Clinical Innovators | Interview by Katlyn Nemani, MD

Steven Nissen, MD, MACC, is the chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic’s Sydell and Arnold Miller Family Heart & Vascular Institute. Dr. Nissen’s research during the last two decades has focused on the application of intravascular ultrasound (IVUS) imaging to study the progression and regression of coronary atherosclerosis. He has served as international principal investigator for several large IVUS multicenter atherosclerosis trials. In addition t to his work as cardiologist and researcher, Dr. Nissen is a renowned patient advocate. He has testified in both the Senate and the House of Representatives on the topic of drug safety as well as the need to reform the Food and Drug Administration (FDA). Dr. Nissen is currently the editor of Current Cardiology Reports. In 2007, he was listed as Time Magazine’s “100 Most Influential People in the World – Scientists and Thinkers.” Dr. Nissen is also a regular Straight Talk columnist for CardioSource WorldNews.

You have led a number of inquiries and authored several manuscripts highlighting concerns about medications such as Vioxx, Avandia, and muraglitazar. What led you to question the scientific integrity of these medications? How was your research received?
In the case of rofecoxib (Vioxx), I served on an FDA Arthritis Advisory panel in the year 2000 as a guest member. The company was seeking a label for the GI benefits of the drug compared with older NSAIDs based on a trial known as Vigor. During the panel, I reviewed the cardiovascular outcome data for their Vigor trial demonstrating GI benefits and became concerned about excess cardiovascular events. My colleagues and I subsequently published our analysis in JAMA. The company was very aggressive in refuting our findings, but 4 years later another company-sponsored trial examining the benefits of rofecoxib in preventing colon polyps was terminated by the data safety committee after cardiovascular harm emerged. The drug was withdrawn from the market within a few days.

In the case of rosiglitazone (Avandia), I observed a trend toward greater cardiovascular events in two published trials run by the company designed to show benefits of the drug. One trial showed reduced progression to diabetes in pre-diabetic patients (the DREAM Trial) and a second trial showed greater durability of glycemic control (ADOPT Trial). In both cases, there was a numerical trend toward worse cardiovascular outcomes. I subsequently sought to perform a meta-analysis of all rosiglitazone trials, but most trials remained unpublished. Fortunately, a lawsuit by the State of New York related to the company’s failure to publish data on the increased risk of suicide in adolescents treated with an antidepressant, was settled with the requirement that the company disclose the results of all of their clinical trials. I used that database to investigate rosiglitazone and published the findings in the New England Journal of Medicine. Unbelievably, the company inappropriately obtained a copy of our manuscript after it was submitted, but before publication. The company was also very aggressive in defending their drug and personally attacking the authors of the manuscript. Eventually, most regulatory authorities around the world withdrew the drug from the market although the FDA refused to do so. Nonetheless, the drug is now virtually never used.

It sounds like bringing forth that data was challenging.
Both episodes were unpleasant and personally difficult, but I am proud that we acted in the best interests of patients. I do not condemn the whole industry for the bad behavior of two companies and continue to work closely with industry in developing innovative therapies.

Pharmaceutical companies often call upon you to consult on the development of new therapies for cardiovascular disease, though you do not accept compensation from industry. Could you tell us about this personal policy and other efforts you have made to avoid conflicts of interest?
This is a personal choice. I am outspoken about the benefits and risks of many therapies and I never want anyone to doubt my motives in advocating such strong opinions. I don’t think it is entirely possible to remain objective while receiving honoraria or other personal income, but I don’t fault others for making their own choices. 

You have spoken out about using surrogate endpoints without outcome data. What are some examples of trials in which surrogate endpoints have led to the overinterpretation of data?
There are many examples. Several come to mind. Estrogen replacement therapy was believed to provide cardiovascular benefits based upon biomarkers. When properly studied in the Women’s Health Initiative, it actually increased cardiovascular risk.

HDL raising therapies such as niacin were believed to be beneficial and widely used. Two trials, AIM-HIGH and HPS-Thrive, showed no benefit and some harms.

Reducing blood sugar was used as the evidence for approval of diabetes medications, but several studies showed worse cardiovascular outcomes despite effectively lowering blood sugar. In the ACCORD Trial, patients treated to lower HgbA1c levels actually showed increased mortality.

You pioneered the development of intravascular ultrasound (IVUS). What new insights have we gained into the systemic character of cardiovascular disease using this technology?
The most amazing finding from IVUS is the widespread and diffuse nature of coronary plaques, which is why systemic therapies improve morbidity and mortality, but focal treatment (stenting) does not improve outcome (at least in stable CAD). We have consistently demonstrated the reduction in disease progression with intensive LDL reduction.

Last year you wrote about reforming the Continuing Medical Education (CME) system in an environment of rapid-paced medical advancements. How can and should the CME system in the United States be reformed?

I have great concerns about the effectiveness of the Accreditation Council for Continuing Medical Education (ACCME) in leading improvements in CME delivery. Historically, ACCME has been extremely defensive and unwilling to police inappropriate and biased CME programs. There is surprisingly little evidence that CME actually changes practice. We need better research into CME effectiveness strategies.

As an advocate for universal health care, what are your thoughts about the Affordable Care Act?
The Affordable Care Act is a step in the right direction, but not sufficient to allow everyone to obtain high quality health care. As one of the richest countries in history, we are one of the few developed countries that does not have universal health care. I favor a single payer system such as Canada or the UK that provides government guarantees of basic health for everyone. We need to extend the Affordable Care Act, not repeal it.

What research projects do you have underway that you are most excited about?
We are finishing several major clinical trials during the next year. These include a study of PCSK9 inhibitor in statin intolerant patients, which uses an innovative design to identify patients with true statin intolerance.

We are planning on reporting the results of a major trial using the CETP inhibitor, evacetrapib, that was terminated early due to futility, again showing the failure of a surrogate endpoint.

Later next year, we’ll report the results of a large IVUS trial of a PCSK0 inhibitor designed to determine if we can regress coronary disease with very intensive LDL cholesterol lowering.

Finally, near the end of the year, we’ll report the results of a 24,000+ patient trial studying cardiovascular outcomes with a the most commonly used NSAIDS (naproxen, ibuprofen, and celecoxib) in high risk patients. This trial took 8 years to complete, but we hope it will be worth the wait because there exist no other high quality CV outcomes trials assessing this class of drugs.

Keywords: CardioSource WorldNews

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