Effect of Addition of Clopidogrel to Aspirin on Mortality

Abstract

Background and Purpose In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, addition of clopidogrel to aspirin was associated with an unexpected increase in mortality in patients with lacunar strokes. We assessed the effect of the addition of clopidogrel to aspirin on mortality in a meta-analysis of published randomized trials. Methods Randomized trials in which clopidogrel was added to aspirin in subjects with vascular disease or vascular risk factors were identified. Trials were restricted to those with a mean follow-up of ≥14 days in which both the combination of aspirin and clopidogrel was tested and mortality was reported. Results Twelve trials included 90 934 participants (mean age, 63 years; 70% men; median follow-up, 1 year) with 6849 observed deaths. There was no significant increase in mortality with the combination therapy either in 4 short-term (14 days–3 months; OR, 0.93; 95% CI, 0.87– 0.99) or in 7 long-term (>3 months; hazard ratio, 0.97; 95% CI, 0.91–1.04) trials after 1 long-term trial (the SPS3 trial) was excluded because of heterogeneity. Addition of clopidogrel was associated with an increase in fatal hemorrhage (OR, 1.35; 95% CI, 0.97–1.90) and a reduction in myocardial infarction (OR, 0.82; 95% CI, 0.74–0.91). Conclusions The addition of clopidogrel to aspirin has no overall effect on mortality. The SPS3 trial results are outliers, possibly because of a lower prevalence of coronary artery ischemia. Addition of clopidogrel to aspirin increases fatal bleeding and reduces myocardial infarction.

Among antithrombotic agents, prasugrel, but not ticagrelor, is associated with reduced 30day mortality in patients with ST-elevated myocardial infarction

“…Numerous large-scale, RCT's suggest that the administration of antithrombotics in addition to aspirin reduces the risk of recurrent thrombotic events including death in patients after ACS or undergoing PCI (3)(4)(5)(6)(7)(8). Therefore, longterm dual antiplatelet therapy on top of intraprocedural novel anticoagulant regimens is mandatory for a certain period of time in these patients.…”

“…Notably, the positive results of numerous randomized clinical trials (RCTs) regarding the composite efficacy endpoint is largely and disproportionately driven by reduction of myocardial infarctions, while the impact of novel antithrombotics on mortality is far less prominent (if any), and, therefore, less established. Results of prior metaanalyses are also somewhat controversial [5,6], which in part may be due to the largely heterogeneous cohorts pooled for these analyses. Special attention has been attributed to ticagrelor, since PLATO was the only RCT claiming huge mortality benefit over clopidogrel [4], up until recent publication of the ATLANTIC trial [7].…”

Platelets, photosensitizers, and PDT

“…The significance of platelet-derived factors in the pathogenesis of vascular diseases is underscored by huge pharmacological relevance of platelet inhibitors such as aspirin, ADP-receptor antagonists or thrombin inhibitors [49,50,51]. Interestingly, aspirin, the most common platelet inhibitor has been found to confer population benefits for cancer prevention [52].…”

ASA failure

“…This is similar to what was reported in the SPS3 main analysis. Although a recent systematic review 19 focusing on the combination of clopidogrel and ASA in diverse vascular conditions did not find an increased risk of global mortality associated with this combination, it did report a trend toward an increase in fatal hemorrhages associated with these 2 antiplatelets. The increased overall mortality associated with the ASA/clopidogrel combination reported in our study cannot be accounted for by an increase in fatal hemorrhages, as discussed previously, 13 leaving the exact reason for this finding uncertain and possibly related either to the specific characteristics of our study population or to chance.…”