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 on the first day followed by 75 mg daily thereafter) and either high-dose aspirin (300 to 325 mg daily) or low-dose aspirin (75 to 100 mg daily).
In the main result of the trial, published in the New England Journal of Medicine, there were no significant differences in the composite outcome of CV death, MI, or stroke at 30 days in either randomization, but more major bleeding occurred in the double-dose clopidogrel group compared to the standard-dose clopidogrel group (2.5% versus 2%, 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 17000 patients who actually underwent the planned PCI. In contrast to the main study, the primary endpoint was reduced in the substudy by 14% from from 4.5% in the standard dose clopidogrel group to 3.9% in the double dose clopidogrel group (p=0.039). (In the NEJM paper the authors state that this difference may have been due to the play of chance.) Definite stent thrombosis was also reduced by 46% from 111 events to 58 events (p=0.0001). However, major bleeding occurred more often in the double-dose clopidogrel group (1.6% versus 1.1%). There were no significant differences in outcome or in bleeding events based on aspirin assignment.
In their publication in the Lancet, the authors concluded 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 ischemic complications in reducing mortality were offset by increased rates of major bleeding with double-dose clopidogrel. A reduction in major ischemic 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 ischemia versus bleeding.”
In a NEJM editorial, Valentin Fuster makes several recommendations and observations:
Noting the lower rates of minor bleeding with low dose aspirin, Fuster 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.”
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Sanjay Kaul provided the following comment to CardioBrief:
I did not find the authors’ original overly sanguine interpretation of the PCI subgroup data at the 2009 ESC hotline session convincing! Nonetheless, the Scientific Program Committees should take note of Dr. Fuster’s caveat regarding the need for simultaneous publication of high-impact clinical trials during presentation at international meetings.
The authors appropriately recommend a conservative interpretation of the clinical significance of an unexpected but nominally significant statistical interaction between clopidogrel and aspirin dose comparisons. I wish they had followed the same advice in interpreting the heterogeneity of double versus standard clopidogrel dose treatment effect amongst PCI and no-PCI subgroup. Given all the caveats of this subgroup analysis—post-randomization subgroup, unreliable qualitative interaction (difference in direction), and lack of adjustment for multiple comparisons—the most reliable estimate of treatment effect in a subgroup is the treatment effect in the overall cohort (a null effect). Although 600 mg clopidogrel loading dose during PCI has been widely embraced in clinical practice (driven primarily by observational data and meta-analysis), the only large randomized controlled evaluation failed to provide evidence in support of such practice. Perhaps, a case of enthusiasm exceeding the evidence!
Here is the Lancet press release: are
DOUBLE-DOSE CLOPIDOGREL REDUCES RISK OF DEATH, HEART ATTACK OR STROKE IN PATIENTS UNDERGOING ANGIOPLASTY (OASIS-7 trial)
An Article published Online First and in an upcoming Lancet (to coincide with the ongoing ESC meeting in Stockholm) shows that using a double-dose of the anticlotting treatment clopidogrel reduces the risk of cardiovascular death, heart attack, or stroke by 14% in patients undergoing angioplasty compared with normal dose. Although risk of major bleeding increased 40% with double-dosing, the risk of bleeding that was intracranial, fatal, or related to coronary artery bypass graft surgery did not increase. Thus the authors, led by Dr. Shamir Mehta, Hamilton General Hospital and McMaster University, Hamilton, ON, Canada, conclude that double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy (also termed percutaneous coronary intervention or PCI).
Patients undergoing PCI are given standard anticlotting treatment consisting of aspirin and clopidogrel. In this study the authors assessed the effect of various clopidogrel and aspirin regimens in prevention of major cardiovascular events and stent thrombosis (narrowing of the inserted stent) in patients undergoing PCI.
8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel, and 8624 to high-dose and 8639 to low-dose aspirin. Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome of cardiovascular death, heart attack or stroke (3·9% vs 4·5%; 14% reduced risk); and definite stent thrombosis (0·7% vs 1·3%; 46% reduced risk). High-dose and low-dose aspirin did not differ for the primary outcome (4·1% vs 4·2%). Major bleeding was more common with double-dose than with standard-dose clopidogrel (1·6% vs 1·1%; 41% increased risk) but did not differ significantly
between high-dose and low-dose aspirin (1·5% vs 1·3%).
The authors conclude: “In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose regimen of clopidogrel was more effective than was the standard dose regimen in reduction of ischaemic events and stent thrombosis. Daily high-dose aspirin did not significantly differ from low-dose aspirin. 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.”
In a linked Comment Dr Gregg Stone, Columbia University Medical Center and New York Presbyterian Hospital, NY, USA, points out that 30-day mortality was the same for both clopidogrel doses, and says: “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.”
He adds: “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.”
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