CardioExchange Archive

In the CURRENT-OASIS 7 trial, more than 25,000 patients with ACS for whom an interventional strategy was planned were randomized to either double-dose clopdiogrel (a 600-mg loading dose on the first day followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose, followed by 75 mg daily thereafter), plus either high-dose aspirin (300-325 mg daily) or low-dose aspirin (75-100 mg daily).

In the main result of the trial, published in the New England Journal of Medicine, there was no significant difference between clopidogrel doses in the composite outcome of CV death, MI, or stroke at 30 days, but more major bleeding occurred with the double dose than with the standard dose (2.5% vs. 2.0%, P=0.01).

In a second paper, published simultaneously in the Lancet, the CURRENT-OASIS 7 investigators report on a large, prespecified substudy of  more than 17,000 patients who actually underwent the planned PCI. In contrast to the main study, the substudy found a 14% reduction in the primary endpoint — from 4.5% with standard-dose clopidogrel to 3.9% with double-dose treatment (P=0.039). (In the NEJM paper, the authors state that this difference may have been due to chance.) In addition, definite stent thrombosis was reduced by 46%, from 111 events to 58 events (P=0.0001). However, major bleeding occurred more often in the double-dose group (1.6% vs. 1.1%). There were no significant differences in outcomes or in bleeding events based on aspirin assignment.

In their publication in the Lancet, the authors conclude that “a double-dose regimen of clopidogrel can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended PCI.” However, in an accompanying comment, Gregg Stone notes that there was no difference in mortality at 30 days and writes: “Presumably, any benefits from reduced ischaemic complications in reducing mortality were offset by increased rates of major bleeding with double-dose clopidogrel. A reduction in major ischaemic complications must be achieved without increasing overall bleeding, or vice versa, to further reduce mortality with antiplatelet and antithrombotic agents. The likelihood of achieving such a balance might be increased by considering individual patient’s risks for ischaemia versus bleeding.”

In an NEJM editorial, Valentin Fuster makes several recommendations and observations. Noting the lower rates of minor bleeding with low-dose aspirin, he writes that “it is time for the proponents of higher-dose aspirin to concede defeat and modify clinical practice.” Fuster also recommends a 600-mg loading dose of clopidogrel, but writes that “there appears to be no role for the routine double dosing of clopidogrel in the subsequent 6 days, particularly in light of the higher rates of major bleeding.”

Fuster also expresses concern stemming “from apparent discrepancies between the reporting of the trial at the annual meeting of the European Society of Cardiology in 2009 and the publication of the trial findings 1 year later in the Journal. During the hotline presentation at the meeting, it was concluded that the use of double-dose clopidogrel significantly reduced major cardiovascular events in patients undergoing percutaneous coronary intervention. It is clear that this conclusion differs from that of the current article, which reports that the trial failed to demonstrate superiority of double-dose clopidogrel over standard dosing for the reduction of cardiovascular events in the interventional subgroup. The conclusions reported at the meeting led many cardiologists to adopt the double-dose clopidogrel strategy, thus leading to more clopidogrel being prescribed. This outcome underscores the need for simultaneous publication of high-impact clinical trials when they are presented at international meetings.”