Pharmacy & Therapeutics - May 2008 - (Page 298) Meeting Highlights: American College of Cardiology ISAR–REACT3: Bivalirudin (Angiomax) versus Unfractionated Heparin • Adnan Kastrati, MD, Deutsches Herzzentrum, Munich, Germany • Har vey D. White, DSc, Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand • Marc Cohen, MD, Professor of Medicine, Mount Sinai School of Medicine, New York, New York In the ISAR–REACT3 (Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment) trial, although bleeding was significantly reduced with bivalirudin (Angiomax for Injection, The Medicines Company), this agent did not improve net clinical benefit significantly, compared with unfractionated heparin (UFH), at 30 days after percutaneous coronary intervention (PCI). Net clinical benefit is a measure that balances clinical gains and adverse events. In a Late-Breaking presentation, Dr. Kastrati said that previous clinical trials had not reflected current anticoagulant or antithrombotic practices and had not included higher-risk populations. It was hypothesized that ISAR–REACT3 would find bivalirudin superior to UFH for biomarker-negative patients undergoing PCI after optimal pretreatment with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Synthelabo). In this trial, 4,570 patients with a mean age of 67 years (76.5% men and 80% with multivessel disease) were negative for biomarkers (troponin T levels below 0.03 mcg/L or creatine kinase [CK-MB] below the upper limit of normal [ULN]) with stable or unstable angina. These patients had been treated with aspirin at a dose of 325 mg or higher and with clopidogrel 600 mg for two hours or more before the procedure. The patients received bivalirudin as an intravenous (IV) bolus at 0.75 mg/kg before PCI, followed by continuous IV infusion during the procedure at 1.75 mg/kg per hour. Patients in the UFH arm received UFH as an IV bolus of 140 units/kg, followed by a continuous infusion of placebo for the duration of the procedure. All patients received clopidogrel 75 to 150 mg/day until discharge or for the first three days after the procedure, then 75 mg/days for at least six months and aspirin 80 mg to 325 mg indefinitely. The primary endpoint was a composite of death, myocardial infarction (MI), urgent target vessel revascularization (UTVR), and major bleeding, according to REPLACE-2 criteria (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events). Dr. Kastrati reported that ischemic events (death, definite ST elevation, MI, UTVR) were similar for both treatment groups. The primary endpoint was also similar between the two groups, at rates of 8.7% with UFH and 8.3% with bivalirudin (P = 0.57; relative risk [RR], 0.94). In the secondary combined endpoint (death, MI, UTVR), differences were also nonsignificant (UFH, 5.0%; bivalirudin, 5.9%). The frequency of bleeding, however, was higher in the UFH group, with major bleeding affecting 4.6% of patients, minor bleeding affecting 9.9%, and transfusions needed in 1.8%) than in the bivalirudin group, with major bleeding affecting 3.1% (P = 0.008), minor bleeding affecting 6.8% (P = 0.0001), and transfusions needed for 1.3% (P = 0.15). A prespecified subgroup analysis of age, sex, diabetes, creatinine, and stable or unstable angina revealed no differences, and the incidence of thrombocytopenia was also similar between the two groups. Concluding that bivalirudin had not improved net clinical benefit, Dr. Kastrati nevertheless said that it did reduce bleeding. He suggested that for some subgroups (e.g., older patients, the bleeding risk might make bivalirudin the better choice. Cost, however, could make UFH the preferred agent overall. Although ISAR–REACT3 was a trial with negative outcomes, ACC commentator Dr. White said that bivalirudin could be an appropriate antithrombotic choice in this setting. He added, “I think bleeding should have been the primary endpoint.” Dr. Cohen pointed out in an interview that the trial’s UFH dose was about double the starting dose used in the U.S., and probably produced higher bleeding rates in the UFH group. He emphasized bivalirudin’s extra cost, compared with UFH ($450–$500), and said that no evidence was given to suggest that the small bleeding increase with UFH led to any major added utilization of health care resources. I LETTER TO THE EDITOR Prescription Drug Abuse Dear Mr. Barlas, I enjoyed your column in P&T, Vol. 33, No. 4, April 2008. Pharmacists, of course, have long been aware of the dangers of prescription drug abuse. It is by far a much more significant problem than most people are aware of, and it is more significant than the typical drugs of abuse (heroin, cocaine, methamphetamine). Interestingly, Mr. [Heath] Ledger’s autopsy repor t showed “normal” levels of each drug that was in his system, thereby concluding that he did not purposely overdose. But even with these normal doses, it is obviously very risky and life-threatening to put seven different depressant drugs into the human body. Your article contained one minor misstatement. You stated, “They are opiates [oxycodone and hydrocodone], as are cocaine and heroin.” You are correct in stating that heroin is an opiate. However, cocaine is not an opiate. Opiates are very potent depressant or sedative drugs, directly or synthetically derived from a specific poppy flower, used to treat moderate-to-severe pain. Cocaine is a very potent stimulant, derived from the coca plant. Its legitimate use is as a topical anesthetic, used prior to and/or during nasal or sinus surgical procedures. Thanks for giving this case and this problem some badly needed awareness. Sincerely, Greg Evans, PharmD, Director of Pharmacy, Memorial Hospital, Los Banos, California Editor’s note: Please see correction on page 256. 298 P&T® • May 2008 • Vol. 33 No. 5
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