AHA Sessions Preview: Highlights Include Long-Awaited Controversial Lipid, Stent Trials

November 10, 2014

CHICAGO, IL — Mark Twain once wrote that the host city for this year's American Heart Association (AHA) 2014 Scientific Sessions is "always a novelty; for she is never the Chicago you saw when you passed through the last time." That could be said about cardiology practice itself, which should emerge from the sessions' 4 days of original research, dialog, and expert discussion with a bounty of insights expected to take the management of patients with heart disease to higher levels.

If there's anyone who exemplifies what the field's advances over the past decades can do for patients with heart disease, it may be Dick Cheney, who will present his take on "Living with Heart Failure" on Monday morning of the sessions. The former vice president's odyssey has included at least five MIs, the first at age 38, followed by coronary stenting, CABG surgery, an implantable cardioverter-defibrillator, a left-ventricular-assist device in July 2010, and, 20 months later, heart transplantation. He has been a one-man test case for best contemporary cardiovascular care throughout most of his adult life and generous about publicly sharing his story.

Antiplatelets, LDL-Lowering Agents: Long-Awaited Answers at Hand?

Dr Robert Harrington

Primary results from at least two major clinical trials, the Dual Antiplatelet Therapy Study (DAPT) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), will be presented at different late-breaking clinical-trials sessions, program chair Dr Robert Harrington (Stanford University, CA) told heartwire . "These are two trials that the community has waited for a long time."

Both studies will be analyzed and discussed from different angles at not only the late-breaking sessions but also the separate Clinical Trials: Special Reports, Harrington observed. A number of controversies surrounding the trials—for example, the variety of stents used in DAPT and protracted patient enrollment in IMPROVE-IT, as long covered by heartwire —are certain to be addressed at one venue or another.

The first late-breaking session on Sunday is devoted entirely to trials of antiplatelet therapy in the setting of coronary stenting and especially to nailing down the most effective but safest duration for treatment with primarily clopidogrel or prasugrel. Should it be given for 6 months, or 12, or 24, or longer after the procedure? The DAPT study along with ISAR-SAFE and two other trials should shed some light on one of interventional cardiology's biggest questions.

Instead of a discussant following each of the presentations, Harrington said, "In this session we shortened the presentations a bit, and then we asked a single commentator to put the entire field in perspective in light of these four trials. [Dr] Gilles Montalescot [Hôpital Pitié-Salpêtrière, Paris, France] will be doing that." The schedule then calls for Montalescot, the presenters, and others to join in a panel discussion.

IMPROVE IT is "the anchor" of Monday's second late-breaking session, observed Harrington. Launched 9 years ago, the trial asked whether adding ezetimibe to simvastatin (the combination drug Vytorin, Merck), which can knock low-density lipoprotein (LDL) cholesterol levels down further than is possible with simvastatin alone, make a difference to clinical outcomes.

Vytorin is often used in clinical practice, but without the kind of clinical-outcomes studies that established statins as the go-to solo drug therapy for dyslipidemia. Harrington noted, "As a community, we're looking forward to this."

Prevention: From Aspirin to PCSK9 Inhibition

Also in that session: primary results of the Japanese Primary Prevention Project, a randomized trial of open-label aspirin at 100 mg/day for primary prevention, which enrolled >14 000 patients aged 60 to 85 years (58% were women) with cardiovascular risk factors including, in one-third of cases, diabetes.

Not only is primary-prevention aspirin a critical public-health question, Harrington said, "Just the fact that somebody did a trial with 60- to 85-year-olds is really important."

Next will be the FACTOR-64 trial, a trial planned for 900 patients with diabetes but asymptomatic for coronary disease to undergo screening with computed tomography (CT) angiography vs standard therapy. Not only does it have lots of patients for an imaging study, said Harrington, it's special for being an imaging study with clinical outcomes.

Last in that session: the primary data presentation of ODYSSEY Alternative, a randomized trial of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab (Sanofi/Regeneron) in statin-intolerant patients with primary hypercholesterolemia and moderate to high cardiovascular risk. The placebo-controlled trial separately compared the drug with ezetimibe and atorvastatin in a projected 314 patients for changes in LDL cholesterol over 24 weeks.

A Wednesday morning Clinical Trials: Special Reports is devoted to other alirocumab trials in the ODYSSEY family, including a comparison of the drug with other statins or ezetimibe in high-CV-risk patients, a trial in severe heterozygous familial hypercholesterolemia, one in patients not well controlled on maximal statins, and another of alirocumab vs placebo in a projected 2100 high-CV-risk patients followed for up to 20 months.

"We're starting the session with an overview of PCSK9-inhibitor therapy, then the four other ODYSSEY studies, and then we have a biostatistician talking about LDL as a surrogate," Harrington said. "We're hoping he's provocative."

Familiar Drugs for Special Populations

The third late-breaking clinical-trial session on Tuesday begins with presentations on two studies that may be remarkable more for their populations, seldom seen in large clinical trials, than for the newness of the tested therapies.

One is a randomized comparison of the beta-blocker atenolol with the angiotensin-receptor blocker (ARB) losartan in young people with Marfan syndrome, and the other a randomized trial of losartan in hypertrophic cardiomyopathy (HCM). "These are trials we don't have a lot of in cardiology," Harrington said. "Six hundred kids and young adults with Marfan's—that's extraordinary! And HCM is another where we've not done a lot of multicenter clinical trials."

He said beta-blockers are standard therapy for patients with Marfan syndrome, "based on literature from a long time ago. And there are some mechanistic data as well as pilot data suggesting that losartan may be beneficial. So this comparison of atenolol and losartan looks at aortic enlargement in these patients."

An accompanying presentation looks at the epidemiology of infective endocarditis in the UK and "raises questions about what the recommendations should be for antibiotic prophylaxis for those with structural heart disease when they get their teeth cleaned."

Two trials leading off the fourth late-breaking clinical-trials session on Wednesday morning look at biodegradable drug-eluting stents (DES). The BASKET-PROVE II and EVOLVE II clinical trials will then be discussed as a pair by Dr Roxana Mehran (Mount Sinai School of Medicine, New York, NY).

"By going with these new types of stents, do you lose anything on the restenosis/repeat-revascularization front, and do you reduce the long-term risk of stent thrombosis? That's part of the question," Harrington said. "We're pretty excited to have these two trials, frankly, because these are the kind of studies that frequently go to the TCT."

A Classic Statin Trial Revisited

There are four other Clinical Trials: Special Reports sessions, besides the one dedicated to the ODYSSEY trials, running Monday, Tuesday, and Wednesday. Among the noteworthy individual presentations, Harrington noted for Tuesday, is a 20-year follow-up on a randomized trial that helped launch the era of statins for primary prevention, the West of Scotland Coronary Prevention Study (WOSCOPS).

With primary results reported in 1995, the trial compared pravastatin with placebo in >6000 men with elevated lipids but no MI history. The risk of coronary events went down by 31% on the statin over 6 months.

Now, in 2014, Harrington seems excited. "How many trials do we have with a 20-year follow-up?"

He pointed to a number of other noteworthy Clinical Trials: Special Reports. For example, on Tuesday there is a secondary analysis from the TOPCAT trial, a test of spironolactone in preserved-ejection-fraction heart failure (HFPEF), by country of the sites enrolling patients. No overall benefit was seen for the intervention for the primary clinical end point, but there seem to be regional differences in a post hoc analysis, as heartwire previously noted. The scheduled secondary analysis will look at whether the treatment might have worked in some countries and not others, especially for North and South America compared with Russia and the Republic of Georgia.

Also on Tuesday, investigators from IMPROVE-IT looking at Vytorin will present its "on-treatment" analysis. The same day, editors of the AHA flagship journal Circulation will report their randomized trial looking at effects of the publication's social-media interactions. The presentation and trial are called "Intention to Tweet."

And on Monday, there will be discussion and analysis of the PARADIGM-HF trial, which shook the heart-failure landscape this year by showing a 20% decline in CV death or HF hospitalization from substituting the angiotensin-receptor/neprilysin inhibitor (ARNI) LCZ696 (Novartis) for the ACE inhibitor enalapril in patients with reduced-LVEF heart failure.

The trial has already had major presentations at the recent European Society of Cardiology 2014 Congress and Heart Failure Society of America 2014 Scientific Meeting, as covered by heartwire . But the PARADIGM-HF presentation in Chicago should contain new findings and insights. "They tell us there will be, and we pushed them to make sure that it does," Harrington said.

Surprise Format Experiments

There are changes in store for several long-time formats at the AHA sessions.

"This year we really limited the number of trials that will be in Meet the Trialists," according to Harrington. "It used to be that if you were a late-breaker trialist, we gave you a Meet the Trialist session. But we've realized over the past couple of years that what people really want to do is ask questions and really probe into these big, potentially practice-changing trials."

So there are only two such sessions scheduled, each focusing on discussion and interaction with the investigators from two clinical trials, including DAPT and ODYSSEY Alternative on Monday afternoon and IMPROVE-IT on Tuesday afternoon.

Also, "Of the original science presentations, that is the abstracts, 85% to 90% of them are now being presented as posters. What we hear from the community is that they want engagement. They want to be able to walk up and ask questions, and people like the poster format for that," Harrington said.

"And then the poster hall is going to be really different. I don't want to give it away—I want you to be surprised. But the way we are using the space is going to be different, and the way we group [topics] is going to be different—we're going for that community feel, using the physical space in a way to encourage interaction and networking."

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