VIOXX all over again:  The drug company knew of the deadly side effects, yet it acted to supress this information.  The FDA has suspended sales of at least one of the 2 major drugs given to prevent thrombi for those who are to undergo the bypass procedure.  The consequence of these non-aspirin therapies is over 100,000 avoidable deaths

Pharmalot is one of two major websites catering to the pharmalogical industry that is centered on current news, product development, and other issues of interest to those working within the industry.   The site is maintained by Ed Silverman, a journalist who had worked for the Star-Ledger of New Jersey, that state’s leading newspaper. 

http://www.pharmalot.com/2008/02/bayers-trayslol-raises-risk-of-death-studies/

Bayer’s Trayslol Raises Risk of Death:  Studies

Feb 21, 2008, Ed Silverman

Trasylol patients were 27 percent more likely to die than those getting a rival drug a decade after open-heart surgery, according to a review of 10,275 patients at Duke University Medical Center. Another study of 78,199 patients, presented to regulators last year after Bayer initially withheld the data, found a 78 percent higher death risk a week after surgery. Both were published in The New England Journal of Medicine.

The controversial med was approved in the US in 1993 to reduce transfusions and bleeding during open-heart surgery, but a 2006 study linked the drug to higher rates of heart attack, stroke, kidney failure and death. Those findings prompted the FDA to hold a meeting to review Trasylol, but Bayer failed to provide data showing a higher risk of death and stroke, even though its own scientists attended the meeting. The internal data was disclosed several days after the meeting, leading to charges of a cover-up, which Bayer last summer denied.

In November, however, Bayer suspended sales after a pivotal Canadian trial linked the drug to higher death rates. “It’s become part of the fabric of cardiac surgery for the past decade,” Andrew Shaw, lead author of one study and associate professor of anesthesiology at Duke, tells Bloomberg News. “Our study doesn’t provide a definitive answer, but it intensifies the debate over the drug safety.”

Indeed, the lives of 22,000 people could have been saved if the FDA removed Bayer’s Trasylol two years ago, when the study revealed a growing number of deaths linked to the heart drug, according to the researcher who conducted the study.

Bayer, meanwhile, challenged the findings from the latest studies, raising questions about how the researchers analyzed the data and accounted for differences between the patients getting Trasylol [aprotinin] and an alternative known as aminocaproic acid.  The drug maker continues to wait for a detailed analysis of the Canadian trial.

“At that time, the temporary marketing suspension will be re-evaluated,” Bayer spokeswoman Staci Gouveia tells Bloomberg, adding that Bayer has no idea when the details will be available. “Bayer believes that the totality of the available data continue to support a favorable risk-benefit profile for Trasylol.”

More than 200,000 bypass patients a year worldwide were getting Trasylol before sales were halted, Bloomberg notes, adding that Bayer has said 4.3 million people have been treated with Trayslol and that the injectable drug costs 10 times more than its closest rival.

“It is the largest cohort study ever on the issue, representing routine care. It’s another data point in the accumulating number of studies that show this increased risk of death,” Sebastian Schneeweiss, the lead researcher of the second study and an associate professor of medicine at Harvard Medical School in Bostonrhe tells Bloomberg, while declining to say if he thought Trasylol should be permanently removed from the market.

“The data have to be reviewed and seen in the light of all the evidence. The bottom line is there are still more people dying using this drug. FDA is the agency that has all the evidence together at this point, and they need to make an informed decision.”

Currently, doctors can get it through a restricted access program in the US.

In an editorial, Wayne Ray, director of drug epidemiology and professor of preventive medicine at Vanderbilt University School of Medicine, wrote: “The manufacturer cannot be relied on to perform these studies voluntarily, because they frequently serve no commercial purpose.” As a result, studies “supervised by the FDA, should be mandatory. To limit the risk for patients, distribution of new drugs should be restricted while these trials are being conducted, with selective extension of patents to reduce the economic burden on manufacturers.”

From Goodman and Gilman, The Pharmacological Basis of Therapeutic, 11^th Ed., 2007, p. 648.

Kallikrein Inhibitors.  Aprotinin (Trasylol) is a natural proteinase inhibitor obtained for commercial purposes from bovine lung, but it is identical with Kunitz’s pancreatic trypsin inhibitor (Waxler and Rabito, 2003).  Aprotinin inhibits mediators of the inflammatory response, fibrinolysis, and thrombin generation [clots] following cardiopulmonary bypass surgery, including kallikrein and plasmin.  In sereral placebo-controlled, double-blind studies administration of aprotinin reduced requirements for blood products in patients undergoing coronary artery bypass grafting.  Depending on patient risk factors, aprotinin is given as a load dose of either 1 or 2 million kallikrein inhibitor units (KIU) followed by continuous infusion of 250,000 or 500,000 KIU/h during surgery.   

New England Journal of Medicine

Vol 358:784-793, February 21, 2008, Number 8

The Effect of Aprotinin on Outcome after Coronary-Artery Bypass Grafting

Andrew D. Shaw, M.B., Mark Stafford-Smith, M.D., William D. White, M.P.H., Barbara Phillips-Bute, Ph.D., Madhav Swaminathan, M.D., Carmelo Milano, M.D., Ian J. Welsby, M.B., Solomon Aronson, M.D., Joseph P. Mathew, M.D., Eric D. Peterson, M.D., M.P.H., and Mark F. Newman, M.D.

ABSTRACT

Background Aprotinin has recently been associated with adverse outcomes in patients undergoing cardiac surgery. We reviewed our experience with this agent in patients undergoing cardiac surgery at Duke University Medical Center.

Methods We retrieved data on 10,275 consecutive patients undergoing surgical coronary revascularization at Duke between January 1, 1996, and December 31, 2005. We fit data to a logistic-regression model predicting each patient's likelihood of receiving aprotinin on the basis of preoperative characteristics and to models predicting long-term survival (up to 10 years) and decline in renal function, as measured by increases in serum creatinine levels.

Results:  A total of 1343 patients (13.2%) received aprotinin [Trayslol], 6776 patients (66.8%) received aminocaproic acid, and 2029 patients (20.0%) received no antifibrinolytic therapy [therapy to prevent thrombi]. All patients underwent coronary-artery bypass grafting, and 1181 patients (11.5%) underwent combined coronary-artery bypass grafting and valve surgery. In the risk-adjusted model, survival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% confidence interval [CI], 1.12 to 1.55) for the comparison with patients receiving no antifibrinolytic therapy (P=0.003) and 1.27 (95% CI, 1.10 to 1.46) for the comparison with patients receiving aminocaproic acid (P=0.004). As compared with the use of aminocaproic acid or no antifibrinolytic agent, aprotinin use was also associated with a larger risk-adjusted increase in the serum creatinine level (P<0.001) but not with a greater risk-adjusted incidence of dialysis (P=0.56).

Conclusions Patients who received aprotinin had a higher mortality rate and larger increases in serum creatinine levels than those who received aminocaproic acid or no antifibrinolytic agent.

Source Information

From the Departments of Anesthesiology (A.D.S., M.S.-S., W.D.W., B.P.-B., M.S., I.J.W., S.A., J.P.M., M.F.N.) and Surgery (C.M.) and the Duke Clinical Research Institute (E.D.P.), Duke University Medical Center, Durham, NC.

Address reprint requests to Dr. Shaw at the Department of Anesthesiology, Duke University Medical Center, Durham, NC 27516, or at andrew.shaw@duke.edu .

Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death

Volume 358:771-783, February 21, 2008, Number 8

Sebastian Schneeweiss, M.D., Sc.D., John D. Seeger, Pharm.D., Dr.P.H., Joan Landon, M.P.H., and Alexander M. Walker, M.D., Dr.P.H.

ABSTRACT

Background Aprotinin (Trasylol) is used to mitigate bleeding during coronary-artery bypass grafting (CABG). Accumulating evidence suggests that this practice increases mortality.

Methods Using electronic administrative records of the Premier Perspective Comparative Database, we studied hospitalized patients with operating-room charges for the use of aprotinin [Trayslol] (33,517 patients) or aminocaproic acid (44,682 patients) on the day CABG was performed. We tabulated the numbers of patients with a hospital-discharge status of death and performed three types of analyses: a multivariable logistic-regression analysis (primary analysis); propensity-score matching in the highly selected subcohort of patients who received full amounts of the study drug, who underwent CABG by surgeons who performed 50 or more CABG surgeries during the study period, and for whom information on 10 additional covariates was available because the surgery occurred on hospital day 3 or later; and an instrumental-variable analysis of data from patients whose surgeons showed a strong preference for one of the two study drugs.

Results In all, 1512 of the 33,517 aprotinin recipients (4.5%) and 1101 of the 44,682 aminocaproic acid recipients (2.5%) died. After adjustment for 41 characteristics of patients and hospitals, the estimated risk of death was 64% higher in the aprotinin group than in the aminocaproic acid group (relative risk, 1.64; 95% confidence interval [CI], 1.50 to 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02). The relative risk in a propensity-score–matched analysis was 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variable analysis, the use of aprotinin was found to be associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14 to 3.04). Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid.

Conclusions Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received aminocaproic acid alone. Characteristics of neither the patients nor the surgeons explain the difference, which persisted through several approaches to control confounding.