Aspirin and Clopidogrel Dose in ACS
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study. This article originally appeared in the October 2010 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, and peer reviewed by Ethan Weiss, MD. Dr. Crawford is Professor of Medicine, Chief of Cardiology, University of California, San Francisco, and Dr. Weiss is Assistant Professor of Medicine, Division of Cardiology and CVRI, University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer, and Dr. Weiss reports no financial relationships relevant to this field of study
Source: The CURRENT – OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010;363:930-942.
For patients presenting with acute coronary syndromes (ACS), the optimal doses of aspirin and clopidogrel remain unknown. There are significant geographical variations in the dose of anti-platelet agents in this clinical setting. Whether higher doses of aspirin or clopidogrel, or both, lead to better outcomes after ACS treated with an early invasive strategy has not been formally tested. Thus, the CURRENT OASIS 7 investigators performed a prospective, randomized clinical trial to address this question.
Patients presenting with ACS, either non-ST elevation ACS (NSTEACS) or ST elevation myocardial infarction (STEMI), were randomly assigned in a 2 X 2 factorial design to high- or standard-dose clopidogrel and to high- or low-dose aspirin. Inclusion criteria included ischemic ECG changes and/or biomarkers of myocardial injury. High-dose clopidogrel was 600 mg loading dose followed by 150 mg daily for one week then 75 mg daily; standard-dose clopidogrel was a 300 mg loading dose followed by 75 mg daily. High-dose aspirin was 300-325 mg daily; low-dose aspirin was a loading dose of 300-325 mg daily and then 75-100 mg daily. The primary endpoint was a composite of cardiovascular death, myocardial infarction (MI), or stroke at 30 days.
Results: They enrolled 24,835 patients who underwent coronary angiography within 72 hours of presentation. Of these, 17,263 received PCI, 1,859 underwent coronary artery bypass graft (CABG) surgery, 3,520 had no significant coronary artery stenoses, and 2,444 were not candidates for any revascularization. The groups were well matched for all baseline clinical parameters, with a mean age of 61 years, 23% had diabetes, 71% presented with NSTEACS, and 29% presented with STEMI. There was a higher rate of proton-pump inhibitor (PPI) use in the high-dose aspirin group after cardiac catheterization.
There was no difference between high- and standard-dose clopidogrel (4.2% vs. 4.4%; p = 0.30), nor between high- and low-dose aspirin (4.2% vs. 4.4%; p = 0.61), in the primary endpoint of cardiovascular death, MI, or stroke.
Secondary endpoint analysis revealed similar outcomes for high- and standard-dose clopidogrel in total mortality, as well as each component of the primary endpoint. However, higher-dose clopidogrel resulted in higher rates of major bleeding (2.5% vs. 2.0%; p = 0.01), blood transfusion (2.2% vs. 1.7%; p = 0.01), and minor bleeding (5.1% vs. 4.3%; p = 0.01). High- and low-dose aspirin showed similar outcomes in all components of the primary endpoint, as well as total mortality. However, high-dose aspirin resulted in less recurrent ischemia (0.3% vs. 0.5%; p = 0.02), although the absolute reduction is modest. There was no difference in major bleeding between aspirin doses, but there was a slight increase in minor bleeding (5.0% vs. 4.4%; p = 0.04) and major gastrointestinal bleeding with high-dose aspirin (0.4% vs. 0.2%; p = 0.04). There was no excess in CABG-related bleeding in any group.
Interestingly, there was an unexpected interaction between the aspirin and clopidogrel dose groups. Among patients receiving high-dose aspirin, those assigned to high-dose clopidogrel had a lower primary outcome rate than those in the standard-dose group (3.8% vs. 4.6%; p = 0.03). However, in patients receiving low-dose aspirin, this difference was not seen. The cause of this interaction is not clear and is somewhat counter-intuitive.
Subgroup analysis showed no differences between groups based on age, gender, race, diabetes, weight, presentation with STEMI or NSTEACS, use of glycoprotein IIb/IIIa inhibitors, or use of PPI. In patients who underwent PCI, double-dose clopidogrel was associated with a reduction in stent thrombosis (1.6% vs. 2.3%; p < 0.001). The authors conclude that in patients with ACS referred for early invasive strategy, there was no difference between high- and standard-dose clopidogrel, nor between high- and low-dose aspirin, in the primary outcome of cardiovascular death, MI, or stroke.
The authors are to be congratulated on this very large trial enrolling high-risk patients (elevated cardiac biomarkers or ECG changes), the population who would be most likely to benefit from more aggressive anti-platelet therapy. The lack of any difference in mortality, in the composite primary endpoint, or in any of its components is very reassuring that the current standard of care in dual anti-platelet therapy has a wide therapeutic index. This allows physicians some flexibility in individually tailoring anti-platelet therapy doses based on an individual patient's risk of ischemic vs. bleeding outcomes, within this range of doses. Despite the large number of patients and the rigorous follow-up (99.9% of patients completed follow-up), several issues should be addressed. Firstly, the follow-up was only 30 days, so whether there is a long-term impact of the early anti-platelet dosing strategy remains unknown. Secondly, the majority of patients underwent PCI, but 58% received bare-metal stents and only 42% received drug-eluting stents. This reflects the heterogeneous nature of this international study performed in 37 countries. We are not told if there are any differences based on the choice of bare-metal vs. drug-eluting stents. Thirdly, all patients received aspirin and clopidogrel loading doses before cardiac catheterization. The results of the study may not be applicable when used after cardiac catheterization, as the full effects of the medications may not be evident for some time after PCI. Finally, we are not told which anti-thrombins were used (heparin, bivalirudin, low molecular-weight heparin, fondaparinux) and there may be an interaction between anti-platelet agents and the type of anti-thrombins used. These issues will likely be the subject of future manuscripts.