Pharmacy & Therapeutics - February 2008 - (Page 99)

Antifibrinolytic Therapy in Cardiothoracic Surgery a multinational, retrospective observational study, Mangano et al. noted an increased risk of cardiovascular and cerebrovascular events and renal insufficiency with aprotinin. 12 Another 2006 study by Karkouti et al. also suggested some renal toxicity but did not show an increased cardiovascular risk.13 Neither study was a randomized, controlled clinical trial, and both compared aprotinin with AA and/or TA. As controversy ensued, on September 21, 2006, the FDA’s Cardio-Renal Advisory Committee discussed these two studies that had questioned the safety of aprotinin in patients undergoing CTS. After reviewing the Mangano study, the FDA had concerns about the methodology and lack of independent analysis of the data. Because this was the only study suggesting an increased cardiovascular risk with the drug, the committee concluded that there was not enough evidence to support changing the labeling in terms of cardiovascular safety.14 Within days after the committee endorsed the safety of aprotinin, an unpublished study conducted for Bayer, which was not disclosed to the FDA, revealed that there might indeed be an increased risk of cardiovascular events with the drug. Bayer admitted to the FDA that it had commissioned an observational study of its own to investigate the cardiovascular safety of aprotinin and that the preliminary results indicated an association between aprotinin and an increased chance of death, serious kidney damage, congestive heart failure, and stroke.14 In light of this information, the FDA required new labeling for aprotinin, specifying that it be used only for prophylaxis to reduce perioperative blood loss and the need for blood transfusion in patients facing an increased risk of blood loss and blood transfusion undergoing cardiopulmonary bypass during CABG. The new labeling focused on indications for use, added a warning about renal dysfunction, revised a warning about anaphylactic reactions, and added a contraindication.15 In February 2007, Mangano et al. published further results stating excess mortality rates with aprotinin use.16 On September 12, 2007, the Cardio-Renal Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 16 to 1 to allow Bayer to continue marketing aprotinin.17 On October 19, 2007, a communication to the FDA from the Data Safety Monitoring Board of a Canadian randomized study evaluating the safety of antifibrinolytic therapies stated that the trial was being halted because of a higher mortality trend in the aprotinin arm.18 Reacting to this negative finding, the FDA and Bayer announced the suspension of marketing for aprotinin (Trasylol) on November 5, 2007.19 Adding to the confusion, Van der Linden et al.’s observational study of 2,064 patients found that perioperative risk factors and advanced age were responsible for higher mortality and morbidity rates in an aprotinin group and that the drug was not an independent risk factor.20 In view of these reports of adverse effects of aprotinin and the concern among medical professionals questioning the efficacy and safety of the drug, we conducted an electronic Listserv survey of academic health center pharmacy directors in early 2006. We sought to determine the formulary status of aprotinin and the extent of its clinical usage. After evaluating data from 21 responding institutions, we found that aprotinin was used from 12% to 100% of the time in cardiac surgery, with 90% of survey respondents stating that it was used more than 75% of the time. AA was used from 0.5% to 88% of the time. Three respondents stated that TA was used from 0.5 to 10% of the time; one hospital used TA exclusively AA n = 12,397 AP 9,340 TA 17 Multi-AF use 1,627 CTS 9,751 (79%) Other uses 2,646 CTS 6,855 (73%) Other uses 2,485 CTS 10 (59%) Other uses 7 CTS 1,238 (76%) Other uses 389 Dropped Dropped Dropped AA — CTS 9,751 vs. AP — CTS 6,855 vs. CTS controls (no AF use) 46,123 CABG 7,064 (72%) No CABG 2,687 CABG 3,066 (45%) No CABG 3,789 CABG 6,879 (15%) No CABG 39,244 Figure 1 Study population receiving antifibrinolytic therapy. Data from 20 hospitals from the fourth quarter of 2002 to the third quarter of 2005. AA = aminocaproic acid; AF = antifibrinolytic; AP = aprotinin; CABG = coronary artery bypass grafting; CTS = cardiothoracic surgery; TA = tranexamic acid. Vol. 33 No. 2 • February 2008 • P&T® 99

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - February 2008

Pharmacy & Therapeutics - February 2008 Contents Editorial Medication Errors Prescription: Washington The Language of (Forgive Us) Change, As P&T Enters the Digital Age New Drugs/Drug News/New Medical Devices Drug Forecast Use and Outcomes of Antifibrinolytic Therapy in Patients Undergoing Cardiothoracic Surgery at 20 Academic Medical Centers in the United States Evaluation of the Management of Acute Venous Thromboembolism and Its Outcomes: One Institution's Experience American Society of Hematology, 49th Annual Meeting Pharmaceutical Approval Update

Pharmacy & Therapeutics - February 2008

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