Ilaria Cavallari1,2, David A Morrow1, Mark A Creager3, Jeffrey Olin4, Deepak L Bhatt1, P Gabriel Steg5,6, Robert F Storey7, Marc Cohen8, Benjamin S Scirica1, Gregory Piazza9, Erica L Goodrich1, Eugene Braunwald1, Marc S Sabatine1, Marc P Bonaca10. 1. TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (I.C., D.A.M., D.L.B., B.S.S., E.L.G., E.B., M.S.S., M.P.B.). 2. Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome, Italy (I.C.). 3. Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH (M.A.C.). 4. Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mt Sinai School of Medicine, New York (J.O.). 5. French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire Fibrosis, Inflammation, Remodeling, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, France (P.G.S.). 6. Université Paris-Diderot, Sorbonne Paris Cité, France (P.G.S.). 7. Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, United Kingdom (R.F.S.). 8. Department of Medicine, Cardiovascular Division, Newark Beth Israel Medical Center, Rutgers-New Jersey Medical School (M.C.). 9. Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.P.). 10. TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (I.C., D.A.M., D.L.B., B.S.S., E.L.G., E.B., M.S.S., M.P.B.) mbonaca@partners.org.
Abstract
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 more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown. METHODS: TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the 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 3 years in both studies there were 343 VTE events in 301 patients (Kaplan-Meier 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 an increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for 1, 1.53% for 2, and 2.45% for 3 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 (hazard ratio, 0.71; 95% confidence interval, 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 ≥1 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 they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01225562.
RCT Entities:
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 more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown. METHODS: TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the 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 3 years in both studies there were 343 VTE events in 301 patients (Kaplan-Meier 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 an increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for 1, 1.53% for 2, and 2.45% for 3 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 (hazard ratio, 0.71; 95% confidence interval, 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 ≥1 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 they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01225562.
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