Cardiology show highlights antiplatelet agent, COX-2 risks

April 18, 2005

The always high-interest Late Breaking Clinical Trials at the Annual Scientific Session of the American College of Cardiology, held in Orlando, Fla., were particularly notable this year. First, they included an unprecedented three individual sessions on the antiplatelet agent Plavix (clopidogrel, Sanofi-Aventis). Second, justifying the plunge to lower and lower LDL-cholesterol (LDL-C) targets, they included strong results for a trial of 80 mg of atorvastatin (Lipitor, Pfizer), and, finally, they featured a session with conflicting messages on the risks of COX-2 inhibitors.

The always high-interest Late Breaking Clinical Trials at the Annual Scientific Session of the American College of Cardiology, held in Orlando, Fla., were particularly notable this year. First, they included an unprecedented three individual sessions on the antiplatelet agent Plavix (clopidogrel, Sanofi-Aventis). Second, justifying the plunge to lower and lower LDL-cholesterol (LDL-C) targets, they included strong results for a trial of 80 mg of atorvastatin (Lipitor, Pfizer), and, finally, they featured a session with conflicting messages on the risks of COX-2 inhibitors.

The link between increased LDL-C and coronary heart disease (CHD) risk is no longer disputed, said John LaRosa, M.D., president of SUNY Downstate Medical Center, who was lead investigator for the TNT (Treating to New Targets) trial. The value of treating CHD patients, particularly those with stable, non-acute disease to LDL levels substantially below 100 mg/dl, however, has not been clearly demonstrated. In TNT, 10,001 patients were randomized double-blind to either atorvastatin 10 mg with a target of 100 mg/dl or to atorvastatin 80 mg with a target of 75 mg/dl. Participants had CHD and LDL-C between 130-250 mg/dl and triglycerides ≤ 600 mg/dl.

The statin regimens were highly effective. LDL-C was maintained at a mean of 101 mg/dl in the 10-mg atorvastatin group and 77 mg/dl in the 80-mg group. The proportion of patients experiencing the primary endpoint of a major cardiovascular event was reduced 22% in the atorvastatin 80-mg group as compared with 10 mg. The reduction with 80-mg atorvastatin in fatal or nonfatal stroke was 25%. Treatment-related myalgias, rhabdomyolysis, and liver enzyme elevation were uncommon. Pharmacologist Carl J. Vaughan, University College, Cork, Ireland, said TNT provided important evidence supporting validity of a "lower-is-better strategy" and LDL targets below 80 mg/dl.

Fibrinolytic therapy for STEMI-ST-segment elevation myocardial infarction-is limited by inadequate reperfusion and/or reocclusion in ~25% of patients. The CLARITY TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction) trial asked whether the addition of clopidogrel to standard fibrinolytic regimens with aspirin would improve patency of the infarct-related artery (IRA) and decrease ischemic complications. Mark S. Sabatine, M.D., MPH, Harvard Medical School, noted the 23-country trial included 3,491 STEMI patients presenting < 12 hours from symptom onset. Each received a fibrinolytic, aspirin, and heparin and was randomized to placebo or clopidogrel (loading dose of 300 mg + 75 mg q.d.). Occluded IRA, the primary endpoint, was reported in 15% of clopidogrel patients and in 21.7% of placebo patients, a 36% reduction.

The second clopidogrel trial, a huge 45,852-patient collaboration between Oxford University and Chinese investigators, randomized similar MI patients presenting within 24 hours of symptom onset. COMMIT/CCS-2 (Clopidogrel & Metoprolol in Myocardial Infarction Trial) patients received 162 mg of aspirin daily and 75 mg of clopidogrel daily or placebo, said principal investigator Zhengming Chen, M.D., Oxford University. Background medications were similar to those given in Western countries. The primary outcomes were death and combined re-MI or stroke at discharge.

Analysis of the primary endpoint showed a highly significant relative risk reduction (RRR) for the group receiving aspirin and clopidogrel (9.3% versus 10.1%). Significant RRRs in that group were also found for in-hospital death, reinfarction, and ischemic stroke. Major bleeding was similar between groups.

The session "Safety of Parecoxib and Valdecoxib in the Treatment of Postoperative Pain Following Coronary Artery Bypass Graft [CABG] Surgery or Major General Surgery" offered a divergence in views. Andrew Whelton, M.D., Universal Clinical Research Center, Hunt Valley, Md., reported on two large, similar trials, one in patients undergoing CABG surgery and the other in patients undergoing major noncardiac surgery. Patients received parecoxib IV (Pfizer) and valdecoxib (Bextra, Pfizer, oral, 20 mg q12h x 7 days), placebo and valdecoxib, or placebo alone. Aspirin and p.r.n. supplemental analgesia were also given in each group.