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In This Week’s Podcast
For the week ending November 15, 2024, John Mandrola, MD, comments on the following news and features stories: Tirzepatide, atrial fibrillation (AF) screening, and an American Heart Association (AHA) meeting preview, including ventricular tachycardia (VT) ablation, left atrial appendage closure (LAAC) at the time of AF ablation, blood pressure (BP) targets and more on GLP1 agonists, this time in heart failure (HF).
This weekend is the AHA meeting. I will miss it because I am traveling to the Swiss electrophysiology (EP) meeting in Basel, Switzerland. But I will cover some of the big studies and offer a preview today.
SURMOUNT 1 Three-year results
But first, The NEJM published an important clinical trial on diabetes prevention with tirzepatide in patients with obesity.
SURMOUNT 1 has already been published and showed that tirzepatide induced sustained weight loss in patients with obesity. This week’s paper from the SURMOUNT investigators reported on 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying the progression to type 2 diabetes (T2D) in patients with obesity and pre-T2D.
About 1500 patients with obesity, of whom 1000 had prediabetes were assigned in a 4-arm randomization to receive once weekly tirzepatide at 5mg, 10mg, 15mg, or placebo.
This analysis included a 176-week period followed by 17 weeks off treatment.
The three secondary endpoints were body weight change, onset of T2D during the 176 weeks, then also at 193 weeks (the extension.)
Results:
Patients were about 48 years old, two-thirds were female, all with pre-diabetes.
As you would have guessed it: weight loss was robust.
Percent weight loss from baseline
12% for 5 mg.
19% for 10 mg.
20% for 15 mg.
1% for placebo.
For the onset of T2D in the tirzepatide group, 1.3% vs 13.3% in the placebo group; hazard ratio (HR) 0.07; obviously significant
Reversion to normoglycemia at week 176 was observed in more than 90% for the three doses of tirzepatide vs 59% of those on placebo.
The trial had a 17 week off treatment period that was placebo controlled.
Here, an additional incidence of T2D of about 2.4% occurred equally in each of the three doses compared with 14% in the placebo arm. This was concordant with a gradual and linear weight regain.
As expected, there were more “GI events” and hypoglycemia in the tirzepatide arms.
The authors begin their discussion by writing that a) there was clear reduction in weight and diabetes prevention. They also note that nearly 99% of those on tirzepatide remained free of diabetes, and that is over 3 years.
Another notable in this trial was that those who only had 5% weight loss also had reduced incidence of diabetes, suggesting a non-weight loss cause. Authers cited a study that suggests that long-acting GIP-receptor agonism may improve insulin sensitivity independent of weight reduction. Recall that unlike semaglutide, tirzepatide is a dual GLP1 agonist and GIP agonist.
GUARD AF
GUARD AF is a randomized controlled trial (RCT) to test whether AF screening in older patients (age > 70 years) using a 14 day ECG monitor could identify patients with undiagnosed AF and reduce stroke.
Recall that the LOOP trial used an implantable loop recorder (ILR), a much more robust screening tool, and showed that you get a ton more AF and more oral anticoagulant (OAC) use, but stroke rates were not significantly lower and bleeding rates were higher.
The primary endpoint of GUARD AF was stroke.
The primary safety endpoint was bleeding.
The trial was carried out in 150 primary care sites in the United States. COVID affected enrollment.
11,900 patients were enrolled. Their power calculation called for 52,000.
Median follow-up was 15 months. Age of patients 75 years and half were female.
Stroke rates were 0.7% in the screening group vs 0.6% in the unscreened group.
Bleeding rates were 1.9% and 1.1% respectively.
Both were not significant.
The screened group had only a little more AF detected — 5% vs 3.3% in the usual care group, though OAC was started in 4.2% vs 2.8%.
Comments. This is another negative trial for AF screening, even though it was enhanced with older people who had stroke risk factors. The mean CHADSVASC was 3.2.
This study really had no chance to show a benefit given its early termination and recruitment of only 20% of the goal number of patients.
AF screening is limited by the fact that screen-detected AF is often short in duration and as shown by LOOP and the device trials (NOAH and ARTESIA) is associated with very low stroke rates. Once stroke rates are that low, it’s hard to lower them much more without increasing bleeding rates.
I also think a 14-day ECG monitor is not enough of a window to detect AF. If you want to have a chance to find AF, you need an always-on monitor, such as an ILR or implanted pacemaker or defibrillator device. The STROKE STOP authors may push back because they used intermittent ECGs for 2 weeks, but they also enrolled nearly 30,000 individuals and followed them for 7 years. And the benefit was tiny in absolute terms and barely significant.
What about the smart watch? It’s always on, is like an ILR or pacer. It might allow AF detection in high risk individuals. And it’s true. The problems with smart watch screening for AF is that smart watches will have more false positives, which turn out to be a big problem at scale. Watches will still pick up short duration low-risk AF that will likely not have a modifiable outcome.
So, on average, I believe AF screening is unlikely to ever improve hard outcomes. The thing is, and this is true of all screening efforts, within the mass of people who get screened will be individuals who are helped (let’s say a person with prior stroke who develops persistent AF), and those who are harmed (let’s say those who are misdiagnosed due to premature atrial contractions) are prescribed OACs and then suffer a fatal bleed related to the OAC.
That’s why we do trials — to sort out average effects in groups. Then we can discuss this with our patients.
I laud the authors for publishing this negative data, and for attempting to study an important and clinically relevant topic.
There is a low stroke rate from short duration AF. We don’t how much AF warrants OAC. It’s an area of clinical judgement and a great place to enroll patients’ values and ideas in the decision.
Brief AHA Preview
OPTION will compare two stroke and bleeding reduction strategies after AF ablation. One is to implant a LAAC device at the time of AF ablation and then stop OAC; the control arm is to continue direct OACs after ablation.
In 30 years of medical practice, I have never been more worried about an era of overuse and potential harm from overzealous doctoring. I am frightened about what may come from a positive trial, marketing push, financial incentives, and gullibility of doctors.
The numbers of AF ablation worldwide is massive, and rising. Nearly every day I get a Google alert telling me how many billions the AF treatment market is expected to be.
If we add LAAC with a device to these ablations, the costs and potential risks could be massive. Every incentive to LAAC at the time of ablation is aligned.
Patients will want it because the doc says they can then stop OACs.
Hospitals will want it because it will bring in dollars and, I don’t know this but suspect that, contracts will include breaks on other products if you hit a LAAC number
Doctors will like it because they will be paid more and doing more procedures also bring status in the field of EP.
Obviously, the makers of LAAC devices will like it because they sell more units.
Already, the Centers for Medicare and Medicaid Services has created a code for simultaneous LAAC with AF ablation.
I felt so strongly about the darkness of where we are heading as a field that I wrote a column about how the OPTION trial was designed to show positive results. I don’t know the results as the study will be presented this weekend, but this is a brief summary of what I wrote.
Both strategies have as their efficacy endpoint reduction of stroke and systemic embolism.
OPTION will test it with non-inferiority (NI), which is debatable but not entirely unreasonable because LAAC will allow coming off drugs. The problem for the authors is stroke rates after ablation are very very low.
Recall that the DOAC vs warfarin trials enrolled more than 10,000 to study NI in stroke.
OPTION will enroll only 1600, so to increase event rates, they added all-cause death to the stroke and systemic embolism endpoint. But. We know from oodles of studies (CABANA and LAAOS 3) that neither AF ablation nor LAAC reduce death. That means that they have added noise to the endpoint. Death is not affected and will likely be equal in both arms. Why is that important?
Because in an NI trial, no difference in endpoints is a “positive” result. Adding an endpoint unaffected by the treatments makes it easier to reach NI. This was done in PREVAIL and PROTECTwhere the trialists added CV death,
The second problem with OPTION comes in their estimate of event rates and choice of noninferiority margin. Trialists estimate an event rate of 10% in the ablation/DOAC arm and a fixed noninferiority margin of 5%. A meta-analysis of AF ablation trials in patients with heart failure (HF), who would presumably be at higher thrombotic risk than those in OPTION, reported stroke rates of about 4%. Given advances in ablation technology and its ability to reduce AF burden, stroke and embolism rates in OPTION probably will be lower than those observed in trials of AF ablation in patients with HF.
The likely scenario, therefore, is that primary outcome event rates will be lower than 10%. Stroke and systemic embolism alone will surely be lower than 10%. The noninferiority margin of 5% was set with the assumption of a 10% rate of events. If the observed primary event rate is lower than that, say 5%, then a 5% NI margin allows for the active arm to be declared noninferior even if those patients have twice as many events. OPTION could have allowed for lower-than-expected event rates by also testing NI with a risk ratio (relative difference). The rationale and design paper does not mention risk ratio testing.
Perhaps the biggest problem is the choice to make the primary safety endpoint include non-procedural bleeding. This is glaringly bad. Patients cannot exclude procedural bleeding. Procedural bleeding is the most obvious upfront risk with LAAC.
Read my whole piece. OPTION has been designed to be positive. Then it will be spun. And marketed. A colleague going to the meeting showed me an invite to an OPTION celebration event at AHA. Another colleague showed me an invitation to a webinar to discuss OPTION results.
If we start adding LAAC to AF ablation based on this flawed trial, I think we may take the win for most gullible cardiologists of all time.
I could be wrong but boy am I worried
Other Notable Studies at AHA
BPROAD is a big RCT in China enrolling 12,000 patients with T2D and studying BP target < 120 mmHg vs < 140 mmHg.
The primary endpoint is major adverse cardiac events composite of MI, stroke, HF hospitalizations (HHF), and cardiovascular (CV) death.
Follow-up is 5 years. The study is designed to find a 20% reduction in the primary outcome.
If this sounds familiar, it should. It is similar to the ACCORD trial: 2010. The HR for intensive arm was 0.88 which did not reach statistical significance. Serious adverse events were nearly three-fold higher in the intensive arm.
If the BPROAD trial is positive for the intensive arm, we should be listening for why they think it is so. One reason is that things change, and patients with T2D may be more robust than 24 years later. There also may be a higher rate of co-morbidities now that favor better BP.
GLP1 Agonists
What would a major medical meeting without a positive GLP1 agonist trial?
At a day 1 late-breaker session, we will hear about the SUMMIT trial -- Tirzepatide for Patients With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity.
On August 1, Lilly announced in a press release that tirzepatide reduced the risk of HF outcomes — HHF or CV death — by 38% vs placebo.
SUMMIT enrolled a common type of patient we see in the United States, with a body mass index > 30 and admission for HFpEF.
We already know from the press release the combined endpoint is massively positive in relative risk terms.
We will learn a) what are the absolute risk reductions? And b) was there a reduction in CV death? I make the distinction because as I have said many times, the endpoint of HHF can be a biased endpoint — especially in an unblinded trial.
Make no mistake, GLP1 agonist trials are unblinded, because it’s not hard for patients and likely clinicians to know that someone is on GLP1 agonist drugs.
The other thing I would push my friend, the principal investigator Dr Milton Packer on is what proportion HHF constitutes for overall hospitalization. HHF is only a good endpoint if it represents a solid chunk of hospitalizations. This has been a problem for HFpEF trials, because HFpEF patients often have multiple comorbidities. For instance, recall that in EMPEROR-PRESERVED trial of empagliflozin vs placebo in HFpEF the endpoint of HHF represented only 10% to15% of total hospitalizations.
Endpoints are important because GLP1 drugs stand to bankrupt the healthcare system. And if we are to use these drugs, they ought to be for patients who stand to derive substantial benefit in hard outcomes, such as death and CV death. If the drugs only reduce one of many causes of hospitalizations, then it’s hard to justify the cost.
Finally, SUMMIT will also have a co-primary endpoint of quality of life by Kansas City Cardiomyopathy Questionnaire. This is an unfair endpoint because GLP1 drugs cause unblinding, rendering patient-reported subjective endpoints about just useless.
VT Ablation
Canadians are great for trials. Professor John Sapp leads the VANISH2 trial in which post-myocardial infarction (MI) patients who had VT are randomly assigned to catheter ablation or antiarrhythmic drugs (AAD). It’s a common question in EP.
The primary endpoint of VANISH2 will be death, appropriate ICD shock, VT storm and treated sustained VT below the ICD detection.
Recall that the VANISH1 trial studied post MI patients who had VT on AADs. One arm had VT ablation and one arm had escalation of AADs. VANISH1 was barely positive. And most of the benefit was seen in patients on amiodarone at baseline. In other words, if you were on sotalol and changed to amiodarone, the Kaplan Meier curves were identical. Recurrent VT drove the benefit. Death rates were similar.
VANISH2 is a more relevant question these days. What to do with de-novo VT; start drugs or ablate?
It’s a good trial on an important topic. The biggest problem with VT trials, VANISH included, is external validity. That is how to generalize results from a trial done totally in expert centers to standard EP practices.
In Canada, ablation procedures are done in extremely exclusive high-volume city centers. This means that Canadians are ablated by highly experienced operators, because there are so few ablation centers.
In the United States, most EP practices, like mine for instance, do 10 times more AF ablation than any other ablation. AF ablation, truth told, can make you dumb. It’s anatomic and robotic. VT ablation requires serious skill in EP. It’s also hazardous. So if VANISH2 comes out positive, similar to VANISH 1, the challenge for patients and clinicians using this evidence is whether low-volume VT ablators can duplicate results found in centers of excellence.
CLEAR-SYNERGY
Last week I covered the results of the CLEAR SYNERGY trial of colchicine after acute MI. Colchicine did not improve outcomes. This was surprising to some because the two previous trials in coronary artery disease (COLCOT and LoDoCo) were positive.
Well, CLEAR SYNERGY was a 2x2 factorial design and one arm included spironolactone as well. At the Transcatheter Cardiovascular Therapeutics meeting, we learned the negative colchicine data. At AHA, we will learn the results of the spironolactone arm.
I think a lot of spironolactone. The RALES trial of spironolactone vs placebo in HF with reduced EF (HFrEF) was one of the most positive trials in all of cardiology. Spironolactone is a really important component in HFrEF care. If you look at the Americas portion of TOPCAT, spironolactone also shines in HFpEF.
The problem with post-MI patients who have percutaneous coronary interventions (PCI) is that they have low outcomes. PCI has transformed post-MI care such that even beta blockers don’t help. I don’t know the results of CLEAR SYNERGY, but it seems unlikely that spironolactone would improve outcomes, not because spironolactone is an ineffective drug, but rather, it’s hard to do much more for a group of patients who do so well.
Even though I am heading to the Swiss EP meeting, I will report on the AHA meeting.
There are many other great studies coming, including a number of non-statin lipid lowering drugs. These are hard to pronounce drugs like Zerlasiran, Muvalaplin, and Obicetrapib. Most of these are early phase 2 studies. Press releases have noted positive results on lipids. I mention these drugs because a lot is happening in the lipid lowering space.
The problem here will obviously be how much (if any) reduction in clinical outcomes we get — and at what cost.
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Cite this: Nov 15, 2024 This Week in Cardiology Podcast - Medscape - Nov 15, 2024.
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