Is prasugrel more effective than clopidogrel at preventing future cardiac events?

Catherine G. Lange, PA-C, MS

February 11, 2011

PDF of Critically Appraised Topic 0211

CLINICAL QUESTION 

Is prasugrel as effective as clopidogrel for the prevention of future cardiac events after PCI? 

BACKGROUND 

A review of a large multicenter trial established that clopidogrel combined with aspirin (ASA) lowered primary end points of cardiovascular death, MI, and stroke in patients with acute coronary syndrome (ACS) significantly more than did ASA alone, 5.2% versus 6.5% (P < .01).¹ In a second review, administration of clopidogrel and ASA versus ASA alone also showed lowered need for coronary artery revascularization, 8.3% versus 21.7%, respectively,¹ and use of clopidogrel with ASA has been standard care after PCI for many years.^1,2  

Several recent studies have suggested, however, that wide variation exists in patient responsiveness to clopidogrel, with estimations that "poor responders" may represent 11% to 29% of patients taking the drug.³ Another antiplatelet agent, prasugrel, has been approved by the FDA as a potential alternative to clopidogrel.¹ Like clopidogrel, prasugrel is a thienopyridine adenosine diphosphate receptor antagonist that irreversibly binds to the P-2Y12 receptor gene and uses the cytochrome P-450 system for metabolism.^4,5  

SEARCH CRITERIA AND  RESULTS 

PubMed and MEDLINE were searched using the terms clopidogrel AND prasugrel or VERSUS prasugrel. The results were limited to the years 2007 through 2009 and the English language. Twenty-nine citations were found, and final selections were based on highest level of review of well-established randomized controlled trials (RCTs). Two current review articles and three RCTs were used in this review. 

EVALUATING THE EVIDENCE 

The Medical Letter on Drugs and Therapeutics reviewed the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 study. In this study, 13,608 patients with ACS undergoing percutaneous cardiac intervention were randomized to prasugrel or clopidogrel in addition to ASA. The primary end points were cardiovascular death, nonfatal MI, or nonfatal stroke; 9.9% of patients treated with prasugrel versus 12.1% of those treated with clopidogrel met end point criteria (P < .0001). Lower incidence of end point for prasugrel was mainly a result of a reduction in MI.⁶ The number of patients needed to treat with prasugrel was 46 in order to prevent one primary end point during the 15 months of treatment relative to clopidogrel.²  

The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thombolysis in Myocardial Infarction (PRINCIPLE-TIMI) 44 trial was the first study to compare prasugrel 10 mg daily standard maintenance dose (MD) with higher-than-standard MD (150 mg daily) of clopidogrel. If patients had PCI, they were entered in an MD phase, a 28-day crossover comparison of prasugrel 10 mg daily versus clopidogrel 150 mg daily with primary end point of inhibition of platelet aggregation (IPA) tested after 14 days and before crossover to the comparison drug. IPA was significantly greater in subjects receiving prasugrel (mean 61.3 ±17.8%) compared with clopidogrel (46.1 ±21.3%). This was a highly significant finding (P < .0001), and similar findings occurred with loading doses (LDs) of prasugrel 60 mg versus clopidogrel 600 mg.⁴  

In a prospective observational study by Buonamici and colleagues, patients who had drug-eluting stent (DES) implantation were assessed for their responsiveness to clopidogrel.⁷ In addition to ASA 325 mg, patients were taking 75 mg of clopidogrel daily, and this cohort of 804 patients was studied during a 6-month follow-up after stenting. There were 105 patients who were not responsive to clopidogrel (13%) as determined by blood analysis, and during the patient follow-up period, stent thrombosis occurred in 9 of 105 (8.6%) of the clopidogrel nonresponders compared to only 16 of 699 (2.3%) of the responders (P < .001). 

Safety issues were examined when comparing prasugrel with clopidogrel in a review of the TRITON-TIMI 38 trial.⁸ The participants received either prasugrel 60 mg LD and 10 mg daily MD or 300 mg LD of clopidogrel with 75 mg daily MD. The key safety end point was noncoronary artery bypass graft (CABG) surgery major bleeding. In a review of that study, Spinler and colleagues said that prasugrel was associated with increased rates of non-CABG bleeding compared with clopidogrel (2.4 versus 1.8%; hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.03-1.68; P = .03).² Participants with a remote history of cerebrovascular event who were given prasugrel were at significant risk of another stroke or transient ischemic attack (TIA). Seventeen of 262 (6.5%) patients in the prasugrel group with stroke history had a stroke during follow-up compared with 3 of 256 (1.2%) of patients in the clopidogrel group (HR, 5.64; 95% CI, 1.65-19.3; P = .002). The study did not include patients with history of hemorrhagic or ischemic stroke within 3 months of enrollment.² Twenty-one patients in the prasugrel group and five in the clopidogrel group had fatal bleeding events. All fatal bleeding events in the clopidogrel group were intracranial, compared with nine fatal intracranial hemorrhages, five GI events, and two events from wound sites in the prasugrel group.² As a result of these findings, the FDA recommended that prasugrel be contraindicated in patients with a history of stroke/TIA.⁹  

Age older than 75 years and weight less than 60 kg were also safety risks. Fatal hemorrhage occurred in 9 of 891 prasugrel recipients aged 75 or older compared with 1 of 894 clopidogrel recipients in that age group. The rate of intracranial hemorrhage was 7 (0.8%) in the prasugrel group and 3 (0.3%) in the clopidogrel recipients in that same age group.² When body weight was considered regardless of age, however, there was no clear clinical benefit from using prasugrel versus clopidogrel in patients who had a body weight less than 60 kg. Both the elderly and low-body-weight patients tended to have fewer primary end point events with prasugrel versus clopidogrel, but that benefit was offset by a greater rate of major bleeding resulting in a neutral net clinical benefit.¹⁰  

CLINICAL BOTTOM LINE 

Efficacy and safety are always important when developing a treatment plan for a patient. The evidence indicates that prasugrel is an effective antiplatelet alternative to clopidogrel when used with ASA. In cases where a patient has recurrent stenosis of a stent or new lesion while taking clopidogrel, it would be beneficial to prescribe prasugrel. In addition, patients at especially high cardiovascular risk, with multiple risk factors such as a family history of heart disease or diabetes, should also be considered candidates for prasugrel as a first-line antiplatelet agent after MI and percutaneous cardiac intervention. Prasugrel is not advised for patients with a history of stroke or who are 75 years or older or have low body weight because of a high incidence of bleeding events. Further studies are underway to evaluate use of prasugrel in these populations. 

The risks and benefits of using prasugrel should be evaluated on a case-by-case basis. When there are no major contraindications, prasugrel can be considered because of its increased rates of effectiveness over clopidogrel. JAAPA

Catherine Lange practices in cardiology at Mount Sinai Multispecialty Physicians, Queens, New York. The author has indicated no relationships to disclose relating to the content of this article.

Mark E. Archambault, MHS, PA-C,  department editor  

REFERENCES 

1. Plosker GL, Lyseng-Williamson K. Clopidogrel: a review of its use in the prevention of thrombosis. Drugs. 2007;67(4): 613-646. 

2. Spinler SA, Rees C. Review of prasugrel for the secondary prevention of atherothrombosis. J Managed Care Pharm. 2009;15(5):383-395.  

3. Lee JM, Park S, Shin DJ, et al. Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans. Am J Cardiol. 2009;104(1):46-51. 

4. Wiviott S, Trenk D, Frelinger A, et al. Prasugrel compared with high loading and maintenance dose clopidogrel in patients with planned percutaneous coronary intervention; The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 Trial. Circulation. 2007;116(25): 2923-2932. 

5. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. European Heart J. 2008;29(1):21-30. 

6. The Medical Letter on Drugs and Therapeutics. September 7, 2009;51(1320). 

7. Buonamici P, Marcucci R, Migliorini A, et al. Impact of platelet reactivity after clopidogrel administration on  drug-eluting stent thrombosis. J Am Coll Cardiol. 2007; 48(24):2312-2317. 

8. Antem EM, Wiviott SD, Murphy SA, et al. Early and late benefits of prasugrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a TRITON-TIMI 38 analysis. J Am Coll Cardiol. 2008;51(21):2028-2033. 

9. US Food and Drug Administration. Cardiovascular and Renal Drug Advisory Committee briefing document: Questions, prasugrel for ACS. February 3, 2009. http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4412b1-01-FDA.pdf. Accessed January 3, 2011. 

10. Wiviott S, Braunwald E, McCabe C, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes.  N Engl J Med. 2007;357(20):2001-2015. 

From the February 2011 Issue of JAAPA