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For the week ending November 22, 2024, John Mandrola, MD, comments on the following news and features stories: AHA review, OPTION, SUMMIT, VANISH 2, SARAH, and CLEAR.
First, This Week in Cardiology takes next week off for Thanksgiving holiday.
Second, I want to say thank you to the SWISS electrophysiology (EP) society for the invitation to speak at SwissRhythm in Lucerne. This was my first visit to Switzerland, and I am shocked at the beauty of the country as well as how perfectly everything seems to work.
There was one special experience to tell you about. I spent a day with the EP group at University Hospital Basel. We did a research conference and then ate lunch in the hospital cafeteria; there were about 10 people. I commented that it was nice to eat with the whole group.
They said they mostly eat as a group every day. That is remarkable because it was a big and busy group. Yet, they said that they make it a priority to stop and eat and talk during the day.
I don't know how your practice is we rarely make time to sit and eat together very often. But the culture of collegiality and friendship should not be underrated.
I have written two columns on this trial of post-ablation stroke prevention strategies. NEJM published the study.
OPTION compared the strategy to implant a left atrial appendage closure (LAAC) device at the time of LA ablation and then stop the oral anticoagulant (OAC) vs continue the OAC after ablation.
At the American Heart Association (AHA) meeting, results were presented and were nearly exactly as I predicted in my pre-trial column.
The trial enrolled 1600 patients after atrial fibrillation (AF) ablation and randomly assigned them to continue the OAC or have a Watchman LAAC device inserted and discontinue anticoagulation after 90 days.
The idea was to show that LAAC could reduce the rate of bleeding while maintaining a low risk for stroke after ablation.
Patients were 70 years old on average, 35% were female, and the mean CHADS-VASc score was 3.5. Just over 40% of patients had LAAC at the same time as their ablation and the rest had the device implanted weeks later.
The primary safety endpoint of nonprocedural major bleeding or clinically relevant nonmajor bleeding occurred in 8.5% of patients in the device arm vs 18.1% in the anticoagulation group. The hazard ratio (HR) was 0.44 (95% confidence interval [CI], 0.33 to 0.59; P <.001 for superiority).
In a noninferiority trial, you aim to establish noninferiority of an efficacy endpoint and superiority in safety. The topline results of OPTION confirm this for LAAC vs anticoagulation, but a closer look at endpoints and trial procedures refute this contention.
As I wrote in my column, there were four problems.
Safety cannot be established as superior with a nonprocedural bleeding endpoint because the main safety concern with LAAC is procedure-related bleeding.
To assess safety properly, they should have used the secondary safety endpoint of major bleeding including procedural bleeding. These rates were 3.9% for LAAC and 5.0% for anticoagulation, which did not establish superiority for the device.
Excluding procedural bleeding from the primary safety endpoint wasn't my only issue with its choice. The inclusion of non-major clinically relevant bleeding creates a possible bias in an unblinded trial. Patients on anticoagulation may be more likely to report nonmajor bleeding events. Indeed, bruising and oral bleeding were higher in the OAC arm.
You could see this in the Kaplan-Meier (KM) curves for the primary safety endpoint, which diverge almost immediately in favor of the device arm despite the fact that the LAAC patients were initially taking an OAC and aspirin. This is unexpected because more intense antithrombotic regimen should cause more, not less, bleeding than anticoagulation alone.
The reason to do a LAAC or prescribe anticoagulation is to prevent thrombotic events, not death.
Including death with stroke and systemic embolism in the composite endpoint simply inflated the numbers of primary efficacy endpoints. As I predicted, death rates were similar in both arms.
Yet even with these inflated rates, the actual event rates of 5.3% and 5.8% (LAAC vs OAC) were far lower than the expected 10% vs 15%. This is important because the fixed noninferiority margin of 5% is based on the expected event rates and translates to a relative risk of 1.5%. In other words, LAAC could have been 50% worse in terms of efficacy and still have met the threshold for noninferiority.
The actual event rates came in much lower than expected at 5.3% vs 5.8%. The risk difference of -0.5% has an upper bound of 1.8%, which is well below the noninferiority margin of 5%.
Proponents might argue that even with the lower event rates, noninferiority is still met using the relative risk ratio. This is true. The HR of 0.91 had a 95% CI of 0.59 to 1.39, and the upper bound of 1.39 is indeed less than the margin of 1.5.
But this is deeply misleading because the actual stroke/systemic embolism rates were 1.2% and 1.3%, respectively. It would have taken nearly five times more patients to properly establish noninferiority in efficacy.
OPTION, therefore, cannot tell us whether LAAC is noninferior to OAC for the reduction of stroke and systemic embolism. It is 100% uninformative as a comparison trial.
One thing we did learn is that stroke rates being this low 3 years after ablation suggests that we should have an arm of no device and no OAC.
The low stroke rates counter the view of many LAAC proponents who argue that the device could be an alternative option for patients who do not want to take OACs. A better alternative in low stroke risk patients could be no device and no OAC. This comparison has never been tested in a trial; OPTION results argue for such a trial.
The authors report missing data for 144 patients (8.8% overall), with most of those patients in the anticoagulation arm (10.5% vs 7.4% missing in the LAAC arm).
The rate of missing data is higher than what I would deem the correct safety endpoint (as outlined above) and the inflated efficacy endpoint.
This just adds even more uncertainty to an already uninformative trial.
The authors report that a complete seal of the opening to the LAA with the device was observed in 80% of patients at 12 months. The translation is that one in five patients had a leak. Device-related thrombus occurred in 1.9% of patients.
The two issues here are that the OPTION trial was done at expert centers. In the United States, large numbers of AF ablation and LAAC will be done by low-volume operators. The incomplete-seal numbers in OPTION probably represent a best-case scenario. If the results of this trial lead to a large increase in the implantation of these devices, there is a risk for serious harm on a population level.
The second issue with incomplete seals is the short duration of the trial. An implanted device that doesn't completely seal the opening to the LAA may be permanent. OAC can be stopped. A device in the heart cannot be easily removed.
My friends, OPTION should not lead to more LAAC. The data is just not convincing, despite the positive top line results.
I worry so much that we could create immense harm from putting this permanent foreign body in people.
Here in Switzerland, my colleagues told me that OPTION will have no effect on their already very low implant rates. But in the United States, I have already seen social media posts from key opinion leaders describing concomitant LAAC at the time of ablation.
Based on the popularity of AF ablation, the downside harm from this strategy could be immense.
At AHA Dr Milton Packer presented the SUMMIT trial, which randomly assigned about 700 patients with heart failure with preserved ejection fraction (HFpEF) and obesity to tirzepatide or placebo. It's an important question to study because a) HFpEF is now the most common cause of HF, and b) obesity is a common associated condition in patients with HFpEF. In fact, obesity may be more than simply associated with HFpEF, it may actually cause HFpEF.
We also know that this GLP-1 agonist class of drugs induces weight loss and tirzepatide is the most potent in the category.
As background for the HFpEF question, two small STEP HFpEF trials have shown that semaglutide induces weight loss and improves quality of life in patients with HFpEF and obesity and type 2 diabetes. These trials enrolled small numbers of patients who had low numbers of HF events, so no conclusions regarding clinical outcomes could be made.
SUMMIT aimed to assess the typical HF endpoints of cardiovascular (CV) death and HF events, though they expanded the HF event endpoint to include three things: hospitalizations for HF, or IV therapy in an urgent care setting, or intensification of oral diuretic therapy.
Before I say anything about patients and results, note the subtle change of a hospitalizations for HF and this endpoint. An increase in oral diuretics is a really soft endpoint, because a patient could say they felt full or had a little edema and the doc changes furosemide from 20 mg to 40 mg. That is hardly a serious event. They also included a change in the Kansas City Cardiomyopathy Questionnaire (KCCQ; quality of life) as a co-primary endpoint.
Patients were 65 years old, slightly more than half female, 53% recruited from Latin America, 22% from the United States, and 15% from Asia. Nearly three quarters had class 2 HF. The average body mass index (BMI) was 38, and high sensitivity CRP high at 5.8.
The results were highly positive:
Comments. The unblinding issue is important, though it is no fault of the authors. These drugs cause GI symptoms, decreased appetite, less ability to eat big meals and even some nausea. Surely most patients guess their treatment arm.
Unblinding patients can also affect HF events, because patients in the placebo arm, who aren't losing weight may be more apt to complain of symptoms requiring medical attention.
I am sorry, this is not personal, but I cannot see SUMMIT as an informative trial. There is no reduction of CV death. The "HF event" is soft, and there are small numbers of events. I recall Dr Packer criticizing the CASTLE AF trial of AF ablation in HF patients because it had so few primary outcome events.
It's exactly the same here.
That said, if you have a patient who has HFpEF and a BMI of 38, weight loss is obviously a good thing. When you lose weight, it's likely you will have fewer events of any sort. You feel better.
The authors invoke a reduction in inflammation as the mechanism of improvement. And they argued for a GLP-1/GIP mechanism independent of weight loss. I would push back -- if that were true, you must show me something more than a reduction in HF hospitalizations and oral diuretic adjustments. Show me a CV death reduction.
The other thing we don't know is the proportion of HF hospitalizations vs total hospitalizations. People with HFpEF have lots of competing risks for hospitalization. I don't know why this was not reported. Surely, they had that data.
The GLP-1 agonist drugs clearly represent an advance, but this trial should not compel us to prescribe them as a "HF drug". Many of these patients had diabetes and established CV disease. For these indications, yes, for HFpEF, we need stronger data.
How best to handle a patient who has had a previous myocardial infarction (MI) and an implanted defibrillator (ICD) and now presents with ventricular tachycardia (VT)?
The three choices are antiarrhythmic drugs (AAD), ablation, or nothing. Usually though, if they get a shock and it's sustained monomorphic VT, we don't choose no therapy because we assume there will be more VT.
Drugs have the advantage of being easy. You simply take a pill. When it works, the VT is suppressed. But drugs are not always effective and can cause adverse effects. The ablation procedure has the advantage of (potentially) being curative; but it is invasive and comes with procedural risks.
Dr John Sapp led the VANISH 2 trial, which randomized these two choices. The trial was conducted in 22 centers in Canada, the United States, and France.
Patients were about 68 years old. The mean left ventricular (LV) EF was depressed at 34%. The trial enrolled just over 400 patients.
The primary endpoint was a composite, but I think a reasonable composite. Trialists chose death from any cause, VT storm, appropriate ICD shock, or sustained VT below the rate cutoff of the ICD.
I like this composite endpoint because all of these are "hard" endpoints resistant to bias. You are either alive or dead, you have VT or you don't.
Unlike, say, heart failure hospitalization, no clinical decisions are required for these endpoints.
VANISH 2 will obviously be open-label or unblinded, so It's important to have bias-free endpoints in an unblinded trial.
In amiodarone patients the KM curves for the primary endpoint were nearly the same. No difference. But in sotalol-eligible patients, VT ablation did much better.
Comments. This is a well conducted study that addresses an important question. The endpoints are low in bias.
Catheter ablation reduced the risk of the composite endpoint over AADs. The absolute risk reduction is 10%; number needed to treat is 10. That is a clinically relevant effect size.
I see three caveats:
Unlike the OPTION trial, I doubt that VANISH 2 will lead to overuse of VT ablation. Yes, it was a positive trial, but VT ablation is hard; time consuming, sometimes harrowing (because the patients are sick) and compensation is low considering how long the procedure can take.
Yet VANISH 2 allows us to sit down with patients and discuss the results. How best to apply these results turns on clinical judgement and patient values.
Before this trial there was little data to inform this decision. Congratulations to Dr Sapp and the VANISH 2 team.
The SARAH trial tested sacubitril/valsartan against placebo for protection of the heart during chemotherapy with anthracyclines.
Anyone who has practiced for a while, knows how bad anthracyclines can be on LV function. Of course, much of this toxicity is dose dependent.
This was a small trial -- 114 patients, average age 52 years, 90% women. The trial was done in Curitiba, Brazil. Patients enrolled had elevated high sensitivity troponin I. Most were receiving anthracycline for breast cancer, the rest for lymphoma, sarcoma, and leukemia.
Obviously, the trial was small and clinical events were rare and occurred at similar rates in both groups.
Comments. I am an outside observer looking in here. I found a 2024 review article in JACC-Cardiovascular Imaging that covered strain imaging. It went on for tens of thousands of words, and even though I am a cardiologist, it was way over my head. The thing is that it's just a start. It's nice that a new echo parameter like GLS is better. But I am not sure any patient ever has cared what their GLS is. They want to not have LV failure or cardiac events.
Novartis has plenty of money. I hope they will fund a proper study powered for clinical endpoints. And, as I have said many times, the proper comparator for sacubitril/valsartan is valsartan at the same dose. Had this been done in PARADIGM-HF there would be no controversy about ARNI drugs in HF with reduced EF (HFrEF).
I don't mean to be negative about a randomized controlled trial (RCT). We need RCTs. But this trial received large attention on social media, perhaps because it was a late-breaker. I believe it is the first of nine innings in the cardio protection game. But I could be wrong, so reach out and teach me.
Spironolactone is an amazing drug for patients with HFrEF. It probably helps those with HFpEF too.
The Canadian CLEAR trial studied it in post-MI patients. Recall that CLEAR was a 2x2 factorial trial that also tested colchicine. The colchicine arm was presented at the Transcatheter Cardiovascular Therapeutics meeting and was stone cold negative.
At AHA, we heard the spironolactone portion. NEJM published two separate papers, one on the non-significant colchicine results as well as the spironolactone arm.
CV death was similar in the two groups: 3.2% in the spironolactone group vs. 3.3% in the placebo group.
Comments. This trial points out that drugs are neither bad or good. Spironolactone is amazing in HFrEF. The RALES trial is one of the most impressive trials in all of cardiology.
But after MI, and PCI, even with a ST elevation MI, the same drug does not improve outcomes.
This makes sense, right? To get an effect size, you have to have both treatment related benefit more than harm, but also, you need a high risk of the primary outcome. If the primary outcome risk is low, it's hard to make it any lower.
And that is the case with acute MI and PCI. After you fix an open artery, restore blood flow, save myocardium, not much else changes outcomes -- that is, except antiplatelet drugs and lipid lowering.
Spironolactone fails post-MI for the same reason that beta-blockers have been failing. The risk of the primary outcome is so low, it's hard to make it lower.
The CLEAR investigators also published the colchicine part of the trial. This too was non-significant, for the same reasons. I've covered that before. The curious thing about the colchicine story is why CLEAR was different than the positive COLCOT and LoDoCo studies.