Pharmacology Watch: Study Shows Oral IIb/IIIa Receptors Increase Mortality

Another study has shown an increase in mortality associated with the use of an oral IIb/IIIa receptor antagonist. The use of intravenous IIb/IIIa inhibitors has become commonplace in the setting of acute coronary syndrome and percutaneous coronary intervention, where these drugs have been found to reduce mortality and nonfatal myocardial infarction. Oral IIb/IIIa antagonists, however, have not shown to be beneficial in the outpatient setting, and now the fourth of these drugs has been shown to increase the risk of death in patients with cardiovascular disease. The Blockade of the Glycoprotein to IIb/IIIa Receptor to Avoid Occlusion trial (BRAVO) was a study of more than 9000 patients with cardiovascular disease who were randomized to SmithKline Beecham’s lotrafiban or placebo plus aspirin for up to 2 years. The trial was stopped early due to a 33% increase in the death rate in the treatment group, due primarily to vascular deaths. Death occurred in 2.3% of patients in the placebo/aspirin group and 3% of patients in the lotrafiban group (HR 1.33; 95% CI, 1.03-1.72; P = 0.026). An interesting additional finding of a study found an aspirin dose of > 162 mg/d was associated with an increased risk of serious bleeding and transfusion but not an increased risk of mortality (Circulation. 2003;108:399-406). Trials such as EXCITE, SYMPHONY-II, OPUS, APPLAUD, and now BRAVO have shown similar results with oral GB IIb/IIIa inhibitors, all with excess mortality in the range of 30%. BRAVO was the first that demonstrated this finding in patients with cerebrovascular disease as well as coronary artery disease. Whether further studies of these drugs in the outpatient setting are warranted is yet to be seen.

Dalteparin Superior to Warfarin

The low molecular weight heparin dalteparin is superior to warfarin in preventing recurrent venous thromboembolism in patients with cancer, according to new study. Nearly 700 patients with cancer who developed proximal deep-vein thrombosis, pulmonary embolism, or both were randomized to receive dalteparin (200 IU/kg subcutaneously once daily for 5-7 days) followed by warfarin for 6 months vs dalteparin alone for 6 months (200 IU/kg SQ/d for 1 month, followed by 150 IU/kg SQ/d for 5 months). During the 6-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism as compared with 53 of 336 patients in the warfarin group (rate of recurrent thromboembolism 9% dalteparin group vs 17% warfarin group, HR, 0.48; P = 0.002). There was no significant difference in the rate of adverse effects, including major bleeding, between the 2 groups. There was no difference in mortality between the 2 groups (N Engl J Med. 2003; 349:109-111). In an accompanying editorial, Dr. Rodger Bick suggests that daily subcutaneous dalteparin for 6 months should become the drug of choice for the treatment of recurrent thromboembolism in patients with cancer, suggesting that the drug may be safer than warfarin and more convenient since it is unnecessary to monitor frequent blood tests while patients are on the drug.

Glucosamine May Impair Glucose Tolerance

Type 2 diabetes and osteoarthritis often overlap in older, overweight patients. Traditional osteoarthritis remedies, including NSAIDs, acetaminophen, and steroid injections, may raise toxicity issues for type 2 diabetics. Many patients are turning to glucosamine, which has shown to be effective in some studies and is available over-the-counter. Doctors and patients however, have concerns that glucosamine may impair glucose tolerance in type 2 diabetics. Three physicians from Lackland Air Force Base in Texas have published a small study to review this issue. Thirty-eight type 2 diabetics were randomized, 26 to treatment with a combination of glucosamine 1500 mg plus chondroitin sulfate 1200 mg per day, and 12 to placebo. Mean hemoglobin A1c levels increased from an average of 6.43% to 6.50% in the glucosamine group, and decreased from 6.25% to 6.09% in the placebo group, a nonsignificant difference (P = .20). One patient withdrew from the glucosamine group due to excessive flatus; otherwise there were no adverse effects. The authors conclude that glucosamine does not affect glycemic control in type 2 diabetics (Arch Intern Med. 2003;163:1587-1590).

Two More Statin Studies

Statin therapy has a vast array of effects. Two new studies shed some light but also raise questions as to the benefits of these amazing drugs. In the first study, simvastatin was tested in patients with nonischemic, idiopathic cardiomyopathy. Previous studies have shown that statins benefit CHF patients with CAD. In the current study, 63 patients with symptomatic, nonischemic dilated cardiomyopathy were randomized to receive simvastatin 5-10 mg per day or placebo. After 14 weeks, patients treated with simvastatin had a lower New York Heart Association functional class compared with placebo, as well as improved left ventricular ejection fraction and improved neurohormonal measures. Patients also showed a modest reduction in serum cholesterol. The authors suggest that statin therapy may benefit patients with heart failure beyond the drug's cholesterol-lowering affect (Circulation. 2003 rapid access: The second study questions whether statins protect postmenopausal women from fractures, as has been suggested by previous studies. Data analysis from the Women's Health Initiative reviewed the records of nearly 8000 statin users among the 93,716 women enrolled in the study. Statin therapy did not appear to reduce fractures of any site, and in fact was linked to slightly increased risk of fracture (HR 1.22 for hip fracture, 1.04 for lower arm or wrist fracture, and 1.11 for other fracture). No difference in bone density was found between statin users and nonstatin users. The authors conclude that statin use did not reduce bone fracture risk or improved bone density in the WHI (Ann Intern Med. 2003;139:97-104).

Acarbose Reduces Risk of CVD

The alpha glucosidase inhibitor acarbose reduces the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance (IGT), according to the STOP-NIDDM trial. This multinational study initially showed the value of acarbose in preventing type 2 diabetes in patients with IGT (Lancet. 2002;359:2072-2077). Another objective of the study was to evaluate whether decreasing postprandial hyperglycemia would diminish the risk of CVD and hypertension. A total of 1368 men and women, average age 54.5 years with a mean body mass index of 31 were randomized to placebo or acarbose 100 mg 3 times a day with the last bite of a meal. The main outcome measures were the development of major cardiovascular events and hypertension. The drug was effective in decreasing postprandial hyperglycemia; however 211 of the 714 patients in the active treatment wing discontinued their participation prematurely, primarily due to GI intolerance (130 of 715 patients in the placebo wing also discontinued prematurely). Altogether, 47 patients had at least 1 cardiovascular event, 32 in the placebo treatment group and 15 in the acarbose group (relative risk reduction, 49%; absolute risk reduction, 2.5%; HR, 0.51; 95% CI, 0.28-0.95; P = .03). The major reduction was in the risk of myocardial infarction. Acarbose also reduced the risk of developing hypertension, 115 patients in the placebo group develop hypertension vs 78 in the acarbose group (relative risk reduction 34%, absolute risk reduction 5.3%, HR, 0.66; 95% CI, 0.49-0.89; P = .006). The authors conclude that postprandial hyperglycemia is the risk factor for CVD and hypertension and that treatment of patients with IGT with acarbose is associated with a reduction in cardiovascular risk (JAMA. 2003; 290:486-494).

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. Telephone: (404) 262-5517. E-mail: In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.