Person:

Braunwald, Eugene

Background: Vorapaxar is a protease‐activated receptor‐1 antagonist approved by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD), without a previous stroke or transient ischemic attack (TIA). Methods and Results: We examined the efficacy and safety of vorapaxar in the intended use population, considering 20 170 patients randomized in the multinational, double‐blinded, placebo‐controlled TRA 2°P‐TIMI 50 trial. Of these, 16 897 qualified with a history of MI in the prior 2 weeks to 1 year and 3273 with PAD. At baseline 97% of the patients were treated with aspirin, 71% with a thienopyridine, and 93% a statin. At 3 years, the endpoint of CV death, MI, or stroke was significantly reduced with vorapaxar compared with placebo (7.9% versus 9.5%, HR, 0.80; 95% CI 0.73 to 0.89; P<0.001). Vorapaxar also significantly reduced the composite of CV death, MI, stroke, and urgent coronary revascularization (10.1% versus 11.8%, HR, 0.83; 95% CI 0.76 to 0.90; P<0.001), as well as the rate of CV death or MI (P<0.001). The safety endpoint of GUSTO moderate or severe bleeding, was increased in the vorapaxar group (3.7 versus 2.4, HR, 1.55; 95% CI 1.30 to 1.86, P<0.001). Intracranial bleeding (ICH) was 0.6% versus 0.4%, P=0.10 with vorapaxar versus placebo, with fatal bleeding 0.2% versus 0.2%; P=0.70. Conclusions: In patients with prior MI or PAD who have not had a previous stroke or TIA, vorapaxar added to standard therapy is effective for long‐term secondary prevention of thrombotic CV events, while increasing moderate or severe bleeding. Clinical Trial Registration URL: clinicaltrials.gov Unique Identifier: NCT00526474.

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.

Background: Interleukin‐6 (IL‐6) is an inflammatory cytokine implicated in plaque instability in acute coronary syndrome (ACS). We aimed to evaluate the prognostic implications of IL‐6 post‐ACS. Methods and Results: IL‐6 concentration was assessed at baseline in 4939 subjects in SOLID‐TIMI 52 (Stabilization of Plaque Using Darapladib—Thrombolysis in Myocardial Infarction 52), a randomized trial of darapladib in patients ≤30 days from ACS. Patients were followed for a median of 2.5 years for major adverse cardiovascular events; cardiovascular death, myocardial infarction, or stroke) and cardiovascular death or heart failure hospitalization. Primary analyses were adjusted first for baseline characteristics, days from index ACS, ACS type, and randomized treatment arm. For every SD increase in IL‐6, there was a 10% higher risk of major adverse cardiovascular events (adjusted hazard ratio [adj HR] 1.10, 95% confidence interval [CI] 1.01‐1.19) and a 22% higher risk of cardiovascular death or heart failure (adj HR 1.22, 95% CI 1.11‐1.34). Patients in the highest IL‐6 quartile had a higher risk of major adverse cardiovascular events (adj HR Q4:Q1 1.57, 95% CI 1.22‐2.03) and cardiovascular death or heart failure (adj HR 2.29, 95% CI 1.6‐3.29). After further adjustment for biomarkers (high‐sensitivity C‐reactive protein, lipoprotein‐associated phospholipase A2 activity, high‐sensitivity troponin I, and B‐type natriuretic peptide), IL‐6 remained significantly associated with the risk of major adverse cardiovascular events (adj HR Q4:Q1 1.43, 95% CI 1.09‐1.88) and cardiovascular death or heart failure (adj HR 1.79, 95% CI 1.22‐2.63). Conclusions: In patients after ACS, IL‐6 concentration is associated with adverse cardiovascular outcomes independent of established risk predictors and biomarkers. These findings lend support to the concept of IL‐6 as a potential therapeutic target in patients with unstable ischemic heart disease.