CURRENT-OASIS 7 in PCI: high-dose clopidogrel cuts ischemia, thrombosis
Last Updated: 2010-09-01 18:25:50 -0400 (Reuters Health)
By Karla Gale
NEW YORK (Reuters Health) - Doubling the standard dose of clopidogrel for a week helps avoid ischemia and stent thrombosis after percutaneous coronary intervention (PCI), investigators reported online today in The Lancet.
The findings, from more than 17,000 patients in the CURRENT-OASIS 7 trial, show that "double-dose clopidogrel for 7 days should be considered for patients with acute coronary syndromes who are treated with an early invasive strategy with early PCI," first author Dr. Shamir R. Mehta, from McMaster University, Hamilton, Ontario, Canada, told Reuters Health.
In the total CURRENT-OASIS 7 cohort - more than 25,000 patients referred for early intervention for acute coronary syndromes - doubling the dose of clopidogrel had no effect. But the complete cohort included patients who went on to have bypass graft surgery or no intervention at all. (Reuters Health reported on that study in a separate article today; the study results appeared online this week in the New England Journal of Medicine.)
Today's Lancet article focused on 17,263 subjects from 39 countries who underwent PCI. The authors had randomly assigned 8560 to the double-dose of clopidogrel (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) and 8703 to the standard dose (300 mg on day 1 then 75 mg daily). They also randomly allocated them to high or low doses of aspirin (300-325 or 75-100 mg daily).
In the PCI patients, the doubled clopidogrel dose significantly reduced the composite rate of cardiovascular death, myocardial infarction, or stroke by day 30, from 4.5% to 3.9% (p = 0.039), although it did not significantly affect mortality. It also lowered the rate of definite stent thrombosis from 1.3% to 0.7% (p = 0.0001).
The higher dose did increase the rate of major bleeding (1.6% v s 1.1%, p = 0.009), but not the risk of severe bleeding or nor the odds of fatal or intracranial hemorrhage.
"It may be that the intensity of platelet inhibition is not overly high to induce these serious bleeds (but enough to reduce thrombotic events)," Dr. Mehta suggested, "or that treatment duration with the high dose regimen was relatively short at 7 days."
Aspirin dosage, on the other hand, had no significant effect on any of the outcomes in the PCI subset, the report states.
"Since double dose clopidogrel results in more bleeding, it should be used carefully in patients at high risk of bleeding," co-author Dr. Christopher B. Granger, from Duke University Medical Center, Durham, North Carolina, told Reuters Health in an email.
In a commentary, Dr. Gregg W. Stone from Columbia University Medical Centre, New York, writes, "Further study is needed to establish whether clinical decision-making can be improved with point-of-care platelet-function testing, by assessing the genetic potential for drug metabolism, or both."
"Today, we do not have evidence that platelet-function testing or genetic testing will improve our ability to treat with clopidogrel, but ongoing trials are testing this important hypothesis. Until those are available, I would not recommend this approach," Dr. Granger said.
Dr. Mehta responded that genotyping "is unlikely to affect treatment decisions in the acute setting as it takes time to get a result." He also noted that his group's recently published research showed no effect of the CYP 2C19 loss of function allele in patients with ACS.
Dr. Laurent Bonello, of Hopital Universitaire Nord in Marseille, France, who did not take part in this research, is more inclined to agree with Dr. Stone.
In an email to Reuters Health, he called the double-dose clopidogrel regimen "a sub-optimal therapeutic strategy," especially in light of the more potent P2Y12ADP receptor that could further increase bleeding with greater amounts of the anticoagulant.
"Caution is warranted because increased platelet reactivity inhibition is clearly associated with increased bleeding," he added. "Studies have suggested that platelet reactivity testing has the potential to detect patients at risk of both thrombotic events and bleeding events."
In conclusion, Dr. Granger said, "The clinician now has multiple choices for antiplatelet regimens to treat ACS: aspirin; whether to add clopidogrel, when, and what loading dose and subsequent dose to use; whether to use prasugrel instead of clopidogrel; whether to use IV GP IIb/IIIa and when. Soon we expect to have ticagrelor."
He added, "The challenge is how to integrate the information from trials, including CURRENT, to make best decisions for individual patients. Given the risk of confusion, many of us believe that this should include algorithms for health care teams to provide a more systematic approach."
Until then, Dr. Mehta says, "(A) double-dose regimen of clopidogrel substantially reduced stent thrombosis and given that the duration of therapy with the higher dose regimen was only one week, it is simple, cost effective and can be easily implemented."
SOURCE:http://link.reuters.com/hav78n
Lancet 2010.
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