Antiplatelet Therapy for Heart Disease: A Mainstay of Prevention and Management

The number of deaths associated with cardiovascular disease (CVD) in 2015 was estimated at 17.7 million and accounted for 31% of global deaths.¹ Among these deaths, 7.4 million were related to coronary heart disease, and 6.7 million were related to stroke,¹ making CVD the No. 1 cause of death worldwide. According to the results of a data analysis conducted by the CDC, heart disease costs the United States about $200 billion every year.²

The most common risk factors for CVD are hypertension, diabetes, and hyperlipidemia.¹ Other risk factors include increased age, tobacco use, decreased physical activity, and increased consumption of unhealthy foods.³ Despite extensive research putting emphasis on standard care, the risk for CVD recurrence remains very high.⁴

Pharmacology

Platelets play an essential role in arterial thrombus formation. Therefore, antiplatelet therapy has been the mainstay of prevention and management of CVD. Over the past decade, tremendous progress has been made in antiplatelet therapy. There now are several drugs, each with its own explicit pharmacological effects and clinical indications, readily available on the market.

Therapeutic Use, Dosing, and Administration

Since the 1900s, aspirin (acetyl salicylic acid [ASA]) has been the most widely used antiplatelet drug in the world. ASA irreversibly inhibits cyclooxygenase to block the production of thromboxane A2, a powerful promoter of platelet aggregation,⁵ and blocks platelet aggregation for prophylaxis of secondary cardioembolic phenomena after a stroke or myocardial infarction (MI).⁶ According to the Antithrombotic Trialists’ Collaboration, use of ASA has resulted in 25% fewer cardiovascular events, including significant reductions in MI, stroke, and CVD deaths in patients with prior occlusive events.⁷ Therefore, >10% of patients with a 10-year risk of MI and stroke are recommended a low-dose ASA regimen for prophylaxis.⁶ Durlaza, an extended-release aspirin capsule that was approved in 2015 to reduce the risk of MI, recurrent transient ischemic attack/stroke, and death, is nonformulary, and the quantity is limited.

Dipyridamole (Persantine), categorized as tier 1, is a phosphodiesterase inhibitor that also inhibits platelet aggregation. Dipyridamole is often used in combination with ASA for secondary prevention of stroke.⁶ In the Second European Stroke Study, deaths from stroke were reduced by 24% with the combination of ASA and dipyridamole.⁸

To date, the most common antiplatelet agents used after ASA are the thienopyridines, which include, clopidogrel (Plavix), tier 2; ticlopidine (Ticlid), tier 1 (not available in the United States); ticagrelor (Brilinta), tier 3; and prasugrel (Effient), tier 3. These agents inhibit the adenosine diphosphate receptor, P2Y₁₂, on the platelet surface, thereby inhibiting platelet activation. Clopidogrel, the dominant member within the class, in combination with ASA, showed a 20% reduction of cardiovascular death in patients with unstable angina/non—ST-segment elevation myocardial infarction for 3 to 12 months in the CURE trial. Although the combination of clopidogrel and ASA showed significant benefits on CVD events, it increased major bleeding, especially with prolonged usage. In the CHARISMA trial, the investigators designed the trial to test whether clopidogrel should be continued beyond 1 year, in addition to aspirin. The trial substantiated no significant benefit in the long term when added to ASA.⁹

The Glycoprotein IIb/IIIa inhibitors, abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat), are potent platelet inhibitors used in patients with MI and after angioplasty, with or without stent placement, to prevent platelets from binding together.¹⁰ These agents are administered only intravenously during hospitalizations and are nonformulary.

Vorapaxar (Zontivity), nonformulary and quantity-limited, is a competitive and selective PAR-1 inhibitor, the first-in its-class antiplatelet medication, which was approved in January 2014. Vorapaxar reversibly blocks protease-activated receptor-1 to inhibit thrombin-mediated platelet activation. It was shown in clinical trials to reduce MI, stroke, and CVD death. The results of some studies have suggested that the use of Vorapaxar was associated with fewer MIs without significantly increasing the risk of bleeding. The results of the GUSTO trial showed that vorapaxar increased the rate of moderate or severe bleeding compared with the placebo. Despite these therapy concerns, vorapaxar has proven cardiovascular benefits when concurrently used with traditional dual antiplatelet.³ However, the TRACER trial, which tested vorapaxar as an adjunctive agent in patients with non—ST-elevation acute coronary syndrome, showed no significant reduction in primary endpoints such as death, MI, and stroke.¹¹ By contrast, there was a substantial increase in major bleeding events (7.2% vs 5.2%) and intracranial hemorrhage (1.1% vs 0.2%) with vorapaxar compared with the placebo.

Safety and Efficacy

The decision-making process in selecting the appropriate antiplatelet therapy for patients with CVD remains ambiguous. Although the FDA has approved the newer agent, Zontivity, as an adjunct therapy, questions have arisen as to which patient population will benefit from it, given major concerns about bleeding.

Conclusion

Further clinical trials are needed to study Zonvitity monotherapy or in combination with different antiplatelets. In addition, lifestyle modifications should be implemented in both primary and secondary prevention categories. Health care professionals ought to be proactive in educating and encouraging patients about the importance of implementing lifestyle modifications for CVD prevention.

Gina Dube, PharmD, CACP, RPh, is an advanced practice clinical pharmacist at Brigham and Women’s Hospital in Boston, Massachusetts.

References

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• Bhatt DL, Fox KA, Hacke W, et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706-1717.
• Cleveland Clinic. Glycoprotein IIb IIIa Inhibitors. CC websitemy.clevelandclinic.org/health/articles/glycoprotein-iib-iiia-inhibitors. Updated May 23, 2012. Accessed September 20, 2017.
• Tricoci P, Huang Z, Held C, et al; TRACER Investigators. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012;366(1):20-33. doi: 10.1056/NEJMoa1109719.