Major Adverse Limb Events in Lower Extremity Peripheral Artery Disease: COMPASS Trial

Squibb/Pfizer, Daiichi Sankyo, during the conduct of the study; grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, Astra Zeneca, Eli Lilly, Glaxo Smith Kline, and Sanofi Aventis, outside the submitted work. Aboyans has received honoraria from Bayer, BMS, Pfizer, and Novartis, Pfizer/BMS alliance, MSD, outside the submitted work. Branch reports grants from Bayer, Astellas, and Janseen during the conducted of the study outside of the submitted work. Bhatt discloses the following relationships ABSTRACT Background: Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). There is limited information on the prognosis of patients who suffer MALE. Objectives: Among participants with lower extremity PAD, we investigated: 1) if hospitalizations, MACE, amputations, and deaths are higher after first episode of MALE compared with PAD patients who do not experience MALE and 2) the impact of treatment with low dose rivaroxaban and aspirin compared to aspirin alone on the incidence of MALE, peripheral vascular interventions, and all peripheral vascular outcomes over a median follow-up of 21 months. Methods: We analyzed outcomes in 6,391 patients with lower extremity PAD who were enrolled in the COMPASS trial - a randomized double blind placebo controlled trial of low dose rivaroxaban and aspirin combination, rivaroxaban alone, as compared to aspirin alone. MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation. Results: A total of 128 patients suffered an incident MALE. After MALE, the one year cumulative risk of a subsequent hospitalization was 95.4%, for vascular amputations it was 22.9%, for death it was 8.7%, and for MACE it was 3.8%. The MALE index event significantly increased the risk to experience subsequent hospitalizations (HR 7.21; P<0.0001), subsequent amputations (HR 197.5; P<0.0001) and death (HR 3.23; P<0.001). Compared with aspirin alone, the combination of rivaroxaban 2.5 mg twice daily and aspirin lowered the incidence of MALE by 43% (P=0.01), total vascular amputations by 58% (P=0.01), peripheral vascular interventions by 24% (P=0.03), and all peripheral vascular outcomes by 24% (P=0.02). Summary: PAD, MALE is associated with a poor prognosis, making its prevention of utmost importance. The combination of rivaroxaban 2.5 mg bid and aspirin significantly lowers the incidence of MALE and its related complications and should be considered as an important therapy for patients with PAD. Condensed Abstract: Peripheral artery disease patients are at risk of suffering Major Adverse Limb Events (MALE) which are associated with a high risk of subsequent amputation and death. Prevention of MALE in PAD patients should be a high priority. Compared to aspirin alone, rivaroxaban 2.5 mg twice daily and aspirin used in combination is effective at reducing the incidence of MALE. at an alpha level of 0.10, the impact of the MALE index event was modelled separately by treatment group. The comparison of treatment effect of rivaroxaban and aspirin combination, rivaroxaban alone, versus aspirin on the outcomes of MALE, peripheral vascular interventions and all peripheral vascular outcomes were calculated using separate log-rank tests. Kaplan-Meier estimates of the cumulative risk were used to evaluate the timing of event occurrences in each of the treatment groups. Hazard ratios and corresponding 95% CIs were obtained from stratified Cox proportional-hazards models. No adjustments for multiple testing were made. revascularization, amputation, severe symptomatic limb ischemia at baseline, or treatment with single antiplatelet therapy. Consistent with the overall COMPASS trial result, we show that use of rivaroxaban 2.5 mg bid and aspirin is superior to aspirin alone in reducing MALE, peripheral vascular interventions, and all peripheral vascular outcomes among individuals with lower extremity PAD. Our work supports prior studies showing the poor prognosis after a MALE. Data from the TRA2P-TIMI 50 - vorapaxar trial showed that after acute limb ischemia, the risk of amputation was 27% and mortality was 14% after a median follow-up of 2 years. (5) A recent retrospective cohort study from 1,085 American acute care hospitals which included 31,538 PAD patients with chronic limb ischemia who underwent peripheral artery revascularization, reported that 21.3% of patients had unplanned hospital readmission within 30 days of being discharged, and among those readmitted, 25% had repeat revascularization or amputation, and 5.2% had died. (8) Common reasons for readmission included procedure-related complications, complications from diabetes, sepsis, and on-going limb ischemia. Furthermore readmission to hospital was costly and priced at $12,394 US dollars (8). progressive PAD