Reduction in overall occurrences of ischemic events with vorapaxar: results from TRACER

Harvey D White, Zhen Huang, Pierluigi Tricoci, Frans Van de Werf, Lars Wallentin, Yuliya Lokhnygina, David J Moliterno, Philip E Aylward, Kenneth W Mahaffey, Paul W Armstrong, Harvey D White, Zhen Huang, Pierluigi Tricoci, Frans Van de Werf, Lars Wallentin, Yuliya Lokhnygina, David J Moliterno, Philip E Aylward, Kenneth W Mahaffey, Paul W Armstrong

Abstract

Background: Clinical trials traditionally use time-to-first-event analysis embedded within the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke. However, many patients have >1 event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER.

Methods and results: TRACER randomized 12 944 patients with non-ST-segment elevation acute coronary syndromes to placebo or to protease-activated receptor 1 antagonist vorapaxar with a median follow-up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD, MI, or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD, MI, stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD, MI, or stroke (14.7% vorapaxar vs. 16.4% placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.02; number needed to treat [NNT], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent (HR, 0.88; 95% CI, 0.80 to 0.98; P=0.02; NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia (HR, 0.92; 95% CI, 0.84 to 1.01; P=0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding (HR, 1.42; 95% CI, 1.21 to 1.66; P<0.001) and Thrombolysis in Myocardial Infarction clinically significant bleeding (HR, 1.550; 95% CI, 1.403 to 1.713; P<0.001).

Conclusions: Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events.

Clinical trial registration url: ClinicalTrials.gov. Unique identifier: NCT00527943.

Keywords: acute coronary syndromes; recurrent events; vorapaxar.

© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1.
Figure 1.
Patient flows and occurrences of ischnemic events. MI indicates myocardial infarction.
Figure 2.
Figure 2.
First and subsequent CVD, MI, or stroke among patients randomized to vorapaxar or to placebo. CVD indicates cardiovascular death; MI, myocardial infarction; rehosp, rehospitalization; revasc, revascularization.
Figure 3.
Figure 3.
First and second ischemic events, CVD, MI, or stroke among patients randomized to vorapaxar or to placebo. CVD indicates cardiovascular death; MI, myocardial infarction; rehosp, rehospitalization; revasc, revascularization.

References

    1. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, Fox KA, Lipka LJ, Liu X, Nicolau JC, Ophuis AJ, Paolasso E, Scirica BM, Spinar J, Theroux P, Wiviott SD, Strony J, Murphy SA. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012; 366:1404-1413.
    1. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, White HD, Aylward PE, Wallentin L, Chen E, Lokhnygina Y, Pei J, Leonardi S, Rorick TL, Kilian AM, Jennings LH, Ambrosio G, Bode C, Cequier A, Cornel JH, Diaz R, Erkan A, Huber K, Hudson MP, Jiang L, Jukema JW, Lewis BS, Lincoff AM, Montalescot G, Nicolau JC, Ogawa H, Pfisterer M, Prieto JC, Ruzyllo W, Sinnaeve PR, Storey RF, Valgimigli M, Whellan DJ, Widimsky P, Strony J, Harrington RA, Mahaffey KW. Thrombin‐receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012; 366:20-33.
    1. TRA*CER Executive and Steering Commzrittees. The thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA*CER) trial: study design and rationale. Am Heart J. 2009; 158:327-334.
    1. Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modelling marginal distributions. J Am Stat Assoc. 1989; 84:1065-1073.
    1. Janzon M, Levin LA, Swahn E. Cost‐effectiveness of an invasive strategy in unstable coronary artery disease; results from the FRISC II invasive trial. The Fast Revascularisation during InStability in Coronary artery disease. Eur Heart J. 2002; 23:31-40.
    1. Kohli P, Wallentin L, Reyes E, Horrow J, Husted S, Angiolillo DJ, Ardissino D, Maurer G, Morais J, Nicolau JC, Oto A, Storey RF, James SK, Cannon CP. Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO study. Circulation. 2013; 127:673-680.
    1. Mahoney EM, Jurkovitz CT, Chu H, Becker ER, Culler S, Kosinski AS, Robertson DH, Alexander C, Nag S, Cook JR, Demopoulos LA, DiBattiste PM, Cannon CP, Weintraub WS. Cost and cost‐effectiveness of an early invasive vs conservative strategy for the treatment of unstable angina and non‐ST‐segment elevation myocardial infarction. JAMA. 2002; 288:1851-1858.
    1. Mahoney EM, Wang K, Arnold SV, Proskorovsky I, Wiviott S, Antman E, Braunwald E, Cohen DJ. Cost‐effectiveness of prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention: results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel‐Thrombolysis in Myocardial Infarction TRITON‐TIMI 38. Circulation. 2010; 121:71-79.
    1. Murphy SA, Antman EM, Wiviott SD, Weerakkody G, Morocutti G, Huber K, Lopez‐Sendon J, McCabe CH, Braunwald E. Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON‐TIMI 38 trial. Eur Heart J. 2008; 29:2473-2479.
    1. Leonardi S, Tricoci P, White HD, Armstrong PW, Huang Z, Wallentin L, Aylward PE, Moliterno DJ, Van de Werf F, Chen E, Providencia L, Nordrehaug JE, Held C, Strony J, Rorick TL, Harrington RA, Mahaffey KW. Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA*CER) trial. Eur Heart J. 2013; 34:1723-1731.
    1. Murphy SA, Cannon CP, Wiviott SD, McCabe CH, Braunwald E. Reduction in recurrent cardiovascular events with intensive lipid‐lowering statin therapy compared with moderate lipid‐lowering statin therapy after acute coronary syndromes from the PROVE IT‐TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy‐Thrombolysis In Myocardial Infarction 22) trial. J Am Coll Cardiol. 2009; 54:2358-2362.
    1. Armstrong PW, Westerhout CM, Van de Werf F, Califf RM, Welsh RC, Wilcox RG, Bakal JA. Refining clinical trial composite outcomes: an application to the Assessment of the Safety and Efficacy of a New Thrombolytic‐3 (ASSENT‐3) trial. Am Heart J. 2011; 161:848-854.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi