At the Center of Rosiglitazone Storm, Steven Nissen, M.D., Focuses on Safety

CLEVELAND, May 25 -- Here, there, and everywhere this week, it was hard to miss Steven E. Nissen, M.D., the Cleveland Clinic cardiologist who revealed heart risks associated with still another prescription drug.

His latest target was rosiglitazone (Avandia), and earlier he set his sights on muraglitazar (Pargluva), a once promising diabetes drug that Dr. Nissen help derail when it was a hair away from FDA approval, and rofecoxib (Vioxx) the Cox-2 inhibitor that was eventually withdrawn from the market.

As director of cardiovascular medicine at the Cleveland Clinic, which is rated as the top heart center in the U.S. by U.S. News and World Report, Dr. Nissen is no stranger to a camera and a microphone. He, personally, is number 72 on Time magazine's list of the 100 most influential people in our world.

But the dustup created this week by his meta-analysis of published data from 42 randomized controlled trials of rosiglitazone has placed him squarely in the glare of critics who charge that Dr. Nissen is an anti-pharmaceutical crusader.

The analysis found a 43% increase in the relative risk of myocardial infarction among diabetics randomized to rosiglitazone (P=0.03). There was also an increase in the number of cardiovascular deaths in the rosiglitazone group, but that didn't reach statistical significance (P=0.06).

Nothing, Dr. Nissen said, could be farther from the truth. "I'm actually a great believer in the value of drugs," he said. "I've devoted most of my life to studying the biology of cardiovascular drugs in an attempt to find new, effective agents."

But at the same time, he has been a leading critic of the Prescription Drug User Fee Act (PDUFA), that allows the FDA to charge drug companies user fees that the agency then uses to pay for its research into drug safety.

Congress is slated to re-authorize PDUFA this year and Dr. Nissen is one of a number of physician-researchers who have been pressing the Democratic majority to re-work the legislation to allow for tougher post-marketing surveillance of new drugs.

To that end, the rosiglitazone study is likely to be cited as a textbook example of the need for more and better FDA safety studies, a point that was not missed by Rep. Henry Waxman (D-Calif.) who announced that he would hold hearings into the FDA handling of rosiglitazone on June 6.

Dr. Nissen, 58, the son of doctor, once entertained thoughts of a career in journalism.

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."

His years as a campus activist left him with an entrenched commitment to righting wrongs and a willingness to challenge the status quo, attributes that he has integrated into his medical career. And he never forgot the power of the press.

In 2001 he was the first physician to link 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.

In October 2005, Dr. Nissen again blew his whistle. This time the drug was muraglitazar (Pargluva), a drug in the same class as rosiglitazone.

When the FDA published clinical trial data about the drug, Dr. 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 in September 2005, recommended by an 8-1 vote that the FDA give it a thumbs-up.

Dr. Nissen said he dropped everything and began an in-depth analysis of the Pargluva data.

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

JAMA published the muraglitazar analysis online on Oct. 20, just two days after the FDA had sent the drug's makers an "approvable letter" that said muraglitazar could be approved if the company supplied more cardiovascular safety data.

On Oct. 27, Bristol-Myers Squibb announced that it would terminate its muraglitazar development agreement with Merck. The drug was dead.

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

Dr. Nissen, who was elected president of American College of Cardiology in 2006, 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 three or four. He would regularly be called upon to show off for his father's colleagues.

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

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

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

But Dr. 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 atherosclerosis.

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 in percutaneous coronary interventions.

But Dr. 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 Dr. 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."

He notes in his disclosure statements that he does work on pharmaceutical industry studies but all funds are given directly to the Cleveland Clinic research institute. He does not claim pharmaceutical funding, honoraria, or grants as income and he claims no tax deduction for moneys given in his name to charity.

That decision has "undoubtedly cost me some income," but Dr. Nissen said he has no regrets.

As cardiologist Mehmet Oz, M.D., of Columbia University wrote in the Time profile of Dr. Nissen, "Nissen's intravascular ultrasound lab has become so powerful that it lures industry leaders back-even if the service they receive sometimes includes more brutal honesty than they want. The activist continues to crusade, but these days lots of folks are listening."