Universal Classification System Type of Incident Myocardial Infarction in Patients With Stable Atherosclerosis: Observations From Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50

Abstract

Background: Our dual aims were as follows: (1) to classify new or recurrent myocardial infarctions (MI) in patients with stable atherosclerosis using the Universal Definition of MI classification system; and (2) to characterize the effects of vorapaxar, a first-in-class platelet protease-activated receptor -1 antagonist, on new or recurrent MI.

Methods and results: We analyzed data from TRA 2°P-TIMI 50, a multinational, randomized, double-blind, placebo-controlled trial of vorapaxar. This analysis included 20 770 patients with previous MI or peripheral arterial disease without a history of transient ischemic attack or stroke. Each new or recurrent MI after randomization that met the trial end point definition was further categorized according to the European Society of Cardiology, American College of Cardiology, American Heart Association, World Heart Federation Universal Definition classification of type and size. Of 1095 incident MIs, 77% were spontaneous (Type 1), with a smaller number (9.8%) of secondary MIs (Type 2). Vorapaxar reduced Type 1 MI (hazard ratio [HR] 0.84, CI 0.73-0.98, P=0.024), with a similar pattern for Type 2 MI (HR 0.74, CI 0.49-1.10, P=0.13). Notably, vorapaxar showed a consistent pattern of reduction across size of MIs, including MIs in the highest Universal MI size class (≥10× upper reference limit, HR 0.83, CI 0.70-0.98, P=0.025). As such, there was a significant reduction in larger, spontaneous MIs (Type 1, ≥10× upper reference limit, HR 0.81, CI 0.67-0.99, P=0.036), and a consistent pattern with respect to fatal MI (HR 0.66, CI 0.39-1.11, P=0.12).

Conclusions: Among stable patients with established atherosclerosis, the most common type of incident MI is spontaneous MI, and the reduction in MI with vorapaxar was consistent across MIs of varying type and size, including spontaneous infarctions ≥10× upper reference limit.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00526474.

Keywords: atherosclerosis; cardiovascular disease; myocardial infarction; platelet inhibitor.

Figure 1

Flow diagram of myocardial infarctions included in the analysis. MI indicates myocardial infarction; PAD, peripheral arterial disease; TIA, transient ischemic attack.

Figure 2

Distribution of incident MIs classified according to the universal MI classification system of type and size. There were a total of 190 STEMI and 732 NSTEMI. Type 4 MIs were dominated by Type 4b with only 15 Type 4a MIs. MI indicates myocardial infarction; NSTEMI, non‐ST‐segment elevation myocardial infarction; STEMI, ST‐segment elevation myocardial infarction; URL, upper reference limit.

Figure 3

Distribution of MI type and size by time from qualifying MI to study enrollment (first 3 bars). The 4th bar in each panel is from a landmark analysis starting at 1 year after enrollment for all subjects. MI indicates myocardial infarction.

Figure 4

Risk of cardiovascular death following an incident MI compared with those without incident MI stratified by MI type and size. There was a consistent risk of CV death after both STEMI (HR 11.6, CI 6.7–20.1) and NSTEMI (HR 7.4, CI 5.6–9.8). CV indicates cardiovascular; HR, hazard ratio; MI, myocardial infarction; NSTEMI, non‐ST‐segment elevation myocardial infarction; STEMI, ST‐segment elevation myocardial infarction.

Figure 5

Effect of vorapaxar on incident MI stratified by universal MI type and size. This analysis is based on the first MI of each given type or size. HR indicates hazard ratio; MI, myocardial infarction.

Figure 6

Kaplan–Meier estimated rates of MIs that were spontaneous (A) or in the highest Universal classification system size class (≥10× URL) (B) with vorapaxar vs placebo. MI indicates myocardial infarction; URL, upper reference limit.