Frequency, Predictors and Impact of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients with Symptomatic Atherosclerosis
Background—Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and whether more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown.
Methods—TRA2P-TIMI 50 (vorapaxar) and PEGASUS-TIMI 54 (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials.
Results—Of 47,611 patients with stable vascular disease followed for three years in both studies there were 343 VTE events in 301 patients (KM rate at 3 years 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease and malignancy. The burden of atherosclerosis manifested as increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for one, 1.53% for two and 2.45% for three territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (HR 0.71, 95% CI 0.56-0.89; p=0.003).
Conclusions—The rate of VTE in patients with atherosclerosis is ~0.3% per year while on treatment with at least one antiplatelet agent with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk and support inclusion of VTE as a prospective endpoint in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01225562.
- Received August 10, 2017.
- Revision received October 10, 2017.
- Accepted October 19, 2017.