Dual Antiplatelet Therapy in ACS: How to Choose the Best Drug and for Whom?
Dual antiplatelet therapy (DAPT) remains a cornerstone of the current treatment of atherothrombotic disease and is recommended in the ACC/AHA guidelines for one year in treatment of patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS).1 Currently, there are three oral P2Y12 antagonists to select from: clopidogrel, prasugrel, and ticagrelor. Given these options, how is a clinician to choose the best drug strategy?
Clopidogrel is the oldest of these agents and is well studied in ACS. In the CURE trial, non-ST segment elevation ACS patients receiving clopidogrel and aspirin had lower death, myocardial infarction (MI), and stroke compared to aspirin alone (11.4% vs. 9.3%; p < 0.001) at one year.2 This benefit was noted not only in patients who underwent PCI, but also in patients who were medically managed.
Similar results were seen in CLARITY-TIMI 28 and COMMIT for patients with a ST-segment elevation myocardial infarction (STEMI).3,4 Furthermore, less risk of subsequent ischemic events were noted in those receiving clopidogrel pre-treatment prior to bare-metal stent placement in the CREDO and PCI-CURE trials.5,6
Now that clopidogrel is generic, the low cost also makes it an attractive option in ACS.
Prasugrel is a newer P2Y12 antagonist that undergoes more efficient metabolism to its active metabolite than clopidogrel, with more rapid onset of action and greater potency.
Prasugrel was compared to clopidogrel in 13,608 ACS patients undergoing PCI in the TRITON TIMI 38 trial and was associated with lower major adverse cardiac events (MACE; 9.9% vs. 12.1%; p < 0.001).7 However, prasugrel was associated with more major bleeding (2.4% vs. 1.8%; p = 0.03).
Furthermore, patients over 75 years of age, body weight less than 60 pounds, and a history of stroke or transient ischemic attack were more likely to experience worse outcomes with prasugrel, prompting the US Food and Drug Administration (FDA) to issue a Boxed Warning. Despite this warning, 18.3% of 27,533 patients with these contraindications from the ACC's National Cardiovascular Data Registry's PINNACLE Registry® received prasugrel.8
The TRANSLATE-ACS trial tested the applicability of these findings in the clinical setting.9 This "real world" comparison of clopidogrel and prasugrel found that patients treated with prasugrel differed from those treated with clopidogrel: they were more likely male, younger, and more likely to have a STEMI. In the unadjusted analysis, the MACE rates were significantly higher with clopidogrel but there was no difference in the MACE rates in the adjusted model. Prasugrel was associated with a lower rate of stent thrombosis in both the adjusted and unadjusted analyses. Again, the greater efficacy came at the expense of more bleeding, as the major and moderate bleeding rates were higher with prasugrel in the adjusted analysis.
Ticagrelor is a direct acting P2Y12 antagonist that, unlike the other two agents, does not require metabolic activation.
Ticagrelor was studied in 18,624 patients in the PLATO trial, where it was shown to significantly reduce major cardiac events compared to clopidogrel (9.8% vs. 11.7%; p = 0.003).10 Interestingly, there was no higher bleeding with ticagrelor as defined in PLATO. However, when investigators used the same bleeding definition used in TRITON TIMI 38 (non-CABG TIMI major bleeding), they found a significant increase in bleeding compared to clopidogrel (2.8% vs. 2.2%; p = 0.03), which was numerically equal to the bleeding increase with prasugrel in TRITON.
A perplexing observation about the PLATO study was the so-called "North American anomaly," where patients randomized in the United States and Canada did not derive a benefit with ticagrelor but actually trended toward harm. While this may only be the play of chance, interactions with the higher aspirin dose have also been proposed as possible explanations of this finding. Thus, in the United States, ticagrelor is only approved with the lower aspirin dose.
Mixed Feelings About Mixed Findings?
Given these mixed findings with the novel agents, how is one to choose between antiplatelet agents? While there is no one single correct answer to this question, the optimal selection may relate to cost and clopidogrel metabolism.
Clopidogrel is a pro-drug that requires a two-step metabolism into its active metabolite.11 Patients with abnormalities in the CYP2C19 allele have reduced efficacy, higher on-treatment platelet reactivity (OTPR), and worse outcomes with clopidogrel.12
About 30% of the population has abnormalities in this CYP2C19 allele, and clopidogrel carries a black box warning of reduced efficacy in these patients. Interestingly, the genetic subgroup analysis of the TRITON TIMI 38 trial failed to demonstrate efficacy of prasugrel in patients with normal CYP2C19 alleles.13 In contrast, the magnitude of benefit of prasugrel was much greater in patients with abnormal CYP2C19 alleles (number needed to treat [NNT] = 16) than noted in the overall trial (NNT = 50). A similar trend was noted for ticagrelor in the genetic subgroup analysis of the PLATO trial.14
Because factors other than CYP2C19 status may also impact clopidogrel metabolism and efficacy, some cardiologists have advocated testing platelet function directly. Large prospective contemporary studies have shown that high OTPR with clopidogrel is associated with higher adjusted stent thrombosis and MI.15
In addition, registry analysis suggests patients with high OTPR treated with prasugrel have low event rates, comparable to patients without high OTPR treated with clopidogrel, suggesting that the more potent agent can negate the higher risk of high OTPR in these patients.16 While randomized trials have failed to demonstrate improved clinical outcomes using a tailored antiplatelet approach guided by platelet function testing, these trials have not enrolled the higher-risk ACS patients who would most likely benefit from such a strategy.17-19
Taken together, these trials suggest the benefits of prasugrel and ticagrelor may be primarily noted in patients with abnormal CYP2C19 alleles or high OTPR with clopidogrel. However, for the remaining 65-75% of the ACS population, clopidogrel may be as effective, safer, easier to use, and more cost-effective.
Indeed, tailored antiplatelet strategies based on genetic testing and platelet function testing are more cost-effective than universal clopidogrel, prasugrel, or ticagrelor strategies.20,21 The ongoing POPular trial is currently investigating a CYP2C19 tailored antiplatelet strategy in patients with STEMI and perhaps will better define the value of a tailored antiplatelet approach.
- Amsterdam EA, Wenger NK, Brindis RG, et al. J Am Coll Cardiol. 2014 September 23. [Epub ahead of print]
- Yusuf S, Zhao F, Mehta SR, et al. N Engl J Med. 2001;345:494-502.
- Sabatine MS, Cannon CP, Gibson CM, et al. N Engl J Med. 2005;352:1179-89.
- Chen ZM, Jiang LX, Chen YP, et al. Lancet. 2005;366:1607-21.
- Mehta SR, Yusuf S, Peters RJ, et al. Lancet. 2001;358:527-33.
- Steinhubl SR, Berger PB, Mann JT, 3rd, et al. JAMA. 2002;288:2411-20.
- Wiviott SD, Braunwald E, McCabe CH, et al. N Engl J Med. 2007;357:2001-15.
- Hira RS, Kennedy K, Jneid H, et al. J Am Coll Cardiol. 2014;63:2876-7.
- Wang T. Presented at Transcatheter Cardiovascular Therapeutics 2014. September 16, 2014, Washington, DC.
- Wallentin L, Becker RC, Budaj A, et al. N Engl J Med. 2009;361:1045-57.
- Herbert JM, Savi P. Semin Vasc Med. 2003;3:113-22.
- Mega JL, Simon T, Collet JP, et al. JAMA. 2010;304:1821-30.
- Sorich MJ, Vitry A, Ward MB, et al. J Thromb Haemost. 2010;8:1678-84.
- Wallentin L, James S, Storey RF, et al. Lancet. 2010;376:1320-8.
- Stone GW, Witzenbichler B, Weisz G, et al. Lancet. 2013;382:614-23.
- Aradi D, Tornyos A, Pinter T, et al. J Am Coll Cardiol. 2014;63:1061-70.
- Price MJ, Berger PB, Teirstein PS, et al. JAMA. 2011;305:1097-105.
- Trenk D, Stone GW, Gawaz M, et al. J Am Coll Cardiol. 2012;59:2159-64.
- Collet JP, Cuisset T, Range G, et al. N Engl J Med. 2012;367:2100-9.
- Lala A, Berger JS, Sharma G, et al. J Thromb Haemost. 2013;11:81-91.
- Coleman CI, Limone BL. Am J Cardiol. 2013;112:355-62.
- Michael McDaniel, MD, is director of the Cardiac Catheterization Laboratory at Grady Memorial Hospital, Emory University School of Medicine, in Atlanta, Georgia.
- Douglas C. Morris, MD, is medical director of Emory Clinic, in Atlanta, Georgia. Dr. Morris is also past Governor of the Georgia Chapter of the ACC.
- S. Tanveer Rab, MD, is an interventional cardiologist at Emory University School of Medicine in Atlanta, Georgia. Dr. Rab is also Councillor of the Georgia Chapter of the ACC and a member of the ACC's Interventional Council Leadership Committee.
Keywords: CardioSource WorldNews Interventions
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