Vorapaxar as secondary prevention in atherosclerosis
Vorapaxar in the Secondary Prevention of Atherothrombotic Events.Morrow DA, Braunwald E, et al.; the TRA 2P–TIMI 50 Steering Committee and Investigators.
N Engl J Med. 2012 Mar 24.
Platelet inhibitors can reduce thrombotic events in patients with ACS al(though there is an increased risk of bleeding) [1-3].
In patients with stable coronary artery disease it has not been established yet that there are less thrombotic events with antiplatelet therapy in addition to aspirin . Vorapaxar is a protease activated receptor 1 (PAR-1) thrombin receptor antagonist. The drug inhibits thrombin-induced platelet aggregation. In the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P)-Thrombolysis in Myocardial Infarction (TIMI) 50 study, the efficacy and safety of vorapaxar were examined in reducing atherothrombotic events in patients with established atherosclerosis who received standard therapy. It was also investigated whether an intensified antiplatelet therapy by adding a drug with a different pharmacological effect is beneficial for secondary prevention in stable patients with a history of MI, ischemic stroke or peripheral vascular disease.
After 3 years, the risk of cardiovascular death, MI or stroke was lower in patients with a history of MI, stroke or peripheral arterial disease who were randomized to vorapaxar (9.3%) compared with patients randomized to placebo (10.5% , P <.001). Cardiovascular mortality, MI, stroke, or recurrent ischemia requiring hospitalization occurred in 11.2% of patients randomized to vorapaxar vs. 12.4% randomized to placebo (p = .001). This reduction in new cardiovascular events was greatest in patients with a previous MI with a decrease of 20% (P <.001).
Vorapaxar was associated with an increased risk of moderate or severe bleeding (GUSTO criteria) at 3 years compared with placebo (4.2% vs 2.5%), including intracranial hemorrhage (1% versus 0.5%, P <0.001 for both). The occurrence of bleeding was less in patients without a history of stroke (0.6% vs. 0.4% vorapaxar with placebo, P = 0.049).
ConclusionAdding vorapaxar to standard antiplatelet therapy significantly reduces the risk of cardiovascular death and ischemic complications in patients with stable coronary artery disease. The risk of bleeding, including intracranial hemorrhage (ICH), however, increases; this risk is lower in patients without ahistory of stroke.
1. Yusuf S, Zhao F, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. [Errata, N Engl J Med 2001;345:1506, 1716.]
2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.
3. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.
4. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17.
Background Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.
Methods We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.
Results At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).
Conclusions Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage.
Share this page with your colleagues and friends: