In patients with active cancer and venous thromboembolism, whether extended treatment with a reduced dose of an oral anticoagulant is effective in preventing recurrent thromboembolic events and decreasing bleeding is unclear. We conducted a randomized, double-blind, noninferiority trial with blinded central outcome adjudication. Consecutive patients with active cancer and proximal deep-vein thrombosis or pulmonary embolism who had completed at least 6 months of anticoagulant therapy were randomly assigned in a 1:1 ratio to receive oral apixaban at a reduced (2.5 mg) or full (5.0 mg) dose twice daily for 12 months. The primary outcome was centrally adjudicated fatal or nonfatal recurrent venous thromboembolism, assessed in a noninferiority analysis (margin of 2.00 for the upper boundary of the 95% confidence interval of the subhazard ratio). The key secondary outcome was clinically relevant bleeding, assessed in a superiority analysis. A total of 1766 patients underwent randomization at a median time since the index event of 8.0 months (interquartile range, 6.5 to 12.6); 866 patients were assigned to the reduced-dose group, and 900 to the full-dose group. The median treatment duration was 11.8 months (interquartile range, 8.3 to 12.1). Recurrent venous thromboembolism occurred in 18 patients (cumulative incidence, 2.1%) in the reduced-dose group and in 24 (cumulative incidence, 2.8%) in the full-dose group (adjusted subhazard ratio, 0.76; 95% confidence interval [CI], 0.41 to 1.41; P = 0.001 for noninferiority). Clinically relevant bleeding occurred in 102 patients (cumulative incidence, 12.1%) in the reduced-dose group and in 136 (cumulative incidence, 15.6%) in the full-dose group (adjusted subhazard ratio, 0.75; 95% CI, 0.58 to 0.97; P = 0.03). Mortality was 17.7% in the reduced-dose group and 19.6% in the full-dose group (adjusted hazard ratio, 0.96; 95% CI, 0.86 to 1.06). Extended anticoagulation with reduced-dose apixaban was noninferior to full-dose apixaban for the prevention of recurrent venous thromboembolism in patients with active cancer. The reduced dose led to a lower incidence of clinically relevant bleeding complications than the full dose. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; API-CAT ClinicalTrials.gov number, NCT03692065.).

Summary: The existence of poor biological response to clopidogrel has been shown in some patients. Despite the increasing number of studies, this phenomenon remains difficult to quantify. We performed a systematic review to estimate the prevalence of poor biological response to clopidogrel and investigate the factors known to modulate this. An exhaustive search was performed. Altogether 171 publications were identified, providing data for a total of 45,664 subjects. The estimated prevalence of poor biological response to clopidogrel ranged from 15.9% to 49.5% according to the platelet function assay employed. The assays most frequently used were light transmittance aggregometry (LTA), the vasodilator-stimulated phosphoprotein (VASP) assay and the Verify -now® assay. For all these assays, higher cut-off values were associated with a lower prevalence of poor biological response to clopidogrel. However, when choosing a fixed cut-off point for each assay, the prevalence of poor biological response to clopidogrel was highly variable suggesting that other factors could modulate poor biological response to clopidogrel. Finally, none of the studied factors could apparently explain the variability of poor biological response to clopidogrel. This meta-analysis shows that the prevalence of poor biological response depends on the assay employed, the cut-off value and on various unidentified additional factors.