The role of platelet function monitoring during thienopyridine/P2Y12 therapy
Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor, such as clopidogrel, is indicated for up to 1 year in patients with ACS and those undergoing PCI with stent implantation.
Approximately 20% to 34% of patients respond poorly to clopidogrel, exhibiting high on-treatment platelet reactivity (HTPR). Although current American College of Cardiology Foundation/American Heart Association guidelines for PCI discourage routine use of platelet function testing, several studies have associated HTPR with thrombotic events after PCI.
Consequently, intensification of antiplatelet therapy in patients with HTPR guided by available point-of-care assays seems intuitive. However, recent studies have shown no benefit using this approach and question the need for platelet function testing altogether.
The PCI guideline recommendations stem from the GRAVITAS study, a multicenter, double blind, active-control trial that evaluated the effect of high- and standard-dose clopidogrel in patients with stable CAD who had HTPR and were undergoing elective PCI with a drug-eluting stent. Patients received standard clopidogrel therapy periprocedurally then underwent platelet-function testing (VerifyNow) within 24 hours after PCI. Those with HTPR (platelet reaction units >230) were randomly assigned standard clopidogrel maintenance doses (75 mg daily; n=1,105) or another 600-mg loading dose and a higher maintenance dose of 150 mg daily (n=1,109).
Although the rate of HTPR was 22% lower in the high-dose clopidogrel group, the primary composite endpoint of CV death, nonfatal MI and stent thrombosis was identical in both clopidogrel groups at 6 months (2.3%; HR=1.01; 95% CI, 0.58-1.76). However, in a post-hoc observational analysis, an on-treatment P2Y12 reaction units (PRU) <208 was significantly associated with lower risk for the primary endpoint at 60 days (HR=0.18; 95% CI, 0.04-0.79) and at 6 months (HR=0.43; 95% CI, 0.23-0.82), and prompted additional research.
The TRIGGER-PCI study evaluated the antiplatelet effects of prasugrel (Effient, Daiichi Sankyo/Eli Lilly) vs. clopidogrel in 423 patients with stable CAD undergoing elective PCI with a DES. All patients had HTPR, using the “new” definition of PRU >208. After a 600-mg loading dose and 75-mg maintenance dose of clopidogrel, patients with HTPR were randomly assigned prasugrel (60-mg loading dose, 10 mg daily) or continued clopidogrel (75 mg daily).
At 3 months, patients assigned prasugrel had a nearly 70% reduction in PRU to 80, whereas patients assigned clopidogrel had minimal change in PRU (241; P<.001 vs. prasugrel). However, the significantly lower median PRU with prasugrel did not correlate with improved clinical outcomes. In fact, the TRIGGER-PCI study was terminated early due to low event rates among the initial 236 patients (only one major adverse cardiac event had occurred).
The ARCTIC study included 2,440 PCI patients who were randomly assigned to DAPT, using an open-label design, guided by platelet-function monitoring (n=1,213) or to conventional clopidogrel therapy without monitoring (n=1,227). Various strategies were employed to overcome HTPR, including administration of an additional bolus of IV aspirin; use of a glycoprotein IIb/IIIa inhibitor; additional clopidogrel or prasugrel loading doses followed by either high-dose clopidogrel (150 mg daily) or prasugrel 10 mg daily; and either switching to prasugrel or increasing the clopidogrel maintenance dose if HTPR persisted 14 to 30 days after stent implantation.
As in previous studies, no significant differences were observed in the composite endpoint of death from any cause, MI, stroke or transient ischemic attack, urgent coronary revascularization and stent thrombosis between patients in the conventional and monitoring groups, respectively (31.1% vs. 34.6%; HR=1.13, CI, 0.98-1.29).
MADONNA was a prospective, nonrandomized, open-label study evaluating “guided” vs. “non-guided” therapy in 798 PCI patients. Patients in the non-guided group received a single clopidogrel loading dose (600 mg) while the guided group received additional loading doses and/or were switched to prasugrel based on platelet-function testing using multiple electrode aggregometry. Unlike the PCI trials discussed above, the guided cohort in MADONNA had a significantly lower rate of probable and definite stent thrombosis compared with the non-guided group (0.2% vs. 1.9%; P=.027). Additionally, the guided group had significantly fewer acute ACS (0% vs. 2.5%; P<.001), but there were no differences in cardiac death and TIMI major bleeding.
The only large-scale evaluation of platelet function testing in ACS was conducted as a substudy of TRILOGY-ACS, a multicenter, double blind trial of medically managed ACS patients randomly assigned to DAPT with aspirin and clopidogrel or prasugrel. The platelet-function substudy included 2,564 patients, in whom researchers investigated the relationship between platelet function and adverse cardiac events. As expected, prasugrel achieved lower PRU than clopidogrel. Predefined cut points of PRU <230 and <208 were both significantly associated with the primary composite endpoint of CV death, MI or stroke, as well as all-cause mortality. However, these associations were no longer significant after multivariate adjustment (adjusted HR for primary composite endpoint=1.03; 95% CI, 0.96-1.11; adjusted HR for all-cause mortality=0.99; 95% CI, 0.90-1.08).
Although HTPR has been considered a modifiable risk factor for adverse cardiac events after PCI and ACS, currently available evidence from well-designed large, prospective studies suggests that intensification of DAPT in patients with stable CAD undergoing PCI guided by platelet function testing does not improve outcomes.
Studies have implemented various strategies to intensify antiplatelet therapy and overcome HTPR, including higher doses of clopidogrel or changing to prasugrel, none of which affected outcomes. Therefore, tailoring therapy according to platelet function testing does not appear warranted post-PCI, at this time.
The utility of platelet-function testing in ACS is less clear. Pharmacogenomics may offer an alternative to platelet-function testing to individualize DAPT in PCI and ACS patients. Clinical data suggest that carriers of the CYP2C19*2 loss of function allele have lower exposure to the active metabolite of clopidogrel and are at increased risk for major CV events. In fact, clopidogrel labeling recommends physicians “consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.”
The ideal method of personalizing DAPT remains unknown, but may ultimately include a combination of both genetic and platelet function testing.