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Cardiologist goes toe to toe with drug companies

Whistleblower said he learned activism during antiwar movement

By Peggy Peck
MedPage Today Managing Editor

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Dr. Steven Nissen was the first physician to link Vioxx to increased risk of heart attack and stroke.

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CLEVELAND, Ohio (MedPage Today) -- As Dr. Steven E. Nissen methodically ticks off the risks of what seemed like a highly promising experimental diabetes drug -- heart attacks, strokes, and death -- he is completely in his element.

As director of the cardiovascular coordinating center at the Cleveland Clinic Foundation, Nissen fills roles as full-time mainstream heart doctor, nationally respected researcher and occasional whistleblower.

His whistle-blowing has been loud, shrill and effective. This latest experimental diabetes drug is no exception.

A glimpse into his background explains a lot. As an undergraduate during the turbulent 1960s at the University of Michigan, he was "on the eight-year plan," a long road to graduation, with a minor in the antiwar movement.

"A political leader, really," he described himself, "and I was also editor of the daily paper -- a very good college paper."

Learned at the barricades

His years as a campus activist left him with a deep-seated commitment to righting wrongs and a willingness to challenge the status quo, attributes also of his professional career. And he never forgot the power of the press.

In 2001 he was the first physician to link Vioxx (rofecoxib) to an increased risk of heart attacks and strokes. When the Journal of the American Medical Association published his study detailing those risks, he was roundly criticized by Merck, the maker of Vioxx, and a number of physicians who praised the drug.

Three years later Merck pulled Vioxx from the market when additional studies confirmed that daily, long-term use of the drug could increase the risk of heart attacks and strokes.

Pulling out the all the stops

A week and a half ago, the 57-year-old Nissen again blew his whistle. This time the drug was Pargluva (muraglitazar), an experimental type 2 diabetes drug that can lower blood sugar while also increasing the level of HDL, the so-called good cholesterol, and decreasing triglycerides, a blood fat that increases the risk of heart disease.

When the FDA published clinical trial data about the drug, Nissen immediately spotted something amiss. All the "cardiovascular markers were going in the wrong direction. There were increases in heart attacks, stroke, and cardiovascular death."

One look told him that an FDA advisory panel charged with reviewing the same documents would not approve the drug. But he was surprised when the panel, which met September 9, recommended by an 8-1 vote that FDA give it a thumbs-up. He dropped everything and began an in-depth analysis of the Pargluva data.

Working nonstop with a Cleveland Clinic statistician and with co-author Dr. Eric Topol, chairman of the department of cardiovascular medicine, Nissen finished his analysis in record time.

The paper was published online on October 20 by the Journal of the American Medical Association, just two days after the FDA had sent the drug's makers an "approvable letter" that said Pargluva could be approved if the company supplied more cardiovascular safety data.

On October 27, Bristol-Myers Squibb announced that it would terminate its Pargluva development agreement with Merck. Bristol-Myers Squibb said it will continue discussions with the FDA, but said it might stop development of the drug.

Asked about the stunning reversal of fortune for Pargluva, Nissen said, "I'm not a crusader, I just want the balance between safety and efficacy to be favorable."

The hip bone's connected to ...

Nissen was born in Toledo, Ohio, where his father was a general practitioner. He recalls reciting the clinical names for all the bones in the body, a skill his father taught him when he was just 3 or 4. He would regularly be called upon to show off for his father's colleagues.

When Nissen was a child, his father moved the family to Baltimore so that at age 40 he could shift specialties to become an obstetrician/gynecologist. Later, the Nissens moved to Fullerton, California, where Nissen's father developed a successful private practice.

After medical school at Michigan, Nissen went to the University of California at Davis for a residency. There he met his mentor, Dr. Anthony DiMaria, then a rising star in the world of heart disease research. When DiMaria was asked to head up a struggling cardiovascular disease research program at the University of Kentucky in Lexington, he asked Nissen to come along to be the first cardiology fellow.

During his time in Lexington, he was approached by a company that was trying to develop an "ultrasound transducer that would fit inside a coronary artery," Nissen recalled. At the time the "smallest ultrasound transducer was the size of a fist," he said.

Heart disease from the inside out

But Nissen quickly realized that an imaging technique that could look at the arteries from the inside out could provide critical information about the real nature of the narrowing of arteries caused by the buildup of fatty deposits called plaque.

By spring 1990, animal experiments had moved to humans. He unveiled intravascular ultrasound imaging (IVUS) at the American College of Cardiology meeting, showing that the tiny device could be threaded into the beating heart to reveal the exact composition of atheromas. These days, IVUS is often used to guide coronary interventions such as opening clogged arteries with tiny, flexible tubes called stents.

But Nissen decided that IVUS would be even more useful as a tool to evaluate the real efficacy of drugs aimed at treating coronary artery disease. This is the research that he has doggedly pursued since he joined the Cleveland Clinic in 1993.

As his reputation has grown, so have offers from the pharmaceutical industry, a fact that led Nissen to a decision that smacks of the 1960s anti-establishment activist he once was.

"In order to be sure that I can be absolutely free of conflict of interest I won't accept any money under any circumstances."

That decision has "undoubtedly cost me some income," but Nissen said he has no regrets. He said his life with his wife, Linda Butler, a renowned professional photographer, is just about perfect.

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