Apr 05 2024 This Week in Cardiology

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In This Week’s Podcast

For the week ending April 5, 2024, John Mandrola, MD, comments on the following news and features stories: Statins and diabetes, antiarrhythmic drugs (AAD) in patients with heart disease, tricuspid valve (TCV) interventions, and an American College of Cardiology (ACC) annual meeting preview.

Statins and Diabetes

The Lancet Diabetes published yet another big meta-analysis of statin randomized control trials (RCTs). There are so many, perhaps because statin drugs are the most studied drugs, ever. This one, from the Cholesterol Treatment Trialists (CTT) group, focused on the effects of statins on diagnoses of new-onset diabetes (DM) and worsening glycemia. You’ve heard this story. Let’s review it again based on the new paper.

CTT has patient-level data from many RCTs. I report on this issue because it comes up a lot in statin discussions. The trialists included only trials with more than 1000 patients. This led to 23 RCTs with, get this, more than 154,000 individuals; 19 trials with statin vs placebo, four trials ith low- vs high-intensity statin.

The main questions involved the effect of randomization to statin on new-DM and the worsening of glucose in people with DM. The median duration of these trials was 4.3 years. I will come back to that.

These were the main results:

Compared with placebo, a low or moderate intensity statin resulted in a 10% proportional increase in the diagnosis of new DM. That sounds terrible so we should discuss absolute risks. (Recall this meta-analysis had more than 150,000 people).
The absolute risk of a new DM diagnosis in the statin arm was 1.3%. The absolute risk of new DM in the placebo arm was 1.2%. So, 1.3% vs 1.2% leads to a relative risk (RR) of 10%. It was statistically significant; again, there were lots of patients.
Now high-intensity statin: The proportional increase here was 36%. Absolute risks were 4.8% vs 3.5% and RR was 1.36.

You might wonder why the absolute values were that much higher in the high-intensity trials — 3.5%-4.8% vs 1.2%-1.3%.

Well, here was another key finding:

“For each trial, the rate of new DM among participants allocated to receive placebo depended mostly on the proportion of participants who had at least one follow-up HbA1c measurement; and this proportion was much higher in the high-intensity than the low-intensity or moderate-intensity trials.”

I did not realize this before. I had thought that the higher intensity statin probably had more DM-producing effects, but it equally could have been that trialists looked harder for DM in the high-intensity trials.
Blood glucose effects were modest. For patients without diabetes, statin allocation increased the mean glucose concentration by minimal amounts – For instance, in the high-intensity statin allocation the increase was only 1.4 mg/dl.
Patients most likely to tip into the diagnostic criteria were those who were closest to the threshold. In fact, nearly two-thirds of all new diagnoses of DM occurred in the highest quartile of blood glucose.
Among the trial-patients with DM, the rate ratios for worsening glycemia were 1.10 (1.06–1.14) for low-intensity or moderate-intensity statin therapy and 1.24 (1.06–1.44) for high-intensity statin therapy compared with placebo.

Comments. There is something about this drug, or perhaps its LDL-lowering effect, that causes a modest increase in glucose. The editorialists cite two studies ( NEJM and JAMA ) that find an association between gene variants that lead to lower-LDL levels and a higher risk of DM.

One way to look at this issue is to say that the DM risk from statin drugs is an important adverse effect (AE). We should worry about it.

Yet I don’t think this is the right way to think about it, exactly. Here is why.

First, I wonder if the higher incidence of DM is just a phenomenon related to reaching an arbitrary threshold of glucose or HbA1c, as most of the new diagnoses of DM occurred in patients close to that threshold. Some observational studies support the thresholds we use to diagnose new DM, but it’s still fairly arbitrary.
Second, and a far bigger reason not to worry too much about this, is that if the DM-signal caused serious harm it would be via higher rates of cardiac (CV) events from the DM. Right? DM is the most bad because it increases CV events.
Yet that is not what we see. We see the opposite. Statins induce a highly reproducible reduction of CV events.

In other words, the primary endpoint of these trials — CV events — incorporates the particular AE of new DM. This comes up a lot in trials.

For instance, I will discuss this issue when I preview the DanGer-Shock trial: Impella vs standard care in acute myocardial infarction (MI) with cardiogenic shock (CS).

The primary endpoint of DanGer Shock is mortality. That is a very broad endpoint. Yet the trialists also wrote that they will measure serious AEs specific to the Impella, such as limb ischemia and bleeding. However, these AEs should be incorporated in the primary outcome, which is death. If these AEs are bad enough, they should affect mortality.

Indeed, the choice of overall death as an outcome is why many of the early heart failure (HF), and MI trials were so helpful: When you measure something so broad, it should incorporate AEs.

In the statin example, the broad major adverse cardiac events (MACE) endpoint incorporates any signal of higher rates of DM and glucose issues.

There is one caveat to the DM-signal being incorporated in the MACE primary endpoints, and that is the time constraints.

Statin trials measure outcomes over 4 years. Yet it may take new DM longer than that to cause an increase in CV events. I doubt it because when you look at Kaplan Meier curves of statin trials, the degree of separation gets larger over time, consistent with the known benefits of longer times exposed to lower LDL. Yet the benefit-harm ratio of the drugs remains somewhat uncertain.

AAD for PVC Suppression in Patients with Heart Disease

I’ve talked often about how the CAST trial — AADs vs placebo in post-MI patients with ventricular arrhythmia (VA) — was one of the most important trials in all of Medicine.

Recall that for years, in the 1980s, we treated post-MI patients who had VA with drugs that suppressed VA. We did this because observational studies showed that VA was a marker for early death. We assumed that suppression of the VA would reduce outcomes.

But CAST showed that not only did this not work, but there was also a much higher death rate in the AAD group. CAST stopped a harmful treatment but, more importantly, it taught doctors the danger of using observational data to establish treatment norms.

One major problem though has been the over-interpretation of CAST. The US Food and Drug Administration (FDA) slapped a black box warning on the class 1C drug flecainide. The label says don’t use it in the presence of “structural heart disease.”

This is a total failure of evidence-based medicine (EBM). CAST enrolled patients who were post MI and had ejection fractions (EFs) in the 20%-30% range.

I think a lot of patients are denied helpful arrhythmia suppressing therapy because of this flawed trial translation.

That is why I want to tell you about a modest study from the University of Pennsylvania electrophysiology ( EP) group, first author Mohamed Raad.

The Journal of the ACC-EP (JACC EP) published this case series of 34 patients who had nonischemic cardiomyopathy, high-burden premature ventricular contractions (PVCs) and implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy device with a pacemaker or ICD (CRT-D) backup.

Before I tell you the results, I should say that high-burden PVCs that occur in patients with left ventricular (LV) dysfunction are bad because they can a) further decrease LV function (through an unknown mechanism) as well as decrease the amount of biventricular (BiV) pacing if there is a CRT.

23 of 34 received flecainide; 11 propafenone.
Most patients (62%) had failed other AADs or catheter ablation (68%) prior to class 1C AAD initiation.
PVC burden decreased from 20% to 6% (P < 0.001).
LVEF increased from 33% to 37%.
BiV pacing percentage increased from 85% to 93%
Sustained ventricular tachycardia (two vs nine patients) and admissions for decompensated heart failure (HF; two vs three patients) decreased compared with the 12 months prior to class 1C AAD initiation.

Comments. I highlight this modest paper because it exposes the mistaken translation of CAST. No. No. Double no. I am not advocating for wily-nilly use of 1C AADs. All AADs deserve serious caution — about their cardiac effects as well as their drug-drug interaction effects. You should be well versed in pharmacology if you use these drugs.

But we should always remember that CAST studied post-MI patients with serious ischemic LV dysfunction.

Yes, 1C drugs can depress LV function –through their Na-channel blockade effects.
But in this study of patients with bad LV function, use of a negative inotrope actually increased LVEF. That’s because suppression of PVCs helps LV function.

I want to point you all to a brilliant paper — one that is still timely. Daniel Kramer and the late Mark Josephson wrote, in Circulation Outcomes, “Three Questions for Evidence-based Cardiac EP .” One of these uestions was about the appropriate translation of CAST.

Seriously, this is one of the best papers I have read in my EP career. Everything they wrote in 2010 applies to everyday decisions today.

FDA Clears TriClip

This week, FDA approved Abbott’s TriClip transcatheter-edge-to-edge repair (TEER) system to repair severe tricuspid regurgitation (TR). This approval was likely because of the favorable advisory committee vote.

I’ve spoken often about the regulatory trial here, called TRILUMINATE. So, I will keep this brief.

TRILUMINATE randomly assigned 350 patients with severe TR to TEER (the procedure) or tablets (no procedure). The endpoint was hierarchical, with death or TCV surgery, HF hospitalizations (HHF), and, wait for it, quality of life (QOL), as measured by the Kansas City cardiomyopathy Questionnaire (KCCQ).
They used the win ratio and the trial was positive, but there was no difference in death, TCV surgery, or HHF. The driver of the positive trial was QOL.
The issue, the monster-sized elephant in the room, was that there was no placebo group. The TEER group knew that had the procedure, the medical group knew they did not get the procedure.
It’s completely, utterly impossible to assess a subjective endpoint like QOL without a control. But even without the placebo or sham control arm, TEER did not improve the 6-minute walk test.
The authors offered a post-hoc analysis that correlated the amount of TR reduction with the degree of improvement of the KCCQ. This may reassure some but it’s no replacement for a proper sham control, which would have been quite easy to do in this case.

The TriClip approval follows shortly after approval in February, of the percutaneous tricuspid valve replacement by Edwards, called Evoque.

Approval of Evoque was just as dubious. First, no advisory committee.

For the not yet published TRISCEND II trial:

The safety endpoint was derived from real world data from TCV surgery with a benchmark set at 44%. Really. That was the benchmark. You could have a 40% complication rate and it met its safety goal.
The first efficacy endpoint was a composite of TR grade reduction or the proportion of patients with TR moderate or less.
The second efficacy endpoint was KCCQ improvement of at least 10 points, New York Heart Association improvement by 1 class or more, and 6-minute walk distance of at least 30 meters.
The trial compared the valve vs optimal medical therapy (OMT; primarily oral diuretics) and had no sham.
It took about 2 hours to place the valve. Hospital stay was about 4 days.
The results favored the valve. But, of the 96 patients randomly assigned to the valve group, 26 had safety events. So, a 27% rate of AEs easily passed the safety goal. Wow.

These safety events were things like three deaths, 10 severe bleeds, two device complications, and 14 new pacers. Recall that pacing will require a coronary sinus lead, not impossible, but not normal either.

The first efficacy endpoint showed marked reductions in TR. The hierarchical endpoint was also positive. But each of the endpoints in the secondary efficacy endpoint were susceptible to placebo effect.

Comments. I will start with something positive. I’ve seen a handful of patients who I believe have TR as their major problem. And in most cases, they are in no shape for surgery. These two innovations may help them. Innovation is good.

But the thing is, primary TR — that is, TR that is the major problem, and not just part of a global HF condition — is rare.
My second problem is that evidence generation doesn’t have to be this weak. The FDA could have demanded a sham procedure. We have it for percutaneous coronary intervention (PCI), why not TR? A proper placebo would be able to sort out true benefit. Then we would know whether this works.
My third issue is that I worry especially about the valve replacement. Three deaths, 10 bleeds, two device complications, and 14 new pacers. A 27% rate of complications. Maybe valve iteration will make it better. But these were the rates of problems in motivated and experienced operators; it’s probably going to be worse in the real world.

There are a lot of patients with TR out there. There is a great potential for overuse of these devices. Especially if re-imbursement is favorable. I worry. We shall see. The evidence generation of these procedures tempts me to be cynical.

ACC Preview

Mandrola's Three Trials to Look for at the 2024 American College of Cardiology Scientific Sessions

ACC begins this weekend in Atlanta. This podcast comes out Friday afternoon. As you head out, please take a look at my ACC preview column that’s up on the theheart.org | Medscape Cardiology site.

I won’t be in Atlanta because I am attending the European Heart Rhythm Association (EHRA) meeting in Berlin, Germany. But I will write about some of the major trials from ACC.

ACC will have a number of trials that could change cardiology practice.

First is the DanGer-Shock trial, which will test the transvalvular microaxial flow pump vs standard of care in patients with acute MI-related cardiogenic shock (AMI-CS). I am normally allergic to brand names, but for simplicity’s sake, I will from here on, refer to Impella as the device.

The pre-DanGer-Shock history is that Impella is widely used but has yet to be proven effective in a proper RCT. I know; that sounds crazy but it’s true. Three small trials of Impella vs an intra-aortic balloon pump (IABP) were non-significant, as was a meta-analysis. Even worse, the IABP, which the Impella was compared against, has failed in its major RCTs against standard of care.

That is why DanGer-Shock was designed to test Impella vs standard of care. Principal investigator (PI) Jacob Moller from Denmark and his colleagues have designed a very detailed trial. They selected patients carefully. In fact, it took them 11 years to recruit more than 300 patients.

Patients had to have low blood pressure (BP), need for vasopressors, elevated lactate, low EF, and could not be comatose on arrival. Nor could shock be greater than 24 hours.
The primary endpoint is excellent. It is all-cause death. That is the best endpoint. Alive or dead. They chose to measure this not at 30 days, like in the IABP-SHOCK II trial, but at 180 days. I will be interested in hearing why they chose this later time point.
They will also measure important safety endpoints, including bleeding, vascular complications (limb ischemia, need for surgical intervention or amputation), significant hemolysis, device failure, and damage to aortic valve.
In the protocol paper, the authors compared patient characteristics of 314 patients in their trial with the IABP-Shock II and CULPRIT SHOCK (two PCI strategies) trials. All patients in DanGer-Shock had elevated lactates. DanGer Shock patients also had lower systolic BP and EF than patients in the other two trials.

This is such an important trial. It comes more than a decade after acceptance of the device. The DanGer Shock team deserves immense congratulations for persisting for a decade to get this data. But it boggles my mind that we don’t do these trials before acceptance of such an important device.

Two words on trial interpretation.

DanGer shock will have high mortality rates. This is the nature of CS trials. (They estimated a 60% death rate in the control arm). How we think about uncertainty around the effect size in such a trial may vary compared with a typical CV outcomes trial with low mortality and composite MACE outcomes.
Second thought – in the translation of this trial, whatever the results, we need to think hard about who these patients were. While it’s an amazing accomplishment to do a trial over 10 years, this means that these are quite special patients. Look hard at Table 1 and listen attentively to Dr. Moller when he describes these patients.

Speaking of important trials, now I want to say a word about TACT 2, an RCT of chelation therapy and high-dose vitamins to reduce MACE in patients with DM.

Recall that the first TACT trial came out positive. Chelation actually reduced MACE. But the medical establishment did not embrace it. It was too non-traditional.

PI Gervasio Lamas was not deterred. He instead took a subgroup from TACT 1, patients with DM who seemed to get the most benefit, and re-tested this group in TACT 2.

We hear the results on Sunday. This too will be huge news. If it is positive, Lamas will have not only found another disease-modifying therapy for patients with DM, but he will also have opened an entirely new way of thinking about preventive cardiology. That is the role of heavy metals in causing atherosclerosis. There is already a fair amount of data on the effects of heavy metals in causing poor health. It’s largely been ignored. TACT 2 could change all that.

As a curious person and someone interested in science, TACT 2 is like the Super Bowl. Week in and week out, I write about studies that, at best, provide incremental change. TACT 2 stands to truly change the game of preventive cardiology. Even though I will be in Germany at EHRA, I can’t wait to hear this presentation.

The third biggie at ACC is REDUCE AMI, yet another Scandinavian trial, this one from Sweden. The test here is use of beta blockers (BB) after MI.

Swedish investigators will randomly assign about 5000 patients with acute MI to standard oral BB vs no BB. Of importance, patients will have to have preserved LVEF. Of course, that is probably the majority of acute MI patients, now that urgent PCI has become standard.
The primary endpoint will be similar to the original BB trials: death or MI.
I am also interested in the secondary outcomes of symptoms — functional status, and health-related QOL, because the only way to sort out true BB side effects is with a proper placebo design.

If this trial comes out non-significant — which I think it will, because even the original BB trials, like BHAT, ISIS-1, and COMMIT, were not that impressive — a dogma will have been changed. We will no longer reflexively put these patients on BBs. And as a person who loves minimizing the burden of medical care, I will be happy.

There are many more trials to learn at ACC. Empagliflozin after MI, semaglutide in obese patients with HF and DM, new therapies for triglycerides, and more trials comparing transcatheter aortic valve implantation valves.

In the coming weeks I will recap these important studies here on TWIC.

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