ACCEL | Platelets are critical in the initiation, progression, and thrombotic complications of atherosclerosis. Clinical guidelines recommend dual antiplatelet therapy (DAPT) after an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI). That raises the important question: which one? Aspirin remains a cornerstone of therapy; clopidogrel, a thienopyridine, has been the primary P2Y12 inhibitor used over the last decade and is a key component of therapy for patients across the spectrum of coronary artery disease.

Take-aways Balancing benefit with risk is challenging in selecting appropriate antiplatelet therapy for patients following acute coronary syndrome (ACS). A number of recent studies, along with a government report, are offering some insights into how to select antiplatelet agents in the setting of ACS. We seem to be on the path to more tailored and effective antiplatelet therapy strategies, but until then there are good options in specific situations and populations.

Newer, more potent antiplatelet agents such as prasugrel (a third-generation thienopyridine) and ticagrelor (a nonthienopyridine P2Y12 inhibitor) both achieve significantly higher levels of platelet inhibition and have demonstrated efficacy in reducing post-ACS ischemic events versus clopidogrel, but this effectiveness comes at the cost of more severe bleeding. Given the association between bleeding and increased mortality, balancing the efficacy and safety of new antiplatelet agents and multidrug antithrombotic regimens has taken on greater importance.

Who Gets What?
Not all patients respond uniformly to standard doses of clopidogrel, which could be due to a number of factors that might interfere with the formation of the active metabolite of clopidogrel, including clinical characteristics, drug-drug interactions, and polymorphisms in genes that encode metabolic enzymes and transporters, particularly CYP2C19.

Jessica L. Mega, MD, MPH, and colleagues have previously reported that among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers.¹

In contrast, for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition. Other studies, too, have suggested that high on-treatment platelet reactivity due to genetic variants in CYP2C19 can be overcome in many patients with genetic variants of CYP2C19 by altering the loading doses of clopidogrel. However, no one knows whether this strategy is practical, clinically efficacious, tolerable for many patients, or cost effective.

Moreover, in patients with ACS the greatest risk period is early, after presentation, so serial loading doses of a medication to achieve an effect over several days might leave a patient incompletely treated during the highest-risk period. Stephen D. Wiviott, MD, and Dr. Mega noted in a commentary in JACC that such a strategy might not be widely adopted into practice, given both the demonstrated benefits of early invasive therapy and concerns regarding hospital stay costs.²

Nailing Down the Specifics
Dr. Mega participated in a recent report on guided antithrombotic therapy from the National Heart, Lung and Blood Institute (NHLBI). The paper addresses attempts to balance therapy against risk in a number of specific settings. Treatment of patients with atrial fibrillation (AF), for example, who require DAPT after ACS and/or PCI is a common clinical dilemma.

Triple therapy after PCI with warfarin and DAPT is associated with a substantial risk of bleeding. Current treatment recommendations are based on expert consensus and follow the general principle of considering the anticipated risk of bleeding and the risk of stent thrombosis for a particular individual.³ One current approach in patients with AF and a stent is to give 1-3 months of triple therapy, followed by an anticoagulant plus an antiplatelet agent. Delineation of the appropriate role, timing, and duration of triple therapy in these patients is required, particularly with the factor Xa and direct thrombin inhibitors, for which clinical experience is limited.

Questions as to which patients ought to be on dual therapy with one antiplatelet agent and one anticoagulant or which patients should only be on anticoagulation for 12 months after a stent require further research. In patients with a history of noncardioembolic ischemic stroke, antiplatelet drugs are recommended for the prevention of recurrent ischemic stroke. The NHLBI paper noted that aspirin monotherapy, clopidogrel monotherapy, and the combination of aspirin and dipyridamole are recommended options for initial therapy.

Although combining aspirin and clopidogrel is contraindicated for routine secondary prevention of stroke, limited-duration combination therapy is indicated in patients with recent ACS and/or vascular stenting. There is a specific issue relating to aspirin and ticagrelor: maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided. Specifically, the package insert for ticagrelor recommends keeping daily maintenance doses of aspirin to 75-100 mg. (For both prasugrel and clopidogrel, the package insert notes maintenance daily aspirin can be from 100-350 mg.)

Some studies have suggested that statins and calcium channel blockers (CCBs) may attenuate the pharmacodynamic effects of clopidogrel. TRITONTIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38) enrolled 13,608 patients with ACS and planned PCI, randomizing them to clopidogrel or prasugrel. Use of a statin or CCB was left to the discretion of the treating physician. In analyzing the data, Dr. Mega and colleagues found that the use of statins or CCBs in this setting was not associated with an increased risk of cardiovascular events in clopidogrel-treated patients.⁴

Consistent results were observed whether the drugs were administered alone, together, or in combination with proton pump inhibitors. The NHLBI report also looked at whether platelet function testing should be used to guide therapy. At this time, the authors concluded, there are insufficient data to recommend platelet function testing to guide antiplatelet therapy in the clinical setting.

Impact of Smoking
Active smoking is known to enhance CYP1A2 activity, one of the isoenzymes responsible for thienopyridine bioactivity, which could significantly influence the antiplatelet efficacy of these drugs. Two retrospective analyses of large clinical trials indicated that clopidogrel might be more effective in active smokers. Some smaller studies focusing on platelet function testing reported an enhanced clopidogrel response in active smokers, which was thought to be caused by an increased metabolic activation of clopidogrel via induction of CYP1A2.

However, while one study suggested that smoking was associated with increased platelet reactivity in patients not treated with a thienopyridine but in those treated with clopidogrel, no association of smoking with platelet responsiveness was seen. Back to TRITON-TIMI 38 for some insights: Various platelet function results were analyzed from two large cohorts of patients undergoing coronary intervention after loading with clopidogrel 600 mg, a cohort of patients undergoing dose adaptation from 75 to 150 mg (according to response to clopidogrel), and a crossover trial comparing clopidogrel 150 mg with prasugrel 10 mg.⁵

In brief, Mega et al. found no significant association of smoking with platelet reactivity on clopidogrel for either unadjusted or adjusted analyses. The variables most consistently associated with on-clopidogrel platelet function were age, sex, diabetes, and body mass index. Nor was there any significant interaction of smoking status at presentation with the clinical efficacy of prasugrel versus clopidogrel (pint = 0.39).

Finally, previous studies have found that approximately 15% of saphenous vein grafts occlude during the first 3 months after coronary artery bypass grafting (CABG). Gao et al. have reported the results of their study randomizing 249 consecutive patients undergoing CABG to either aspirin or aspirin plus clopidogrel, started as soon as chest tube drainage was ≤30 cc/h.⁶ Three months post-operatively, subjects underwent 64-slice computed tomography angiography. A total of 8.4% of grafts were occluded in the clopidogrel group compared with 14.3% in the aspirin-only group, suggesting that aspirin plus clopidogrel is more effective for maintaining venous graft patency after CABG than aspirin alone.

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References

1. Mega JL, Hochholzer W, Frelinger AL 3rd, et al. JAMA. 2011;306:2221-8.
2. Wiviott SD, Mega JL. J Am Coll Cardiol. 2010;56:1637-8.
3. Fuster V, Bhatt DL, Califf RM, et al. Circulation. 2012;126:1645-1662.
4. Ojeifo O, Wiviott SD, Antman EM, et al. JACC Cardiovasc Interv. 2013;6:1275-81.
5. Hochholzer W, Trenk D, Mega JL, et al. Am Heart J. 2011;162:518-26.e5.
6. Gao G, Zheng Z, Pi Y, et al. J Am Coll Cardiol. 2010;56:1639-43.

To listen to an interview with Jessica L Mega, MD, about selecting antiplatelet agents in ACS, visit youtube.cswnews.org. The interview was conducted by Glenn A. Hirsch, MD.

Keywords: CardioSource WorldNews Interventions

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