Measuring Platelet Reactivity after Clopidogrel-Has it Reached the End of the Road?

Abstract

Clopidogrel is traditionally prescribed at 75 mg daily after a 300 mg loading dose. It is a pro-drug, with a two-step activation process involving a series of cytochrome P-450 (CYP) isoenzymes. Its antiplatelet effect is variable and susceptible to genetic polymorphisms. In particular, patients with either 1 or 2 loss-of-function CYP2C19 alleles have an attenuated pharmacologic response and worse clinical outcomes with standard dose clopidogrel [1]. Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had higher risk of cardiovascular death, myocardial infarction, or stroke as compared with non-carriers (12.1% vs. 8.0%; P=0.01) and higher risk of stent thrombosis (2.6% vs. 0.8%; p=0.02) [1]. Also, the common polymorphisms in the CYP2C19 gene, seen in approximately 30% of whites, may be more common in other ethnic groups -40% of blacks and >55% of East Asians [2].To achieve higher platelet inhibition, Prasugrel and Ticagrelor are newer P2Y 12 ADP receptor blockers that surpass clopidogrel in platelet inhibition [3,4]. Alternatively increasing clopidogrel dose may sometimes suffice. 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 non-carriers; for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition [5]. When is Intense P2Y 12 ADP Receptor Blockade Needed?The CURRENT OASIS-7 trial [6,7], undertaken in 597 centres in 39 countries, randomly assigned, in a 2×2 factorial design, 25086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600 mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300 mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). Aspirin dose had no effect on outcome.These findings illustrate that clopidogrel dosage and consequently the degree of platelet inhibition only matters in patients undergoing stenting but not in those managed medically. This conclusion echoes well with the recent findings from the TRILOGY ACS study [8] and its platelet function sub study [9] showing that both the use of prasugrel and the consequent stronger platelet inhibition as measured by the point-of care Verify Now P2Y 12 testing (Accumetrics, San Diego, California) have no independent relationship to outcome compared to the use of standard dose clopidogrel, in a cohort of medically managed patients.

Trials Evaluating Ticagrelor in Cardiovascular Disease: Will It Reign Supreme in the Anti-Platelet World?

“…Clopidogrel is a pro-drug requiring a 2-step hepatic activation processes. Speed of activation varies according to the cytochrome P-450 2C19 allele [1,2]. Ticagrelor is a direct non-thienopyridine P2Y12 antagonist producing equal or stronger inhibition of the P2Y12 receptor even when compared to the newer thienopyridine prasugrel [3].…”

From Arctic to Antarctic: Is There any Remaining Role for Platelet Function Testing to Tailor Therapy after Coronary Stent Implantation?

“…Relevant CYP isoenzymes involved in activating clopidogrel (and to a lesser extent prasugrel) may be affected by genetic polymorphisms which lead to different levels of their final active metabolites binding irreversibly to the platelet P2Y 12 receptors. For clopidogrel, patients with either 1 or 2 loss-of-function CYP2C19 alleles are known to have an attenuated pharmacologic response and worse clinical outcomes, with greater impairment in those who had both alleles affected [3].…”

“…The situation is different with the use of clopidogrel for which up to 40% of patients are somewhat resistant [4] with the occasional patients (often having 2 loss-of-function CYP2C19 alleles) actually having minimal platelet suppression and potentially unduly high risks of stent thrombosis. The latter situation should be remedied by switching clopidogrel to prasugrel or ticagrelor [3].…”

“…The cut-points for determining high PRU were obtained from observational studies [3]. The ADAPT-DES registry supported the use of the PRU cut-point of 208 on the VerifyNow P2Y 12 cartridge platelet function test [4].…”

“…An editorial in this journal commenting on ARCTIC questioned whether measuring platelet reactivity after clopidogrel could be reaching the end of the road [3], given that more efficacious antiplatelet medications such as prasugrel were becoming available. Indeed in ANTARCTIC, a "low" dose of prasugrel of 5 mg turned out to give sufficiently adequate platelet suppression in >96% of patients.…”