Benefits and Drawbacks of Clopidogrel 600mg Double Loading Dose Versus Newer P2Y12 Receptor Blockers

Prolonged dual antiplatelet therapy With aspirin and clopidogrel is recommended for all patients undergoing percutaneous coronary intervention (PCI). Although oral aspirin works within minutes of administration, clopidogrel takes several days to achieve its maximal antiplatelet effect; therefore, a loading dose of clopidogrel is used to achieve earlier inhibition of the platelet P2Y12 receptor, with300mg achieving peak effect in 6 to 8 hours and 600mg achieving peak effect in 2 to 4 hours.¹

It has been well established that 20% to 30% of patients receiving clopidogrel have less platelet aggregation inhibition than expected with initial dosing. Compared with normal responders, these “low responders” produce less active metabolite to bind to the P2Y12 receptor when clopidogrel, a prodrug, is metabolized by the liver cytochrome P450 system. Genetic polymorphisms and drug-drug interactions explain some of the inter-individual variability in hepatic metabolism. The percentage of low responders decreases by 50% after several weeks of maintenance therapy (75mg daily) and is acutely reduced by using 600mg, instead of 300mg, as the loading dose. Attempts at further reducing the low-responder rate by using a 900mg loading dose have proven unsuccessful.

The PREPAIR study suggests that two sequential doses of clopidogrel 600mg separated by at least 15 hours is a more effective treatment strategy than preloading with300mg or acutely loading with600mg.² This strategy could be adopted when PCI is electively scheduled; however, many PCI procedures are emergent or ad hoc procedures, so this strategy would not be available to improve platelet inhibition in the periprocedural period for these patients. Nevertheless, it could reduce the number of low responders in the first days after PCI and is a more clinically attractive strategy than measuring clopidogrel response daily with a flow cytometer and dosing with600mg until the platelet inhibition target is achieved.³ In the future, point-of-care measurement devices may allow identification of early nonresponders, making targeted therapy clinically possible.

A more likely strategy is that one of the newer P2Y12 receptor blockers will replace clopidogrel for PCI. Prasugrel achieves platelet inhibition within 1 hour and has almost no low responders. Compared with clopidogrel in the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel—Thrombolysis in Myocardial Infarction 38) trial, which enrolled patients with acute coronary syndromes undergoing PCI,⁴ prasugrel reduced the composite end point of cardiovascular death, myocardial infarction, or stroke by 19%, the subacute stent thrombosis rate from 2.4% to 1.1%, and the composite end point in the diabetic subgroup from 17% to 12.2%. Ticagrelor is a competitive P2Y12 receptor blocker, similarly without low responders, that is reversible and offers the opportunity for therapy before angiography without risking a prolonged hospital stay for recovery of platelet function if coronary artery bypass graft surgery is required. Cangrelor is an intravenous P2Y12 receptor blocker that has rapid onset and offset and could be used for acute treatment in the interventional cardiology laboratory. Nevertheless, with generic clopidogrel available in 2 years, new clopidogrel loading strategies that minimize the rate of low responders could make clopidogrel an attractive treatment option to the newer agents for many patients undergoing PCI.

References:

1. Müller I, Seyfarth M, Rüdiger S, et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart. 2001;85(1):92-93.

2. L’Allier P, Ducrocq G, Pranno N, et al; PREPAIR Study Investigators. Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: results from the PREPAIR randomized study. J Am Coll Cardiol. 2008;51(11):1066-1072.

3. Bonello L, Camoin-Jau L, Armero S, et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol. 2009;103(1):5-10.

4. Wiviott S, Braunwald E, Mc-Cabe C, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.