In Reply

Gordon comments on the importance of platelets in the propagation of venous thrombosis and suggests that this may explain our findings,¹  that aspirin is more effective in preventing large versus small thrombi. He also expresses concern about the widespread use of anticoagulant prophylaxis because of the risk of bleeding, infection, and other serious complications, such as heparin-induced thrombocytopenia. We agree that critical reevaluation of benefits and risks of pharmacologic prophylaxis and in particular the use of anticoagulant compared with aspirin prophylaxis is warranted. The Comparative Effectiveness of Pulmonary Embolism Prevention after Hip and Knee Replacement trial currently ongoing in the United States is comparing aspirin plus intermittent pneumatic compression, low-intensity warfarin, and rivaroxaban for prevention of venous thromboembolism in 25,000 patients undergoing elective total hip or total knee replacement (clinicaltrials.gov No. NCT02810704). The results of this trial are expected in 2021.

We believe that the concerns raised by Madi-Jebara and Sleilaty are misplaced. Although the primary outcome for the aspirin versus placebo comparison in PeriOperative ISchemic Evaluation-2 (POISE-2) was death or nonfatal myocardial infarction at 30 days, venous thromboembolism was a prespecified outcome and was systematically collected and reported. Formal testing found no evidence to contradict the assumption of proportionality in the Cox regression models. Exploratory subgroup analyses demonstrated similar results irrespective of whether participants received anticoagulant prophylaxis or whether they received anticoagulant prophylaxis in the first 3 days after surgery. Results were consistent across age and diabetes subgroups, and there is no basis for speculating that these subgroups “would have been potentially significant” if the trial had been larger. It is not the 95% CI that informs a subgroup; rather, it is the interaction P value. As reported in the article,¹  the interaction P values were 0.13 and 0.81 for the age and diabetes subgroups, respectively. These nonsignificant results do not support a subgroup effect.

The low rate of venous thromboembolism in POISE-2 limited power to detect an effect of aspirin, but the point estimate was consistent with the results of earlier trials, and the pooled analysis presented in the article¹  provides readers with what we believe are the best estimates of the efficacy of aspirin for venous thromboembolism prevention in surgical patients. This approach has previously been taken by others²  and is also the approach that we took in the original publication of POISE.³  As presented in our article,¹  the best evidence indicates that aspirin compared with placebo reduces the risk of postoperative venous thromboembolism by approximately one third.