Introduction: Individual randomized controlled trials (RCTs) have shown beneficial effects of low dose rivaroxaban and PCSK9 inhibition (PCSK9i) in addition to background aspirin and statin in patients with peripheral artery disease (PAD). However, the combined effect of these pharmacotherapies is not known. In this analysis of RCT data, we sought to estimate the combined effect of contemporary risk reduction therapies in patients with PAD. Methods: We used data from the COMPASS (n=4,129) and FOURIER (n=3,642) trials to estimate the combined effect of contemporary (aspirin, statin, low dose rivaroxaban and PCSK9i) versus standard therapy (aspirin and statin) in symptomatic PAD patients. The primary outcome was a composite of major adverse cardiovascular (MACE) or limb (MALE) events. Using the hazard rates for low dose rivaroxaban versus control and PCSK9i versus control from the two trials, we estimated the hazard rate for combined therapy by assuming that the treatment effects are approximately additive on the log hazard rate (no interaction between the two treatments). We then used an exponential model to simulate event-free survival and cumulative incidence functions, and hazard ratios (HRs) for the combined versus the standard therapy group. Results: Compared with standard therapy, combined contemporary pharmacotherapy estimated a 50% reduction in MACE or MALE (HR, 0.50; 95% confidence interval [CI], 0.36-0.70; P<0.001). The 3-year cumulative incidence probability of MACE or MALE was 9.1% in the combined group and 15.4% in the standard therapy group ( Figure ). The hazards for MACE (HR, 0.52; 95% CI, 0.36-0.75; P=0.001) and MALE (HR, 0.35; 95% CI, 0.18-0.68; P=0.002) also favored combined contemporary therapy. Conclusions: Thoughtful incorporation of contemporary pharmacotherapies that include low dose rivaroxaban and PCSK9i in addition to aspirin and statin has the potential to substantially reduce cardiovascular and limb events in patients with PAD.