Triple therapy: Boon or bane for high-risk CV patients?

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Applied Evidence

Triple therapy: Boon or bane for high-risk CV patients?

J Fam Pract. 2011 April;60(4):187-192

By

Candace B. Griffith, PharmD

Haley M. Phillippe, PharmD, BCPS

The combination of 2 antiplatelet agents and warfarin may be beneficial to a select group of patients, but its use remains controversial. Here’s why.

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References

1. Manzano-Fernandez S, Pastor FJ, Marin F, et al. Increased major bleeding complications related to triple antithrombotic therapy usage in patients with atrial fibrillation undergoing percutaneous coronary artery stenting. Chest. 2008;134:559-567.

2. Ruiz-Nodar JM, Marin F, Hurtado JA, et al. Anticoagulant and antiplatelet therapy use in 426 patients with atrial fibrillation undergoing percutaneous coronary intervention and stent implantation. J Am Coll Cardiol. 2008;51:818-25.

3. Nguyen MC, Lim YL, Walton A, et al. Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent? Eur Heart J. 2007;28:1717-1722.

4. Gilard M, Blanchard D, Helft G, et al. Antiplatelet therapy in patients with anticoagulants undergoing percutaneous coronary stenting (from STENTIng and oral anticoagulants [STENTICO]). Am J Cardiol. 2009;104:338-342.

5. Hansen ML, Sorensent R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170:1433-1441.

6. Hermosillo AJ, Spinler SA. Aspirin, clopidogrel, and warfarin: is the combination appropriate and effective or inappropriate and too dangerous? Ann Pharmacother 2008;42:790-805.

7. Rothberg MB, Celestin C, Fiore LD, et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143:241-250.

8. Eikelboom JM, Hirsh J. Combined antiplatelet and anticoagulant therapy: clinical benefits and risks. J Thromb Haemost. 2007;5:255-263.

9. Triple antithrombotic therapy Pharm Lett/Prescr Lett. 2009;25:250901.-

10. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. ACC/AHA guideline revision. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. J Am Coll Cardiol. 2007;50:e1-e157.

11. Furst DE, Ulrich RW. Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics, and drugs used in gout. In: Katzung BG. Basic and Clinical Pharmacology. New York: McGraw Hill; 2008;573-598.

12. Smyth EM, FitzGerald GA. The eicosanoids: prostaglandins, thromboxanes, leukotrienes, and related compounds. In: Katzung BG. Basic and Clinical Pharmacology. New York: McGraw Hill; 2008;293-308.

13. Steinhubl SR, Bhatt DL, Brennan DM, et al. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med. 2009;150:379-386.

14. Campbell CL, Smyth S, Montalescot G, et al. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA. 2007;297:2018-2024.

16. Spinler SA, Rees C. Review of Prasugrel for the secondary prevention of atherothrombosis. J Manag Care Pharm. 2009;15:383-95.

17. Spinler SA, Denus SD, et al. Acute coronary syndromes. In: Dipiro JT, Talbert RL, Yee GC, Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw Hill; 2008;249-277.

18. Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/ Sanofi Pharmaceuticals Partnership; 2010.

19. US Food and Drug Administration. FDA announces new boxed warning on Plavix. March 12, 2010. Available at: http://www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm204253.htm. Accessed March 11, 2011.

20. US Food and Drug Administration. FDA approves Effient to reduce the risk of heart attack in angioplasty patients. July 10, 2009. Available at: http://www.fda.gov/NewsEvents/News-room/PressAnnouncements/ucm171497.htm. Accessed March 11, 2011.

21. US Food and Drug Administration. FDA approves Pradaxa to prevent stroke in people with atrial fibrillation. October 19, 2010. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm. Accessed March 11, 2011.

22. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists. American College of Chest Physicians Evidence-Based Clinical Guidelines (8^Th edition). Chest. 2008;133(suppl):160S-198S.

23. Haines ST, Witt DM, Nutescu EA. Venous thromboembolism. In: Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw Hill; 2008;331-369.

24. Lip G. The balance between stroke prevention and bleeding risk in atrial fibrillation: a delicate balance revisited. Stroke. 2008;39:1406-1408.

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26. Schafer JA, Kjesbo NK, Gleason PP. Critical review of prasugrel for formulary decision makers. J Manag Care Pharm. 2009;15:335-343.

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PRACTICE RECOMMENDATIONS

• In a patient with a high risk of reinfarction, thienopyridine therapy (with clopidogrel or prasugrel) should be continued for at least a year. B

• Risk factors for reinfarction and stent thrombosis are the same ones that increase the risk of ACS initially, and include diabetes mellitus, heart failure, smoking, hyperlipidemia, and hypertension. A

• For patients who are good candidates for triple therapy but have an elevated bleeding risk, using a lower dose of aspirin or limiting thienopyridine use to one month may be a reasonable option. B

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

CASE Anthony D, a 61-year-old patient of yours with hypertension and diabetes, is admitted to the hospital with atrial fibrillation and chest pain that radiates to his left arm and hand. On Day 1, he receives aspirin 325 mg and enoxaparin 1 mg/kg; the following day, the patient receives a 600-mg loading dose of clopidogrel prior to catheterization. He undergoes percutaneous coronary intervention and a bare metal stent is placed in his circumflex artery.

The following day, Anthony is ready for discharge and you consider which maintenance drugs to put him on, given that he already takes multiple medications. Is he a candidate for triple therapy?

Triple therapy—the concurrent use of aspirin, a thienopyridine antiplatelet agent, and warfarin—is often prescribed for patients with atrial fibrillation who experience acute coronary syndrome (ACS) or require percutaneous coronary intervention with the placement of a stent (PCI-S). The danger associated with concomitantly treating a patient with 3 agents, each of which has a distinct mechanism that increases bleeding risk, is high, but for carefully selected patients, the benefit may outweigh the risk.

Several studies have evaluated triple therapy and compared it with single or dual therapy (TABLE).^1-5 Due to a lack of robust outcome studies, however, the benefits and risks of triple therapy cannot be directly quantified, nor are they generalizable to all potential candidates for triple therapy. Thus, finding the optimal treatment for secondary prevention of ACS or prevention of stent thrombosis in a patient with atrial fibrillation requires an understanding of the potential consequences of triple therapy—and a thorough assessment of the patient’s risk of reinfarction, stroke, and bleeding complications.^6-9 To make the best treatment decisions and provide adequate support to patients who were started on triple therapy during a recent hospitalization, here’s what you need to know.

TABLE
Triple therapy: What the studies show

Study type (N)	Intervention	Efficacy	Bleeding
Retrospective (124)¹	Group 1: Aspirin + clopidogrel + warfarin Group 2: Nontriple therapy	No significant difference	No significant difference in early major bleeding Group 1: Significant increase in late major bleeding
Retrospective (373)²	Group 1: Anticoagulant + antithrombotic therapy* Group 2: Antithrombotic therapy only	Group 1: Significant improvement in efficacy Significant improvement in combination of efficacy and bleeding outcomes	Group 1: Significant improvement in combination of efficacy and bleeding outcomes
Cohort (800)³	Group 1: Warfarin + single antiplatelet agent Group 2: Warfarin + dual antiplatelet therapy	No significant difference in mortality or MI	NR
Prospective (359)⁴	Group 1: Continued OAC + dual antiplatelet therapy Group 2: Discontinued OAC but continued antiplatelet therapy	No significant difference	Group 1: Significant increase in moderate and severe bleeding
Cohort (82,854)⁵	Group 1: Warfarin monotherapy Group 2: Aspirin monotherapy Group 3: Clopidogrel monotherapy Group 4: Clopidogrel + aspirin Group 5: Warfarin + aspirin Group 6: Warfarin + clopidogrel Group 7: Warfarin + aspirin + clopidogrel	No significant difference	Groups 6 and 7: Significant increase in crude incidence of bleeding
*50% of the participants in Group 1 received triple therapy (aspirin, clopidogrel, and warfarin). MI, myocardial infarction; NR, not reported; OAC, oral anticoagulant.

First, a review of the components

Aspirin, a key component of triple therapy, is the only nonsteroidal anti-inflammatory drug (NSAID) indicated for primary or secondary prevention of cardiovascular events.^10,11 The reason: Aspirin is more selective for cyclooxygenase-1 (COX-1) than other NSAIDs and irreversibly inhibits COX enzymes.¹¹ The aspirin-induced decrease in thromboxane production leads to a decline in platelet activation and aggregation, which accounts both for aspirin’s beneficial cardiovascular effects and the associated risk of bleeding—aspirin’s most common adverse effect.¹²

Most major bleeds linked to aspirin use involve the gastrointestinal (GI) tract, primarily because of the drug’s direct and indirect effects on the GI mucosa.^11-14 Aspirin’s toxicities are dose related, but its antiplatelet properties do not appear to be.¹⁴

Adding a thienopyridine
Thienopyridine antiplatelet drugs indicated for the secondary prevention of cardiovascular events after ACS or PCI-S include ticlopidine, clopidogrel, and prasugrel.¹⁵ Ticlopidine, the first such agent approved in the United States, is rarely used because of potential neutropenia and thrombotic thrombocytopenia purpura.¹⁶