ACCP Cardiology PRN e-Journal Club

TRA 2P-TIMI 50 Trial

Kazuhiko Kido

  1. Summary

Vorapaxar is the first Protease Activated Receptor (PAR) 1 antagonist which antagonizesthrombin on platelet surface. Currently, only FDA approved indication is to reduce thrombotic cardiovascular events in patients withstable myocardial infarction (MI) or with peripheral artery disease (PAD)histories,based on findings from the TRA 2P-TIMI 50 trial.1 The trial was double blind randomized controlled trial comparing vorapaxar 2.5 mg daily oral vs. placebo. The primary efficacy outcome was composite outcome of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was GUSTO moderate or major bleeding. Vorapaxar significantly reduced the primary efficacy outcome compared with placebo {10.5 % vs. 9.3%, Hazard ratio (HR) 0.87 (95% CI, 0.80-0.94), NNT 84}. Subgroup analysis showed that patients with MI retained significant differences between vorapaxar and placebo but there were not significant differences in patients with PAD or stroke. In contrast, vorapaxar significantly increased GUSTO moderate or severe bleeding {4.2% vs. 2.5%, HR 1.66 (95% CI, 1.43-1.93), NNH 58}. Post-hoc subgroup analysis based on a history of stroke showed that patients with a history of stroke in vorapaxar group had significantly higher intracranial bleeding {2.4% vs. 0.9%, HR 2.55 (95% CI, 1.52-4.28), NNH 66}, as supposed to the patients without a history of stroke having significantly higher intracranial bleeding but smaller absolute rate difference {0.6% vs. 0.4%, HR 1.55 (95% CI, 1.00-2.41), NNH 500}. The authors concluded that the benefits of vorapaxar are only compelling to the patients with a history of MI but without a history of stroke.

  1. Questions during discussion session
  • How would you (will you) incorporate this agent into practice?

This is not something that I would recommend starting inthe inpatient setting because TRA-2P study population had stable atherosclerotic disease. In my opinion, good candidates include patientsalready on aspirin and clopidogrel with multiple myocardial infarction histories and without a history of stroke.

  • Would you recommend addition of this drug to your formulary?

I would not recommend adding it to the inpatient formulary at this time, because the indication is to prevent recurrent myocardial infarction or peripheral artery disease for patients with stable established atherosclerosis. Based on currently available literature, the only appropriate timing of initiation is outpatient setting.

  • Were there biomarkers measured to indicate who might benefit the most (e.g.hsCRP)?

Biomarker sub-study was conducted to assess the interaction between baseline biomarkers and clinical efficacy outcome per protocol but the results are not published yet.2 The biomarkers measured were as follows: inflammation (high-sensitivity C-reactive protein, metalloproteinases), thrombosis (soluble CD40L), atherogenesis (lipoprotein phospholipase A2), and myocardial injury (high-sensitivity troponin).

  • What measures did they (or could you) apply to ameliorate a GUSTO bleeding event? AKA how would you manage bleeds?

There is no known reversal agent for the antiplatet effect of vorapaxar.TRA 2P-TIMI 50 trial protocol did not specify measures to manage bleedingduring trial. Package insert mentions that platelet infusion or dialysis is not beneficial if bleeding occurs.Based on GUSTO bleeding definition, the management for GUSTO severe bleeding is to give blood or fluid replacement, vasopressor/ inotrope support, or surgical intervention. If the bleeding is GUSTO moderate bleeding, the main measures are transfusion of whole blood or packed red blood cells. Healthy volunteer studies showed no changes in coagulation test parameters (TT, PT, aPTT, ACT, ECT) after multiple dose for 28 days of vorapaxar. Therefore, it is expected that PCC, FFP or factor VII would not be effective.3

  • How would you approach holding therapy prior to a high-risk procedure given the drugs long half-life?

Pharmacologic half-life of vorapaxar is 3-4 days and pharmacodynamics effects following a single dose of vorapaxarlast 2 to 3 weeks. Currently, there is no specific recommendation from package insert regarding perioperative management of vorapaxar.3However, some data showed the possibility of using vorapaxar during the perioperative period. In TRACER trial, there was a numerical increase in major CABG related bleeding but it did not meet statistical difference.4 Also, the results for patients undergoing non-urgent PCI did not increase surgical bleeding.5Future study to assess the safety of vorapaxar in non-cardiac surgery will be needed to further assess the safety of vorapaxar during surgical procedures.

  1. References
  1. Morrow DA, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366:1404-13.
  2. Morrow DA, et al. Thrombin-receptor antagonist in secondary prevention of atherothrombotic ischemic events TRA 2P-TIMI 50 trial. Am Heart J. 2009;58:333-341.
  3. Zontivity [package insert]. Whitehouse station, NJ: Merck & Co., Inc; 2013.
  4. Ben-Yehuda O. Vorapaxar in patients undergoing coronary artery bypass grafting. J Am CollCardiol. 2014;63:1058-60.
  5. Becker RC, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomized, double-blind, placebo-controlled phase II study. Lancet. 2009;14:919-28.