Tifaine Magnusson, BSc(Pharm), Aaron M Tejani, BSc(Pharm), PharmD, ACPR
CURRENT-OASIS 7, a 3-year randomized controlled trial, was designed to determine whether a doubling of the loading and initial maintenance doses of clopidogrel is superior to the standard-dose regimen for patients with acute coronary syndrome who have been referred for percutaneous coronary intervention.1
In this double-blinded trial, adult patients with non-ST-segment elevation acute coronary syndrome or ST-segment elevation myocardial infarction for whom percutaneous coronary intervention was to be performed within 72 h were randomly assigned to receive double the usual loading dose of clopidogrel (600 mg) or the standard loading dose (300 mg). For the 25 086 patients included in the study, the authors assessed the composite end point of cardiovascular death, myocardial infarction, and stroke as the primary outcome and found no significant difference between a 7-day double-dose regimen and the standard-dose regimen.1
Of the study group enrolled, 17 263 patients actually underwent the percutaneous coronary intervention, and the authors performed a subgroup analysis of these patients.2 The report of this subgroup analysis is the focus of our letter. In our view, the abstract and conclusion of the study report2 do not adequately represent the results of the study, instead leading the reader to believe that the results are more profound than they truly are.
Our first issue of concern is the unknown. No data are presented for serious adverse events, which would include any untoward medical occurrence that results in death, is life-threatening, necessitates admission to hospital or prolongs the hospital stay, or results in persistent or significant disability.3 Documentation of serious adverse events should encompass all adverse events that occur during the trial, not only the serious events thought to be related to use of the drug. For example, if there had been fewer serious cardiovascular adverse events in the treatment arm than in the control (standard therapy) arm, but no change in total serious adverse events, then it could be concluded that serious noncardiovascular events were occurring more frequently and should be investigated. Information about all serious adverse events throughout the trial would also help to determine the “net effect” of the intervention. We have requested these data from the authors of the original study, but as of this writing (late 2010) had not received them.
Now, for argument’s sake, let’s say that the serious adverse events are not a factor in assessing the relative benefit of the doubled dose of clopidogrel. There are still some other considerations to be made.
Our second issue of concern is the following statement in the conclusion section of the abstract: “In patients undergoing PCI [percutaneous coronary intervention] for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose”.2 We think that this statement is misleading. The term “cardiovascular events” implies a much broader meaning than the results actually show. In fact, there were no significant reductions in stroke, ischemia, or cardiovascular death, so it would have been more appropriate to refer to a reduction in the incidence of myocardial infarction, as opposed to cardiovascular events.
Our third issue of concern relates to the data for myocardial infarction, which was 1 of 3 outcomes measured in the study. The authors reported a 0.6% reduction in this outcome among patients assigned to receive double-dose clopidogrel, relative to those receiving the standard dose. There are 2 reasons why we question the clinical importance of this result. First, the effect size was small and of debatable clinical importance. Second, it is possible that this finding is a false positive (type 1 error), as no p value adjustment was made for the multiple comparisons performed in the trial.4 The authors also used a postrandomization subgroup of the overall trial population, which leads to additional risk of a type 1 error.5
Our fourth issue of concern is the lack of reporting of harm in the conclusion statements of the abstract and the full article, which might lead a reader to believe that there are no risks associated with the double-dose regimen. In fact, the incidence of major bleeding (as defined by the CURRENT-OASIS 7 authors) was higher in the double-dose group than the standard-dose group (1.6% versus 1.1%, hazard ratio 1.41, 95% confidence interval 1.09–1.83, p = 0.009).2 This represents a 0.5% absolute increase in the hazard of harm (major bleeding). The omission of this information from the concluding statements appears to be selective reporting, which is misleading.
Our final issue of concern relates to the overall assessment of harm versus benefit. Specifically, the 0.6% reduction in risk of myocardial infarction would seem to be nullified by the 0.5% increase in the risk of major bleeding. Although some would argue that the benefit of preventing myocardial infarction outweighs the risk of a major bleeding event, these 2 outcomes are only a subset of the possible effects of the double-dose regimen. Returning to our first issue of concern, described above, a full analysis of serious adverse events could help in determining the net effect of the double-dose regimen and provide more confidence in saying whether the benefit outweighs the risk.
Does this study provide enough information to support a double-dose regimen of clopidogrel? We’re not convinced. Does something need to be done about the selective reporting of harm in conclusion statements? Absolutely.
1. CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Eikelboom JW, Fox KA, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010;363(10):930–942. Erratum in: N Engl J Med 2010;363(16):1585.
2. Mehta SR, Tanguay J, Eikelboom JW, Jolly SS, Joyner CD, Granger CB, et al.; CURRENT-OASIS 7 Trial Investigators. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010;376(9748):1233–1243.
3. Serious adverse event analysis: lipid-lowering therapy revisited. Therapeutics Letter 42. Vancouver (BC): Therapeutics Initiative; 2001. Available from: www.ti.ubc.ca/newsletter/serious-adverse-event-analysis-lipid-lowering-therapy-revisited
4. Feise RJ. Do multiple outcome measures require p-value adjustment? BMC Med Res Methodol 2002;2:8. 
5. Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ 2010;340:c117. doi:10.1135/bmj.c117.
Canadian Journal of Hospital Pharmacy, VOLUME 64, NUMBER 2, 2011