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Surgeon Points to Need for Improved Drug Evaluation

By Doug Boyd

A study of an anti-bleeding drug that can lead to kidney damage and death points to the need for better evaluation of drugs and medical devices, according to an editorial by an East Carolina University surgeon published in this Wednesday’s issue of the “Journal of the American Medical Association.”

Aprotinin, a drug used for limiting blood loss in patients undergoing cardiac surgery, is associated with an increased risk of death in the five years following surgery, according to the study. That illustrates the need for more study of drugs before and after the federal Food and Drug Administration approves them, according to Dr. T. Bruce Ferguson, a cardiothoracic surgeon and professor at the Brody School of Medicine at ECU. His editorial accompanied an article about aprotinin’s adverse effects.

Ferguson
Ferguson

“Aprotinin may or may not be a drug that can add benefit and reduce risk in high-risk cardiac surgery patients,” Ferguson said. “This aprotinin story illustrates nicely what is wrong with our drug and device approval and follow-up processes at the FDA and industry levels.”

Ferguson compared the aprotinin story to the situation with Vioxx and drug-eluting stents, where the drugs or devices were found in some cases to have undesirable effects, including death, after being approved and used widely by providers, particularly “off-label,” or outside the scope of the trials that were performed to obtain FDA approval.

“There needs to be a better, more comprehensive way of evaluating the ‘real world’ use of FDA-approved technologies, because, one, they are used off-label to a greater and greater degree where there are no pre-market data available to assess benefit or harm; and, two, because the design of the pivotal, pre-market trials cannot account for all possible factors,” Ferguson said. “Right now, the post-market issue is much more important of an issue, and needs serious attention. The trick is getting industry to step up to the plate and be willing to fund these types of efforts and in some cases to curb the enthusiasm of providers until additional data are available.”

Aprotinin, made by Bayer and sold under the brand name Trasylol, is a protein administered by injection to reduce bleeding during complex operations, such as heart and liver surgery. Its main effect is slowing fibrinolysis, the process that leads to the breakdown of blood clots. The goal is to decrease the need for blood transfusions during surgery and reduce organ damage due to low blood pressure as a result of significant blood loss.

In 1993, the FDA approved aprotinin for use in high-risk patients needing coronary artery surgery. More than 4 million patients worldwide have received aprotinin since 1985, principally during cardiac surgery, according to the new study. The safety of aprotinin came under scrutiny in 2006, and aprotinin use was associated with a doubling to tripling of the risk of kidney dysfunction during surgery and failure requiring dialysis in some patients.

Dr. Dennis T. Mangano of the Ischemia Research and Education Foundation in San Bruno, Calif., and colleagues assessed survival rates at six weeks, six months and annually for five years for 3,876 patients undergoing coronary artery bypass graft surgery at 62 medical centers around the world. The researchers examined death rates of these patients according to the use of three medications used to reduce bleeding -- aminocaproic acid, tranexamic acid or aprotinin -- or no anti-bleeding agent.

During those five years, 223 deaths occurred among 1,072 aprotinin-treated patients (20.8 percent), a death rate nearly two-thirds greater than control patients (128 deaths among 1,009 patients, 12.7 percent), researchers found. Rates were similar for patients given aminocaproic acid (132 deaths among 834 patients, 15.8 percent) and tranexamic acid (65 deaths among 442 patients, 14.7 percent).

Researchers estimated that over the past year, aprotinin was prescribed worldwide to at least 200,000 cardiac surgery patients having a profile similar to patients in the study. For such patients, the study found a 5 percent absolute increase in five-year mortality, or 1 percent a year for five years, associated with aprotinin use, compared with either aminocaproic or tranexamic acid use.

Researchers concluded that using aprotinin on patients undergoing coronary artery bypass surgery “does not appear prudent because safer and less expensive alternatives (i.e., aminocaproic acid and tranexamic acid) are available,” according to the study.

In his accompanying editorial, Ferguson writes: “Thirteen years after the initial approval of aprotinin by the (FDA), the report by Mangano and colleagues in this issue of JAMA will intensify the debate about the benefits and risks associated with use of this drug. Perhaps more important, this aprotinin story illuminates the larger issue of post-market safety evaluation surrounding drugs and devices in the current medical environment.”

Ferguson said health care providers, regulators and industry need to work together to better refine U.S. drug and device evaluation and follow-up processes. Last week, the FDA announced plans to strengthen its measures to ensure drugs and medical devices are safe. That followed a report last year by the Institute of Medicine that recommended ways to improve U.S. drug testing and safety.

Ferguson added that the Mangano aprotinin study has limitations. For instance, it doesn’t fully account for why the surgeons used aprotinin in the selected patients in the registry. Ferguson said aprotinin use has never been standardized. He uses it in selected patients at high risk for blood loss during surgery and who have no pre-existing evidence of kidney problems.

The Ischemia Research and Education Foundation funded much of study. Two study co-authors reported receiving grants and expense reimbursement from Bayer.

8/2/10
This page originally appeared in the Feb. 23, 2007 issue of Pieces of Eight. Complete issue is archived at http://www.ecu.edu/news/poe/Arch.cfm.