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Heart Drug Raises Questions

Heart Drug Raises Questions [Milwaukee Journal Sentinel]

From Milwaukee Journal Sentinel (WI) (November 19, 2010)

Nov. 19--CHICAGO -- A heart drug that was the subject of a Journal Sentinel investigative report earlier this year has been linked to an increasing number of adverse side effects, according to an analysis by a watchdog group that monitors medication errors and drug use in the U.S.

The drug Multaq, or dronedarone, was associated with cases of heart failure, lethal irregular heart beats, problematic interactions with other drugs and impaired kidney function in a report released earlier this month by the Institute for Safe Medication Practices.

"We have seldom seen a drug with so many issues in so many areas of its safety profile," the report said.

Since the drug was approved by the U.S. Food and Drug Administration in 2009, Multaq has been linked to 387 reports of adverse events, including 24 deaths, the report said. The drug is approved to treat atrial fibrillation, a type of irregular heart beat that affects about 2.5 million Americans.

The Journal Sentinel reported in May that all six co-authors of a large study that led to the drug’s approval by the FDA had financial ties to Sanofi-Aventis, the company that makes the drug. The report found increasing criticism of the way medical research is done in America and pointed to cases in which drug companies controlled the data.

In interviews this week, doctors who met at the American Heart Association annual conference in Chicago said the report raises new concerns about the drug and that the adverse events suggest the drug is being used to treat patients for whom it was not approved, so-called off-label use.

"It is somewhat concerning," said Sanjay Kaul, who served on the FDA advisory panel that recommended approval of Multaq. "This drug is known to be dangerous in patients with heart failure."

The report is a reminder to doctors that they need to exercise caution in prescribing the drug, said Kaul, who also serves as director of the vascular physiology and thrombosis research laboratory at Cedars-Sinai Heart Institute in Los Angeles.

The adverse side effects noted in the report are an example of how clinical trials sometimes do not adequately predict what will happen in the real world once a drug gets on the market, said Clyde Yancy, a cardiologist with the Baylor University Medical Center in Dallas.

Both Kaul and Yancy said that while the report noted 387 adverse events, it does not provide the total number of patients taking the drug.

"It’s easy to say the original study was flawed, but you can’t say that" based on the report, Yancy said.

Richard Page, now chairman of the department of medicine at the University of Wisconsin School of Medicine and Public Health, co-authored the large, international study that led to Multaq’s approval in the U.S. by the FDA last year, a move that could mean millions of dollars in sales for Sanofi-Aventis.

Critics respond

Doctors not associated with the trial said it was an example of how drug companies have too much control of medical research.

Page put his name on the influential research paper, but he allowed Sanofi-Aventis to dictate the terms. He vouched for the accuracy and completeness of the study despite not seeing the raw data. The company, which paid for the study, collected that information and performed the analysis without an external audit for accuracy or completeness.

Critics say this kind of study is an example of a problem with the way medical research is done in America. They point to a growing number of scandals in which drug companies have been accused of suppressing or manipulating research and skewing results to make their drugs look better and safer, although that has not been alleged in the Multaq trial.

In the Multaq case, Page and his co-authors had financial ties to Sanofi-Aventis at the time of the study.

Two authors worked for the company and owned its stock. Page and the four other authors moonlighted as consultants or speakers.

The study, which was published in the New England Journal of Medicine, also was criticized because it cited a 29% reduction in cardiovascular deaths with the drug, a finding that was disallowed by the FDA panel.

And now there are reports of additional problems with the drug.

The authors of the new report noted that there have been problems with Multaq dating back to 2005 when a clinical trial of the drug had to be stopped because it doubled the risk of death in patients with severe heart failure.

A second trial, the one co-authored by Page, was allowed to continue in patients who did not have heart failure. It eventually led to the drug’s approval because it was found to reduce hospitalizations.

Page declined to comment for this story.

Company reacts

Paul Chew, chief science and medical officer for Sanofi-Aventis, criticized the new report as being unfair and simplistic.

He said atrial fibrillation is most common in older people, many of whom have other chronic health problem such as diabetes. Without knowing the incidence of adverse events in those kinds of patients, the report does not provide any valuable insight into the drug, he said.

"It is like having a yard stick without the markings," said Chew, a cardiologist.

Also the report did not list the total number of patients who were taking the drug. "It’s just a number."

He said Sanofi-Aventis is taking all the precautions it can to warn doctors about inappropriate off-label use, including taking out monthly full-page ads in three medical journals for two years.

Data review

Beyond that, he said both the independent steering committee for the clinical trial and the FDA analyzed and reviewed the data.

Mariell Jessup, a professor of medicine at the University of Pennsylvania, said there always have been questions about the effectiveness and safety of the drug.

"I’m not surprised they are finding more cases of heart failure," she said.

Jessup said the rules are changing about how clinical trials are done so that drug companies have less control over data.

She said the report on adverse events is an indication that not enough information was gained from the clinical trial or that doctors just don’t understand which patients should get the drug.

She and Yancy, the Baylor cardiologist, said the FDA should require to company to submit more data on the drug because it still is not clear how the drug causes heart failure.

About this series This article is part of an ongoing series about how money and conflicts of interest affect medicine and patient care. To read more stories in the series, go to

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Posted: November 2010