The GRAVITAS (Gauging Responsiveness with A VerifyNow assay–Impact on Thrombosis And Safety) study has demonstrated the detrimental impact of high on-treatment platelet reactivity following stent implantation and the failure of a double clopidogrel maintenance dose to reduce cardiovascular events in patients deemed clopidogrel non-responders ( Fig. 1 ) . However, there was still evidence after the GRAVITAS study to support personalized medicine-based on platelet reactivity. The combination of a low-risk population together with platelet reactivity assessment after percutaneous coronary intervention (PCI) was recognized as a relevant limitation that may have accounted for the negative results of the GRAVITAS study.
The TRIGGER-PCI (Testing Platelet Reactivity in Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy with Prasugrel) study design was similar to that of the GRAVITAS study, but treatment intervention was more aggressive, using prasugrel instead of an increased clopidogrel maintenance dose ( Fig. 1 ). The study was stopped prematurely due to a low event rate .
Platelet reactivity has been consistently reported as an independent predictor of ‘hard’ post-PCI endpoints, including stent thrombosis, myocardial infarction and cardiovascular mortality ( Fig. 2 ) . Notably, the hazard associated with high platelet reactivity is greater in patients with an acute coronary syndrome (ACS) than in patients undergoing PCI for stable angina; it accounts for approximately 60% of the definite/probable stent thrombosis events, demonstrating the dominant contribution that inadequate P2Y 12 receptor inhibition makes to thrombotic events . As a consequence, the bedside platelet function test has become an opportunity to guide antiplatelet therapy, particularly when there is an unexpected complication. This is also the case when new P2Y 12 inhibitors are not available, in the absence, however, of a recommendation for this type of use .
The ARCTIC (Assessment with a double Randomization of a fixed dose versus a monitoring-guided dose of aspirin and Clopidogrel after drug-eluting stent implantation and Treatment Interruption versus Continuation, 1 year after stenting) multicentre randomized study sought to determine whether a strategy based on systematic platelet function testing to tailor antiplatelet therapy is superior to standard care in 2440 patients with stable angina or non-ST-segment elevation ACS (NSTE-ACS) undergoing PCI . In contrast to the GRAVITAS trial, this study randomized the use of platelet function testing with treatment intervention (monitoring arm) versus standard of care according to clinician’s preference without platelet function test (conventional arm) ( Fig. 3 ). In the monitoring arm, serial platelet function tests (before stent implantation and during the maintenance phase) and treatment adjustments using a predefined treatment algorithm were performed. In addition to treatment intensification due to high on-treatment platelet reactivity, patients could be switched back from prasugrel to clopidogrel after PCI if low on-treatment platelet reactivity was measured. Despite halving the rate of high platelet reactivity to adenosine diphosphate ( Fig. 4 ), the primary endpoint of death, myocardial infarction, stent thrombosis, stroke or urgent revascularization was similar after 1 year with the two strategies (hazard ratio [HR] 1.13, 95% confidence interval [CI] 0.98–1.29; p = 0.10).
The take-home message is that platelet reactivity is not only a measure of drug response, but also integrates the effect of response to P2Y 12 receptor antagonists and comorbidities, such as advanced age, diabetes and renal insufficiency. Platelet reactivity should also be considered as a surrogate marker for studies on antiplatelet treatments that may be helpful to explain the results of trials. This has been confirmed by the prespecified pharmacodynamic TRILOGY-ACS (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects with Unstable Angina/Non-ST-Elevation Myocardial Infarction Who Are Medically Managed) study, which demonstrated a real effect of treatment intensification but a lack of independent relationship between platelet reactivity and clinical outcome . Such results further support the lack of benefit of intensification of antiplatelet therapy in medically managed patients ( Fig. 5 ).
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