Randomized, Double-Blind, Placebo-Controlled, International Trial of the Oral IIb/IIIa Antagonist Lotrafiban in Coronary and Cerebrovascular Disease

Abstract

Background-This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients. Methods and Results-Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, Pϭ0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, Pϭ0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; PϽ0.001). Serious bleeding was more common among patients who received higher doses of aspirin (Ͼ162 mg/d), with or without lotrafiban. Conclusions-Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses Ͼ162 mg/d is noteworthy. (Circulation. 2003;108:399-406.)

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

“…12 Also, the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial found that serious bleeding was more common among patients with vascular disease who received ASA doses of >162 mg/day. 13 Substitution of another antiplatelet agent has been proposed as a possible strategy to avoid ASA hyporesponse. Given its different mechanism of action of inhibiting platelet activation, clopidogrel would be the logical choice for substitution.…”

Modified-Release Dipyridamole Combined with Aspirin for Secondary Stroke Prevention

“…This has been shown in the MATCH trial for the combination of clopidogrel plus aspirin versus clopidogrel monotherapy [11]. Glycoprotein IIb/IIIa antagonists are more potent antiplatelet drugs than aspirin, but have also failed in the secondary prevention of stroke due to the increased rate of bleeding complications [28]. The future of stroke prevention, therefore, lies is in the optimal treatment of vascular risk factors and in drugs that offer protection to the endothelium.…”

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“…It is important to know that both the subjective gastrointestinal side effects (such as nausea, dyspepsia etc.) as well as bleeding complications are dose dependent (Yusuf et al 2001, Topol et al 2003. In ASA-doses of > 150 mg / day the risk of bleeding complications increases significantly (Topol et al 2003).…”

“…as well as bleeding complications are dose dependent (Yusuf et al 2001, Topol et al 2003. In ASA-doses of > 150 mg / day the risk of bleeding complications increases significantly (Topol et al 2003). In patients that develop side effects during ASA therapy, clopidogrel can be used (see below).…”

“…However, one has to assume that in these studies the bleeding complications will outweigh the therapeutical benefit, too. All studies that investigated oral glycoprotein-IIb / IIIa-inhibitors in secondary stroke prevention had to be stopped due to an increased bleeding rate (BRAVO) (Topol et al 2003). Therefore, GPIIb / IIIa-antagonists should not be used in secondary stroke prevention.…”