Mandrola Previews the 2019 ACC Meeting

John Mandrola, MD


March 12, 2019

ACC organizers gave the Apple Heart Study[1] an entire late-breaking clinical trial session. Six luminaries in cardiology will question primary investigator Mintu Turakhia, MD, from Stanford University after he presents results of Apple’s entre into health.

The Apple Heart study has nearly 420,000 participants but no control arm. Its two co-primary endpoints are (1) atrial fibrillation (AF) of more than 30 seconds detected on subsequent ambulatory electrocardiography (ECG) in any person who received a watch notification of an irregular pulse and (2) simultaneous ambulatory ECG-detected AF at the time of an irregular pulse notification.

The first endpoint will be positive because the planned analysis is simply to estimate the number of participants who have AF confirmed on the subsequent ambulatory ECG monitor divided by all participants who have analyzable ECG patch data. This is descriptive; there’s no comparator.

The second endpoint will also likely be positive. The researchers consider the irregular pulse notification algorithm to be clinically meaningful if the concordance with AF identified on the simultaneous ECG is "high." They define a meaningful positive predictive value (positive test result actually is AF) as approximately 75%. This means the irregular notification can give false-positive recordings 25% of the time and the endpoint is still positive.

Crucially, the primary analyses for these endpoints will be performed only in participants older than 65 years of age—which will surely be a small subgroup of the 400,000+ enrolled.

The Apple Heart Study advances science because it is a first step in understanding base rates of arrhythmia in populations rich enough to buy Apple products. It will steal the attention of mainstream media, and hype-laden headlines will gush forth.

But the Apple Heart Study will not be the most important study for practicing cardiologists.

TAVR in Low-Risk Patients With Aortic Stenosis—A New Era in Cardiology?

Two randomized controlled trials (RCTs) of transcatheter vs surgical approaches to treating low-risk patients with aortic stenosis may usher in a new era in cardiology. To date in the United States, transcatheter aortic valve replacement (TAVR) has been reserved for patients at moderate or high surgical risk. The vast majority of surgical aortic valve replacements (SAVR) procedures are performed in lower-risk patients.

The PARTNER 3 trial enrolled about 1300 low-surgical-risk patients (<4%) with severe aortic stenosis to the Edwards Sapien 3 transcatheter valve or surgical replacement. The primary endpoint of all-cause mortality, all stroke, and re-hospitalization at 1 year will be evaluated in a noninferiority analysis. Perhaps you can see the bias for TAVR and against SAVR: by counting re-hospitalization in the primary endpoint, of which surgery always has more of early on, TAVR will almost surely achieve noninferiority and possibly even superiority. Since a key question with TAVR vs SAVR is durability of the valve, a report on 1-year outcomes is inadequate.

The EVOLUT trial will compare the Medtronic self-expanding valve against SAVR in approximately 1200 low-risk patients. I prefer its primary endpoint of all-cause death or disabling stroke at 2 years.

Two positives: Both trials plan to follow patients for a decade, and limited long-term data (~6 years) on TAVR durability[2,3] are encouraging. But I’m still worried that the short-term results may induce widespread use of TAVR in lower-risk patients without solid evidence for long-term durability. Given the large numbers of lower-risk patients with aortic stenosis, the downside risk of being wrong on this is big.

One more thing: If these trials are "positive" and TAVR clears regulatory approval for use in lower-risk patients, this would be an ideal case for decision support tools. Calling Dan Matlock and colleagues from the University of Colorado.

MitraClip News

COAPT trial[4] authors will present two substudies of the main trial looking at echocardiography and quality-of-life outcomes after transcatheter mitral valve repair in patients with heart failure. The COAPT results were positive, so I’d expect these to also report good news.

Since publication of the COAPT and Mitra-FR[5] trials, Milton Packer, MD, and colleagues have proposed the concept of proportionate and disproportionate mitral regurgitation (MR) to explain their disparate results.[6] Their theory holds that patients in COAPT had MR out of proportion to the degree of left ventricular dilation, whereas patients in Mitra-FR had proportionate MR. This is why the former trial was positive and the latter negative. Dr Packer told me that a patient-level meta-analysis is in the works.

A Good Test for Prevention of Infection in Cardiac Devices

Cardiac implantable electronic device (CIED) infection is an asymmetric risk: It occurs rarely but has severe consequences. Medtronic’s TYRX Absorbable Antibacterial Envelope encases the CIED and is implanted along with it, eventually resolving at about 9_weeks. In small studies, it has been associated with low rates of infection and favorable cost efficacy.[7,8]

At ACC, Khaldoun Tarakji, MD, from the Cleveland Clinic, will present results of the WRAP-IT trial. This multicenter 3-year trial of more than 7000 patients will compare the envelope to standard of care for a primary outcome of major infection. We learn from this trial regardless of the results. If no difference, then we can stop using an expensive add-on device. If positive, we will have to assess the absolute benefits vs the cost.

AF Ablation and Alcohol

Estimates project the market for cardiac ablation in the billions of dollars by 2026. While industry races to make better tools to create scar in the left atrium, the elephant in the room is that the key to AF ablation success lies outside the electrophysiology lab. This includes making better decisions on whom to ablate, and paying attention to AF risk factors, such as weight loss, sleep-disordered breathing, exercise, and alcohol intake.

This is why I am excited to hear Aleksandr Voskoboinik, MBBS, from the Melbourne group present the results of Alcohol-AF, a randomized trial of abstinence from alcohol vs continued drinking in an all-comers AF population. Observational evidence links alcohol intake with AF.[9] Dr Voskoboinik and colleagues recently published an elegant mapping study of patients presenting for AF ablation, showing that moderate alcohol consumption (vs no alcohol) was associated with slower atrial conduction velocity, lower-amplitude atrial signals, and a higher proportion of complex atrial signals—all markers of a pro-fibrillatory substrate.[10] But the ultimate test is the RCT.

Treating High Blood Pressure in Older Patients

One of the (many) discussion points surrounding the 2017 hypertension treatment guidelines[11] was that the authors recommended treating older patients largely the same as everyone else. Clinicians who treat the elderly rightly worry about the harms of aggressive blood pressure–lowering therapy. Recall that the average age of patients in the pivotal SPRINT trial[12] was 68 years, and less than 30% of patients were older than 75.

At ACC, researchers from the University of Connecticut will present results of the INFINITY trial,[13] a randomized comparison of hypertensive elderly (≥75 years) patients who have detectable cerebrovascular disease treated to an intensive blood pressure goal of 130 mm Hg or less or a standard goal of 145 mm Hg or less.

There’s a lot to like about this trial, including its extreme clinical relevance, patient-centered outcomes (such as changes in mobility and cognitive function), and use of ambulatory blood pressure recordings.

"Marketing Disguised as Science" Award

The New England Journal of Medicine recently published results of the PIONEER-HF trial, an RCT comparing valsartan-sacubitril vs enalapril in patients with acute decompensated heart failure with reduced ejection fraction.[14] The most remarkable aspect of this trial and its publication in a leading medical journal was that it measured a nearly meaningless endpoint in reduction of N-terminal pro B-type natriuretic peptide.

At ACC, we will hear results of the open-label extension of this trial. I’m not sure how these data help clinicians.


My colleague Steve Stiles has a more extensive preview of the featured studies at ACC.

Another notable is that the ACC invited me to present—a skeptical view—in a session on "digital health." If you have a chance, come by and heckle me at the Engage ACC19 Studio during lunch on Saturday. I will talk without slides, finish early, and seriously challenge the notion that the words digital and health belong together.

Editor’s Note: An earlier version of this column incorrectly stated that the Alcohol-AF randomized trial was in post ablation patients only, it is an all-comers trial.

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