ESC: Upping Plavix dose meets with less stent thrombosis, more bleeds
The use of a seven-day, double-dose of clopidogrel reduced cardiovascular events and stent thrombosis in patients with acute coronary syndromes undergoing PCI, but resulted in higher bleeding rates, according to a substudy of the CURRENT-OASIS 7 trial presented at the European Society of Cardiology (ESC) congress in Stockholm and simultaneously published in the Lancet.

“Findings from several studies suggest that doubling of the clopidogrel loading dose (from 300 mg to 600 mg) and maintenance dose (from 75 mg to 150 mg daily) results in a faster onset of action and greater inhibition of platelet aggregation than lower doses can achieve,” the authors wrote. “This more intense dose regimen could further protect against ischemic events and stent thrombosis in patients with acute coronary syndromes.”

Shamir R. Mehta, MD, of McMaster University and Population Health Research Institute in Hamilton, Ontario, and colleagues evaluated the effect of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and aspirin regimens to prevent CV events and stent thrombosis in 25,086 patients at 597 sites between June 2006 and July 2009 during the CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trial.

Patients were randomized to receive either a double-dose of clopidogrel (600 mg on day one, 150 mg on day two through seven then 75 mg) or a standard dose of clopidogrel (300 mg on day one then 75 mg daily), and a high 300 mg to 325 mg daily dose of aspirin or a low 75 mg to 100 mg daily dose of aspirin.

Of the 25,086 patients, 12,520 patients receive the double-dose of clopidogrel—6,253 received high-dose aspirin and 6,267 low-dose aspirin—and12,566 patients received a standard-dose of clopidogrel—6,254 received high-dose aspirin and 6,312 received low-dose aspirin.

The researchers used CV death, MI and stroke as the trial’s primary endpoint.

Results showed that 3.9 percent of patients who received a double-dose of clopidogrel experienced primary endpoints of CV death, MI or stroke compared to 4.5 percent in patients who received a standard dose of clopidogrel. For aspirin, rates of primary endpoints did not statistically differ amongst the two groups. These rates were 4.1 percent of patients administered a high-dose of aspirin compared to 4.2 percent in those administered the lower dose.

Of the patients administered high-dose aspirin and who experienced a primary outcome, 149 were administered a double-dose of clopidogrel compared to 207 administered a low-dose of clopidogrel. For patients who received low-dose aspirin, 181 who experienced a primary event received a double-dose regimen of clopidogrel compared to 185 who received the standard-dose.

Mehta and colleagues reported that a higher incidence of major bleeding events occurred in the patients administered a double-dose of clopidogrel compared to those on the standard regimen, 1.6 percent versus 1.1 percent, respectively.

As early as day two, rates of definite stent thrombosis were 0.2 percent in patients in the double-dose clopidogrel arm compared to 0.4 percent in patients in the standard-dose arm. These rates for days three through 10 were 0.4 percent and 0.6 percent, respectively.

The authors wrote that these numbers suggests “that both the high-loading dose and high maintenance dose contributed to the decreased rates of stent thrombosis.”

For the aspirin comparison, rates of definite stent thrombosis were 0.9 percent and 1 percent for those who received high-dose and low-dose aspirin, respectively. These rates for definite or probable stent thrombosis were 1.9 percent versus 2 percent, respectively.

While rates of major and severe bleeding did not differ significantly between the high-dose and low-dose aspirin patients, rates of minor bleeding occurred more frequently in patients who received the high-dose aspirin regimen.

Of patients who did not undergo PCI, rates of primary outcomes and defined major bleeding events did not statistically differ between those who received a double-dose of clopidogrel and those who received a standard regimen—4.9 percent versus 4.3 percent, and 4.4 percent versus 4.1 percent, respectively.

“An important pragmatic question is how the data from CURRENT-OASIS 7 might be incorporated into clinical practice, since whether a patient will ultimately receive a PCI cannot be known at presentation. In individuals who did not receive PCI, no apparent increase was recorded in the risk of bleeding with the high-dose regimen, and most major bleeding events occurred after PCI rather than before PCI,” the authors wrote.

“Therefore, a 600 mg loading dose could be considered for all patients with acute coronary syndromes with planned early invasive treatment.”

The researchers noted that potential limitations may stem from the fact that while clopidogrel dose randomization was double-blind, aspirin dose comparison was open-label.

“A double-dose regimen of clopiodgrel can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended PCI,” the authors concluded.

In an accompanying editorial, Gregg W. Stone, MD, of Columbia University Medical Center and New York Presbyterian Hospital in New York City, wrote, "CURRENT-OASIS 7 has unearthed the spectre of a possible clopidogrel-aspirin interaction.

"Despite impressive reduction in MI and stent thombosis with double-dose clopidogrel in patients who had PCI, the 30-day rates of CV death were identical in the standard-dose and double-dose groups. Presumably, any benefits from reduced ischemic complications in reducing mortality were offset by increased rates of major bleeding with double-dose clopidogrel," Stone wrote.

"Further study is needed to establish whether clinical decision making can be improved with point-of-care platelet-function testing, by assesssing the genetic potential for drug metabolism, or both."