Seth Bilazarian, MD


December 13, 2013

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Seth Bilazarian, MD: Hi. This is Seth Bilazarian from the American Heart Association (AHA) meeting in Dallas. I titled this blog, "Keeping Positive About Negative Trials at National Heart Meetings." Today, we have additional negative trials at the late-breaking clinical trials (LBCTs) session. Yesterday, 4 trials were presented that were all negative. I wanted to give you a sense of my feelings about this and why it was having an impact on me.

There are some data that there's been a decline in meeting attendance. I actually looked this up. The AHA last year was the largest-attended American heart meeting with over 15,000 professionals, 18,000 total; the American College of Cardiology (ACC) had fewer with 13,000; Heart Rhythm Society had 8000; and the Cardiovascular Research Foundation Transcatheter Cardiovascular Therapeutics had about 6000. So people are still going to meetings, but this LBCTs issue may be a concern about why I'm sort of disappointed with it.

My attendance every year for the last several years at both ACC and AHA is based on several things.

I, of course, want to be up to date. I want to learn and interact with my national and international colleagues to hear best practices. I want to review the state of the art in cardiovascular medicine and fill in the multiple holes in my personal knowledge base.

But I do desire a certain return on investment. When I go home, my colleagues ask: How were the meetings? And, of course, what that means is: Did you learn anything that's valuable? It's expensive and time-consuming to come to these large meetings. What can I take home to share with my colleagues, my hospital, and my practice that will improve care for our patients?

So the LBCTs play an important role in my view of a return on investment because when I see LBCTs that are of value that will make an impact on my practice and delivery of care to patients, I'm able to hear both official critiques of the data and actually hear peer critiques of the data. On the bus back to the hotel, I'll actually hear physician colleagues who are in private practice or clinical community practices talk about how the data will be integrated into their practices and what challenges will be faced. So I think it really is valuable.

This negative trial situation here at AHA, where the first 4 trials that were presented yesterday were all negative, made me go back and actually look at the last few meetings.

At ACC, there were 4 negative trials: ASTRONAUT, aliskiren in acute heart failure[1]; PEITHO, fibrinolysis in intermediate-risk pulmonary embolism (PE)[2]; CORONARY, evaluation of off-pump bypass[3]; and RED-HF, a trial of erythropoietin in anemia with systolic dysfunction and heart failure.[4] These were 4 trials in different areas that were potentially practice-changing, but all were negative.

At the European Society of Cardiology (ESC) meeting, there were 4: TASTE,[5] aspiration thrombectomy; RE-ALIGN,[6] dabigatran and mechanical heart valves; EchoCRT,[7] the echo guidance in left ventricular (LV) dyssynchrony for cardiac resynchronization therapy (CRT) implantation; and ACCOAST,[8] pretreatment with prasugrel for non-ST-segment elevation myocardial infarction (NSTEMI) patients before catheterization. All 4 again were negative trials that didn't change behavior.

And then yesterday at AHA, there were 4 LBCTs: NIAMI,[9] a sodium nitrite intravenously (IV) in NSTEMI patients to prevent perfusion injury trial that was negative; CATIS,[10] a trial of blood pressure (BP) reduction in early acute stroke patients treated with tissue plasminogen activator (t-PA); and then 2 trials of hypothermia.[11,12] All 4 were negative trials.

Now I began to think about this. From a research standpoint, you could think about this as: Are they really negative, or are they just inconclusive and open the door to more treatment? As a community-based practitioner, they're frankly negative because they don't change practice or don't change practice immediately.

But there were many criticisms of these trials, and you can go through all of the trials I just mentioned that are negative; those who were enthusiastic about them will actually conclude that there may have been differences in the trial designs that might have made a difference.

For instance, in NIAMI IV therapy was given. Should sodium nitrate have been given via an intracoronary (IC) route? In CATIS, should the BP reduction have been more? Was it too little? And in the hypothermia trials, the concern was that of the patients selected, many may not have been sick enough to demonstrate a benefit.

These are some of the things that come up when negative trials are presented. But at the end of the day, for my return on investment, there is, as I mentioned, no change.

The term "negative trial" is perhaps a misnomer. Clinical studies that yield unexpected or unwanted results might be a more wordy way to say it. But, of course, at the end of the day, they are negative for the practitioner.

However, these studies all show that the drug or device or technique was not effective for the indication that was tested. They rarely show any kind of negative or harm to patients. And usually the conclusion from the dais at these meetings is that we need additional randomized controlled trials, again fueling this research enterprise.

Why was it negative? There are a variety of reasons: There's a lack of statistical power of a trial design. There's inappropriate choice of the therapy's route of delivery, IV vs IC, as in NIAMI. There is an inappropriate dose. There is an inappropriate frequency. The choice of patient group to study is often criticized; for example, the patients weren't sick enough or the drug wasn't tested in the right sex or the right race or ethnic group. But at the end of the day, for those in community practice, the drug was simply not safe or effective in the group in which it was tested. So a variety of things obviously are learned at these meetings.

What I realized yesterday after the fourth LBCT that was negative is that the fanfare at these national meetings with the embargo and the simultaneous release by the press and simultaneous publication in a peer-reviewed journal is partly to blame for our disappointment. There's this big buildup. And then these trials land with a thud because they don't change medical practice. That was a revelation for me and why I was disappointed.

One of the questions that comes up in the literature about negative trials is: Is there a publication bias? In The New England Journal of Medicine, the National Heart, Lung, and Blood Institute (NHLBI) published a paper illustrating that this was really not the case.[13] For trials that NHLBI funded and that had negative results, there was no evidence of a publication bias; they get published and are not buried. So I think that can be dispelled from what I can see in this New England Journal article.

Finally, are we at a plateau in cardiovascular research advancement? I guess I'm asking myself: Have we gone about as far as we can go? As the "Oklahoma" musical goes, everything is up to date in Kansas City. They've gone about as far as they can go. Is that where we are in medicine or at least in cardiovascular medicine right now? Are we victims of our own success?

We really have had phenomenal advancements in my 20 years of practice in medical therapy with angiotensin-converting enzyme inhibitors (ACEIs), statins, and beta-blockers. Are we now just stalled? Or is this the shape of things to come for the next several decades? Well, we really are stalled in some areas: atrial fibrillation (AF) medical therapy and obesity treatments. Reduction in cardiovascular risk for diabetes hasn't gone anywhere in 20 years. We don't have any therapies for residual risk with lipid control beyond statins. And diastolic dysfunction heart failure patients don't have any additional therapies.

So we really are stuck. And, obviously, I'm excited about having some new therapies in this regard.

Given these negative trials, should we persist or stop? Are they just inconclusive, or are they unsuccessful? Are there caveats that we should push on?

In some areas, I would say enough is enough -- with fish oil, with glucose and sodium potassium in myocardial infarction, with niacin, with fibrates, with aliskerin, we've really gone as far as we can go. Enough is enough.

But there are some areas that are uncertain in my mind, like personal testing for platelet function with dual antiplatelet therapy (DAPT) and genetic testing for DAPT. It really is unclear what we should do, and obviously we need to press on. And then there's plenty of history that we should have pressed on in the past with interventional techniques like early percutaneous coronary intervention (PCI) and transcatheter aortic valve replacement (TAVR), which is what's happening now with AF ablation and genetic evaluation. As anybody in medicine knows, science doesn't progress linearly. There are leaps and bounds. And maybe we're just in a pause.

In conclusion, I'd say that after the period of depression I had yesterday after the 4 LBCTs were negative and today's presentation of the TOPCAT trial, a diastolic dysfunction trial using spironolactone that was also negative,[14] I'm taking a step back to feel grateful for the successes that the cardiovascular enterprise has had from discovery to delivery. It's very heartening, and I have confidence that the knowledge base will regain momentum; attendance at meetings isn't just about LBCTs.

There's an incredible amount of fanfare here at AHA about the integration of the new cholesterol guidelines. And a lot can be gained by interactions at these meetings. So from initial depression to, I hope, a positive attitude about the state of affairs as we move forward, thanks here from AHA in Dallas. I'm Seth Bilazarian.

To download the slides used in Dr. Bilazarian's presentation, click here.


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