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Drug Used in Coronary Artery Bypass Graft Surgery May Increase Risk of Death

CHICAGO, Feb. 6, 2007—Aprotinin, a drug used for limiting blood loss in patients undergoing cardiac surgery, is associated with an increased risk of death during five years following the surgery, according to a new study in the February 7 issue of JAMA.

Aprotinin was first approved for use in high-risk patients needing coronary artery surgery in the United States in 1993. As background information in the article, the authors state that more than 4 million patients worldwide have received aprotinin since 1985, principally during cardiac surgery. Annual use has increased to 600,000 patients (2005) throughout the world, including 246,000 uses in the United States in the past year. The safety of aprotinin came under scrutiny in 2006. An “observational study reported that aprotinin use was associated with a doubling to tripling of the risk of perioperative renal [kidney] dysfunction and failure requiring dialysis in patients undergoing primary, repeat or complex coronary artery surgery.”

Dennis T. Mangano, Ph.D., M.D., from the Ischemia Research and Education Foundation, 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 (CABG) 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 lessen bleeding—aminocaproic acid and tranexamic acid, aprotinin, or no anti-bleeding agent.

“During 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),” the researchers found. “Rates were similar for aminocaproic acid patients (132 deaths among 834 patients, 15.8 percent) and for tranexamic acid patients (65 deaths among 442 patients, 14.7 percent).”

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

“These findings indicate that in addition to the previously reported acute renal and vascular safety concerns, aprotinin use is associated with an increased risk of long-term mortality following CABG surgery. Use of aprotinin among patients undergoing CABG surgery does not appear prudent because safer and less expensive alternatives (i.e., aminocaproic acid and tranexamic acid) are available,” the authors conclude.
(JAMA. 2007;297:471-479. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Co-authors Drs. Filipescu and Fontes report receiving grants and meeting expense reimbursement from Bayer Incorporated. No other authors reported financial disclosures. The Ischemia Research and Education Foundation (IREF) funded the EPI-II in-hospital and long-term follow-up study. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

EDITORIAL: APROTININ — ARE THERE LESSONS LEARNED?

In an accompanying editorial, T. Bruce Ferguson Jr., M.D., from Brody School of Medicine at East Carolina University, Greenville, N.C., writes: “This past year has been a complicated one for aprotinin, an antifibrinolytic serine protease inhibitor used to lessen bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass. Thirteen years after the initial approval of aprotinin by the U.S. Food and Drug Administration, 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.”

“The studies by Mangano et al are important because they have generated new information not otherwise available about aprotinin use. However, it is not clear that the reasons patients received any specific agent (or no agent) are determinable. In the registry used by Mangano et al, the use of antifibrinolytics varied widely across surgeons, sites and countries during the enrollment period, and was influenced by cost, case complexity, physician judgment and other factors including differing patient selection and indication criteria.” Ferguson continues, “Aprotinin use in cardiac surgery has never been uniformly standardized, but generally has been reserved for patients in whom the surgical team anticipated a higher risk for intraoperative blood loss.”

“While the admonition to ‘First, do no harm,’ certainly applies to the ongoing use of aprotinin, an equally important consideration is when and where, at the drug/device safety evaluation level, the issue of first, do no harm actually could have been initially identified. Ultimately, going forward, the most important lesson learned from the aprotinin story is determining better ways to ensure drug safety and to eliminate and prevent these harms.”
(JAMA. 2007;297:527-529. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Please see the article for additional information, including author contributions and affiliations, financial disclosures, funding and support, etc

For More Information: Contact the JAMA/Archives Media Relations Department at 312/464-JAMA (5262) or email: mediarelations@jama-archives.org .

Posted: February 2007


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