BACKGROUND:Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial. METHODS: In TRA 2°P-TIMI 50--a randomised, placebo-controlled, parallel trial--we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474). FINDINGS:17,779 of 26,449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 toplacebo). Median follow-up was 2·5 years (IQR 2·0-2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in theplacebo group (3-year Kaplan-Meier estimates 8·1%vs 9·7%, HR 0·80, 95% CI 0·72-0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3·4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2·1%, 3-year Kaplan-Meier estimate], HR 1·61, 95% CI 1·31-1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups. INTERPRETATION: For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding. FUNDING: Merck.
RCT Entities:
BACKGROUND:Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial. METHODS: In TRA 2°P-TIMI 50--a randomised, placebo-controlled, parallel trial--we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474). FINDINGS: 17,779 of 26,449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2·5 years (IQR 2·0-2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8·1%vs 9·7%, HR 0·80, 95% CI 0·72-0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3·4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2·1%, 3-year Kaplan-Meier estimate], HR 1·61, 95% CI 1·31-1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups. INTERPRETATION: For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding. FUNDING: Merck.
Authors: Renato D Lopes; Richard C Becker; L Kristin Newby; Eric D Peterson; Elaine M Hylek; Robert Giugliano; Christopher B Granger; Kenneth W Mahaffey; Antonio C Carvalho; Otavio Berwanger; Roberto R Giraldez; Gilson Soares Feitosa-Filho; Marcia M Barbosa; Maria da Consolacao V Moreira; Renato A K Kalil; Marildes Freitas; Joao Carlos de Campos Guerra; Marcio Vinicius Lins Barros; Thiago da Rocha Rodrigues; Antonio C Lopes; David A Garcia Journal: J Thromb Thrombolysis Date: 2013-07 Impact factor: 2.300
Authors: H M H Spronk; T Padro; J E Siland; J H Prochaska; J Winters; A C van der Wal; J J Posthuma; G Lowe; E d'Alessandro; P Wenzel; D M Coenen; P H Reitsma; W Ruf; R H van Gorp; R R Koenen; T Vajen; N A Alshaikh; A S Wolberg; F L Macrae; N Asquith; J Heemskerk; A Heinzmann; M Moorlag; N Mackman; P van der Meijden; J C M Meijers; M Heestermans; T Renné; S Dólleman; W Chayouâ; R A S Ariëns; C C Baaten; M Nagy; A Kuliopulos; J J Posma; P Harrison; M J Vries; H J G M Crijns; E A M P Dudink; H R Buller; Y M C Henskens; A Själander; S Zwaveling; O Erküner; J W Eikelboom; A Gulpen; F E C M Peeters; J Douxfils; R H Olie; T Baglin; A Leader; U Schotten; B Scaf; H M M van Beusekom; L O Mosnier; L van der Vorm; P Declerck; M Visser; D W J Dippel; V J Strijbis; K Pertiwi; A J Ten Cate-Hoek; H Ten Cate Journal: Thromb Haemost Date: 2018-01-29 Impact factor: 5.249