorialist Rod Passman pointed some of these out. They say it’s hard to properly isolate the PW, because of epicardial connections and thick tissue on the roof.
If done properly, PW isolation may be durable, and durable isolation, will indeed lead to better outcomes.
Proponents will also say, the ablative technology, called pulsed field ablation, will work better for PW isolation because you can ablate without damaging the esophagus.
All these may be true, but regular listeners know what comes next. The onus of proof remains on the proponents to show us a group of patients for whom PW ablation succeeds in RCT format.
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Cite this: Jan 13, 2023 This Week in Cardiology Podcast - Medscape - Jan 13, 2023.