By: Azia Tariq, Section Editor

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Myocardial infarctions, more commonly known as heart attacks, are prevalent in the United States. Each year, approximately 720,000 Americans suffer a heart attack.¹ The approval of vorapaxar by the Food and Drug Administration (FDA) presents an additional treatment option for patients at high risk for myocardial infarction and stroke.^1,2

Myocardial infarctions largely occur due to a blood flow blockage in the coronary arteries. The blood flow blockage can be caused by a blood clot or from the buildup of plaque in the coronary arteries. The lack of oxygen to the heart causes the cells to die, resulting in the heart attack. Hallmark symptoms include chest pain or numbness that spreads to the shoulder blades, neck, and jaw. Additional symptoms may include anxiety, coughing, fainting, light-headedness, dizziness, nausea or vomiting, palpitations, shortness of breath, and sweating.^3,4

Immediate treatment includes nitroglycerin and morphine to help reduce chest pain, in addition to aspirin to prevent blood clots. Subsequent steps may include angioplasty, a procedure to open narrowed or blocked blood vessels that supply blood to the heart. An angioplasty should be done within 90 minutes of the patient’s arrival to the hospital and usually no later than 12 hours after a heart attack. Pharmacologic treatment is also given in order to break up the clot during thrombolytic therapy. Some patients may undergo bypass surgery to restore blood flow to the heart by diverting the flow around a section of a blocked artery.³

Vorapaxar (Zontivity^TM) is an oral protease-activated receptor-1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation and is FDA approved for to reduce the risk of heart attack, stroke, and cardiovascular death.⁵ The 2.08 mg tablet is taken orally once daily in addition to aspirin.⁵ It will also be used for procedures that restore blood flow to the heart in patients with a previous heart attack or blockages in the arteries to the legs.⁶ As an anti-platelet agent designed to decrease the tendency of platelets to clump together to form a blood clot, vorapaxar decreases the risk of heart attack and stroke.²

In the clinical trial referred to as TRA2P TIMI 50, 26,449 patients were randomly selected to receive either vorapaxar 2.5mg daily in addition to standard of care, or placebo in addition to standard of care. The primary efficacy endpoint was the composite rate of cardiovascular death, MI, stroke, or urgent coronary revascularization. Eligibility criteria required a diagnosis of atherosclerosis—specifically MI, PAD, or ischemic stroke during the prior period of 2 weeks to 12 months. Baseline characteristics of the patients indicated that 67% had a previous MI, 19% had a previous stroke, and 14% had PAD.

In January 2011, after an increase in intracranial hemorrhage (ICH) was seen in patients with a history of stroke, The Data and Safety Monitoring Board (DSMB) recommended that these individuals stop taking vorapaxar. Other patient groups continued the trial as expected, with a median follow-up of 2.5 years. At 3 years, the results showed a reduction in the primary endpoint in the vorapaxar group (9.3% vs. 10.5%; HR 0.87; 95% CI 0.8-0.94, p<0.001). A greater reduction was observed in patients without a history of stroke (8.3% vs. 9.6%; HR 0.84; 95% CI 0.76-0.93). Moderate to severe bleeding was increased in the vorapaxar group (4.2% vs. 2.5%; HR 1.66; 95% CI 1.43-1.93; p<0.001), with a significant increase in ICH (1% vs. 0.5%, p<0.001).^7,8

An independent companion trial, the TRACER study, analyzed whether the addition of vorapaxar to standard of care would lead to a reduction in atherothrombotic ischemic events compared to standard of care alone. A total of 12,944 non-ST-segment elevation acute coronary syndrome (NSTEACS) patients were randomized to receive either vorapaxar in addition to standard of care or standard of care alone. NSTEACS refers to a number of conditions ranging from unstable angina to NSTE myocardial infarction (MI) which have an underlying cause of atherosclerotic plaque disruption and differing degrees of associated thrombosis and distal embolization.⁹   Of those patients, 8750 (67.6%) had undergone percutaneous coronary intervention or coronary artery bypass grafting and 4194 patients (32.4%) had not undergone revascularization during the trial.⁷ Patients who were managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography.⁹

In the medically managed group, two year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischemia with re-hospitalization, and urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with only standard of care (HR 0.99, 95% CI 0.83-1.17) with no interaction between drug and management strategy (p=0.75). Secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with only standard of care (HR 0.89, 95% CI 0.74-1.07) with no interaction (p=0.58). Vorapaxar also increased moderate to severe bleeding in medically managed patients (adjusted HR 1.46, 95% CI 0.99-2.15).⁹

In patients undergoing coronary artery bypass grafting (CABG) during the trial, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012) compared to CABG patients with only standard of care.¹⁰ The trial follow-up was terminated early after a safety review by the DSMB. After a median follow-up of 502 days, the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving standard of care (18.5% vs. 19.9%; HR 0.92; 95% CI 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; HR 0.89; 95% CI 0.81 to 0.98; P=0.02).

Rates of moderate/severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (HR 1.35; 95% CI 1.16 to 1.58; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (HR 3.39; 95% CI, 1.78 to 6.45; P<0.001).⁶ Trial follow-up was terminated in January 2011 after a safety review by the DSMB.

Rosser et al examined the beneficial effect of vorapaxar on global thrombotic and thrombolytic status in patients with coronary disease by testing the blood of 57 patients who were given vorapaxar with the point-of-care global thrombosis test. This is an automated test that employs non-anti-coagulated blood to assess thrombotic and thrombolytic status by measuring the time required to form a shear-induced thrombus under physiological conditions, called the occlusion time (OT), and the time to achieve endogenous lysis of the thrombus, called the lysis time (LT).

A longer OT on and off treatment was observed for patients on vorapaxar [median 561 seconds (interquartile range 422-654) vs. 372 s(338-454), P = 0.003] and shorter LT on treatment than off treatment [1,158 s(746-1,492) vs. 1,733 s(1,388-2,230), P = 0.016]. Patients on placebo showed no difference in OT [419 s(343-514) vs. 411 s(346-535), P = 0.658] or LT [1,236 s(985-1,594) vs. 1,400 s(1,092-1,686), P = 0.524] on and off treatment. During treatment, OT was longer in patients taking vorapaxar [561 s(422-654) vs. 419 s(343-514), P = 0.009], but LT was similar in vorapaxar and placebo arms [1,158 s(746-1,492) vs. 1,236 s(985-1,594), P = 0.277]. It was observed that vorapaxar prolongs OT and shortens LT and has favorable antiplatelet effects on thrombotic and thrombolytic status. In addition, vorapaxar enhances thrombolysis, which is often impaired in coronary disease.¹¹

Director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research, Ellis Unger, M.D., stated, “In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death. In the study that supported the drug’s approval, Zontivity^TM lowered this risk from 9.5 percent to 7.9 percent over a 3-year period – about 0.5 percent per year.”²

As with any medication, vorapaxar has a range of adverse effects which include life-threatening and fatal bleeding, intracranial hemorrhage, anemia, depression, rash, and exanthema. Usage is contraindicated in patients with history of stroke, TIA, or ICH and with patients with active bleeding such as ICH or peptic ulcer. Withholding vorapaxar for a brief period will not be useful in managing an acute bleeding event due to its long half-life. There is no known treatment to reverse the antiplatelet effect of vorapaxar. Platelet aggregation inhibition can be expected for weeks after discontinuation of normal dosing. Significant inhibition of platelet aggregation remains 4 weeks after discontinuation.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed in an interaction study with vorapaxar and warfarin in healthy subjects. No pharmacokinetic effects were noted between vorapaxar and prasugrel following multi-dose administration as well.⁵

Healthcare professionals must consider underlying risks of bleeding before initiating vorapaxar. Risk factors for bleeding include older age, low body weight, reduced renal or hepatic function, history of bleeding disorders, and use of certain concomitant medications that increase the risk of bleeding (anticoagulants, fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs [NSAIDS], selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors). Avoid concomitant use of vorapaxar and warfarin or other anticoagulants.

No renal or hepatic dose adjustment is required, however, vorapaxar is not recommended for patients with severe hepatic impairment due to increased risk of bleeding. No adequate studies were preformed for use of vorapaxar in pediatric populations or pregnant women. The potential for serious adverse reactions and the possibility of being excreted in human milk suggests nursing mothers should not take vorapaxar.⁵

With recent FDA-approval of vorapaxar to help reduce the risk of myocardial infarction and stroke through the mechanism of inhibited thrombin-induced platelet activation, patients who are at risk now have an additional efficacious treatment option.

 

SOURCES:

1. Heart Disease Facts. CDC. 2014. Available at: http://www.cdc.gov/heartdisease/facts.htm. Accessed 09/2014.
2. FDA approves Zontivity to reduce the risk of heart attacks and stroke in high-risk patients. FDA. 2014. Available at: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm396585.htm. Accessed on 11/16/2014.
3. Zeng H, Li L, Chen JX. Loss of Sirt3 limits bone marrow cell-mediated angiogenesis and cardiac repair in post-myocardial infarction. PLoS ONE. 2014;9(9):e107011.
4. Michelis KC, Olin JW, Kadian-dodov D, D’escamard V, Kovacic JC. Coronary Artery Manifestations of Fibromuscular Dysplasia. J Am Coll Cardiol. 2014;64(10):1033-46.
5. Zontivity (vorapaxar) [package insert]. Whitehouse Station, NJ; Merck; Revised 04/01/2015.
6. Tricoci P, Huang Z, Held C, et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012;366(1):20-33.
7. O’Riordan M. FDA review endorses Vorapaxar approval in prior MI patients. Medscape. 01/13/2014. Available at: http://www.medscape.com/viewarticle/819061. Accessed 11/16/2014.
8. Held C, Tricoci P, Huang Z, et al. Vorapaxar, a platelet thrombin-receptor antagonist, in medically managed patients with non-ST-segment elevation acute coronary syndrome: results from the TRACER trial. Eur Heart J Acute Cardiovasc Care. 2014;3(3):246-56.
9. Fitchett DH, Borgundvaag B, Cantor W, et al. Non ST segment elevation acute coronary syndromes: A simplified risk-orientated algorithm. Can J Cardiol. 2006;22(8):663-77
10. Whellan DJ, Tricoci P, Chen E, et al. Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). J Am Coll Cardiol. 2014;63(11):1048-57.
11. Rosser G, Tricoci P, Morrow D, et al. PAR-1 antagonist vorapaxar favorably improves global thrombotic status in patients with coronary disease. J Thromb Thrombolysis. 2014;38(4):423-9.

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