John M. Mandrola, MD

Disclosures

August 20, 2018

This year's European Society of Cardiology meeting in Munich, Germany, is one for the clinician. If you see patients, pay attention to ESC 2018. 

While last year's meeting featured headline-friendly stories, such as a yet-to-be-approved indication for a drug targeting inflammation and a randomized controlled trial (RCT) testing catheter ablation in a small subset of patients with atrial fibrillation, this year's Hot-Line studies address everyday questions faced by practicing cardiologists and primary care doctors alike.

Prevention and Clots

Venous thromboembolism (VTE) in hospitalized patients continues to be a vexing problem that contributes to iatrogenic harm. The makers of rivaroxaban aim to help. The industry-sponsored MARINER trial will test the efficacy and safety of rivaroxaban compared with placebo in the prevention of symptomatic VTE events and VTE-related death after hospital discharge in high-risk, medically ill patients.[1] The findings will be presented Sunday, August 26.

On that same day, three of the four young investigator award sessions for thrombosis include studies on predicting VTE and pulmonary embolism outcomes. This is an important area because small increments in reducing harm from thrombosis in patients with serious illness could deliver big gains in public health.

Speaking of public health: Millions of people take aspirin as if it were an apple-a-day. Investigators from the United Kingdom recently sparked grave concern that low-dose aspirin given for primary prevention may work only for people who weigh less than 70 kg.[2] I modified "concern" with "grave" because the authors of this paper estimated that 80% of people taking aspirin for primary prevention weigh more than 70 kg (154 lbs).

Two RCTs presented at ESC will address aspirin utility. The Bayer-sponsored ARRIVE study was designed to prove the efficacy and tolerability of 100 mg enteric-coated aspirin vs placebo for the prevention of major adverse cardiac events (MACE) in patients at moderate risk  (10% to 20% 10-year risk) for heart disease events.

Bayer is also collaborating with researchers at the University of Oxford on the ASCEND trial of aspirin vs placebo and omega-3 fatty acid (FA) supplementation vs placebo for primary prevention of MACE in people with diabetes. In ASCEND, more than 15,000 participants were assigned to one of four groups: aspirin plus omega-3 fatty acids, aspirin plus placebo omega-3 fatty acids, placebo aspirin plus omega-3 fatty acids, and double placebo.[3]

The aspirin arms of ASCEND look more relevant than the omega-3 FA arms given that a recent Cochrane systematic review of 79 studies of more than 112,000 people found no evidence that increasing consumption of α­-linolenic acid and the long-chain omega-3 fatty acids (fish oils) enhanced cardiovascular health or protected against all-cause death or cardiovascular events.[4]

Alas, in both ARRIVE and ASCEND, two of the four components of the primary composite outcome are soft: unstable angina and transient ischemic attack.

Treating Patients With ACS

The aptly named VERDICT trial addresses another everyday problem faced by emergency medicine doctors and cardiologists: the management of patients with non-ST-segment elevation ACS. I don't know about your world, but in mine, the mere mention of a deferred invasive strategy for managing these patients draws looks of bewilderment and utterances such as, "Mandrola, stick to the EP lab, everyone knows early intervention is best."

That sort of thinking defines the word "apocryphal." "An early invasive strategy does not reduce the risk for death or myocardial infarction compared with a delayed strategy," reads the conclusion of a meta-analysis of seven trials comparing early and delayed invasive strategies in non-ST-segment elevation acute coronary syndrome — notably published in JACC Interventions.[5]  The largest driver of that neutral meta-analysis was the TIMACS trial,[6] which randomly assigned more than 3000 patients with ACS to early or delayed intervention and found no statistical difference in the composite primary outcome of death, myocardial infarction (MI), or refractory ischemia at 6 months.

It's remarkable that cardiology will once again depend on Denmark to help sort out a common clinical problem. The VERDICT study chair is Professor Lars Kober from the University of Copenhagen; it was he and his Danish colleagues who gave us the DANISH trial,[7] the third straight neutral trial of defibrillators for primary prevention in patients with nonischemic cardiomyopathy.

ACS has always been a common problem, but the advent of increasingly sensitive (and, some say, decreasingly useful) troponin testing adds relevance to the VERDICT trial. That is, as clinicians take time to learn how to use the much more sensitive troponin assay, many more patients will be diagnosed — rightly and wrongly — with ACS.

In High-STEACS, a stepped-wedge cluster RCT in 10 hospitals, Scottish investigators will test whether adjudication of these patients by using high-sensitivity troponin testing leads to a reduction in a legitimate primary endpoint: death due to cardiovascular causes or MI.

Again, these trials may not gain the attention of mainstream media, but they inform everyday problems for clinicians. 

Diet Debates

Lots has happened in the last 12 months in nutrition science. At the 2017 ESC, Canadian authors of PURE, one of the largest observational studies of health determinants, shook the core of the nutrition world, especially authors of American Heart Association presidential advisory on dietary fats,[8] when they reported that a diet high in fat, even saturated fat, was associated with a reduced risk for mortality. These authors also reported a statistically significant increase in mortality (hazard ratio, 1.28; 95% confidence interval, 1.12-1.46) in the highest quintile of carbohydrate intake.[9]

These findings momentarily tilted the debate on dietary fats toward the Mediterranean advocates. Then came the PREDIMED retraction this summer, which weakened the RCT-level evidence that eating (some) fat reduced the risk for major cardiac adverse events.[10]

Then, this August, data from the 25-year-long longitudinal ARIC (Atherosclerosis Risk in Communities) study found that low-carbohydrate diets high in animal-derived protein and fat sources were associated with higher mortality, whereas low-carbohydrate diets that favored plant-derived protein and fat intake were associated with lower mortality.[11]

And if that isn't enough controversy, the Journal of Clinical Epidemiology just published a scathing review of the empirical evidence surrounding memory-based dietary assessment methods used in most nutritional studies. The authors concluded that these methods are fatally flawed and pseudo-scientific.[12]

At ESC this year, the PURE investigators will present data on the association of dietary quality and risk for cardiovascular disease and mortality in more than 218,000 people from over 50 countries. I don't think it's risky to predict that this presentation will not stop the great diet debates.

AF, TAVI, and Mitral Valve Disease

At the 2017 Heart Rhythm Society meeting, the CABANA trial authors reported that atrial fibrillation (AF) ablation did not reduce hard clinical outcomes compared with drug therapy. The paper is not yet published, likely because of discussions over how to sort out the intention-to-treat and as-treated analyses. At ESC, CABANA investigators will present findings on recurrence of AF episodes. Of course this will show less AF in the ablation arm. That adds little new knowledge. The question is not whether AF ablation reduces AF episodes; it's whether doing so reduces stroke or death. Remember, too, that the lack of a placebo control arm in CABANA renders quality-of-life measures in this study much less valuable. Anyone who doubts the need for a sham-control arm in trials of cardiac procedures, please see ORBITA.[13]

German, French, and US investigators will present numerous registry studies on transcatheter aortic valve implantation (TAVI) or transcatheter aortic valve replacement (TAVR) in US parlance. TAVR is at an inflection point. Previous studies have shown that it can benefit patients with aortic stenosis who are at high surgical risk for aortic valve replacement. The two big questions now, which will be addressed at ESC, are durability and outcomes in patients at lower surgical risk.

Interventional cardiologists don't sit still. Now that TAVR has become a well-established procedure, the next frontier is the mitral valve and the treatment of another everyday problem: mitral regurgitation.

Thus far, however, the evidence for percutaneous intervention for mitral regurgitation has hardly been impressive. The only two citations from the ESC guideline document for use of percutaneous repair for primary mitral regurgitation (MR)[14] go to a small RCT (EVEREST II) that showed lower rates of efficacy of percutaneous repair vs surgical repair[15] and higher rates of residual mitral regurgitation at 5 years with the percutaneous vs surgical approach.[16] The only cited data on the use of percutaneous valve surgery for functional MR is a noncontrolled registry.[17]

At this year's ESC, French investigators will add to the evidence base for this increasingly accepted procedure. The Mitra.fr study is an RCT evaluating the effectiveness of percutaneous mitral valve repair in secondary MR and reduced left ventricular ejection fraction.

Academic-Industry Relations

In recent years, the ESC meeting has surpassed US cardiology meetings in size. But this is the first year of new European regulations limiting industry sponsorships of physician travel. It will be interesting to see whether or how this affects the vibrancy of ESC.

Cardiology would not be where it is today without the confluence of interests between academics and industry. You can't save people from heart attacks without stents and antithrombotics; you can't vanquish arrhythmia foci without ablation catheters. Collaboration with industry in this field is necessary. That's why I look forward to Professor Eugene Braunwald's Keynote Address, "Academic and Industry Relations."

We will have a strong team of news and features writers to cover the ESC meeting — stay tuned.

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