In the past decade, there has been compelling evidence from nonrandomized and randomized clinical trials demonstrating the relation of high on-treatment platelet reactivity (HPR) with adverse CV outcomes in stented patients treated with dual antiplatelet therapy (DAPT). After the initial demonstration of clopidogrel response variability by the "gold standard" platelet function testing (PFT) method—light transmittance aggregometry (LTA) to determine adenosine diphosphate (ADP)—induced platelet aggregation—this observation has been confirmed with other assays employing ADP as the agonist.^1,2,3 However, recent data underscore the need for HPR to be evaluated as a risk marker in the context of disease and predicted outcome. There are controversies about how well PFT predicts risk and whether risk can be modified by an adjustment of antiplatelet therapy based on the test result. The latter uncertainties have caused confusion about how and whether to implement PFT into clinical practice.

Platelet Function and Adverse CV Risk in PCI Patients
Numerous studies have demonstrated that HPR during clopidogrel treatment is associated with post-stenting ischemic event occurrence. Some studies have identified cut-off values by receiver-operator characteristic curve analysis to predict events.³

This association may be more robust for the occurrence of early events, like early stent thrombosis in PCI patients, and has biological plausibility.⁴ Platelets are activated by the PCI procedure. This process may be even more pronounced in patients who already present with various risk factors (e.g., patients with ACS, diabetes, renal failure, or prior CABG) and is only partially prevented by standard DAPT. Effective platelet inhibition has its most favorable result in the initial phase after coronary stent placement, and platelet function–guided antiplatelet treatment most likely plays a major role in this very early period. The role of HPR may be even more relevant in the phase of an acute coronary event.^1,3

In ACS, and STEMI in particular, the prevalence of HPR is more frequent, occurs despite more potent P2Y12 blockade, and is associated with greater short-term risk. In a time-dependent analysis of the GRAVITAS trial, platelet reactivity units (PRU) of ≥208 and ACS were independently associated with CV events at 60 days, but not at 6 months, favoring the concept of platelet reactivity for short-term risk prediction and, in particular, in the ACS patient.⁵ These findings are also underscored by the early benefits of enhanced platelet inhibition demonstrated in ACS patients undergoing PCI in the CURRENT-OASIS-7 and TRITON-TIMI 38 trials.

However, in the ADAPT-DES study, HPR defined as >208 PRU was significantly associated with 30-day, as well as 1-year, stent thrombosis occurrence.⁶ Similarly, in the 3T/2R study of 1,277 patients undergoing PCI, HPR measured by VerifyNow assay was strongly associated with both periprocedural and 1-year ischemic event occurrences.⁷ These studies highlight the strong relation of HPR to ischemic event occurrence in the PCI population.

High On-Treatment Platelet Reactivity in Medically-Managed ACS Patients
In the TRILOGY study, 9,326 patients with medically-managed unstable angina or NSTEMI were randomly assigned to treatment with either clopidogrel or prasugrel, and 27.5% were included in the platelet function substudy (prasugrel = 1,286; clopidogrel = 1,278).^8,9 In this study, the largest serial platelet function investigation ever conducted and the only one of significant size to inform clinical outcomes with a large-scale trial, prasugrel was consistently associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. However, there was no significant independent association between platelet reactivity and the occurrence of the primary ischemic endpoint.

The median time from presentation to randomization and start of study drug in TRILOGY was 4–5 days.¹⁰ Thus, it is tempting to speculate that the period of highest thrombotic risk, when the degree of platelet reactivity and the effects of a potent antiplatelet therapy to lower prevalence of HPR are of highest clinical impact, was missed. Additionally, TRILOGY enrolled a significant proportion of patients who did not have proven evidence of CAD, meaning it included a substantial proportion of patients in whom platelet reactivity may not influence outcomes. Furthermore, in the ADIRE study that enrolled 771 stable CV outpatients, platelet reactivity was not associated with 3-year major CV adverse events.¹¹

Personalized Antiplatelet Therapy Guided by PFT Recent randomized trials have investigated the role of antiplatelet therapy adjustment based on platelet function determined by the VerifyNow assay. The GRAVITAS trial randomized primarily stable, low-risk patients with HPR (≥230 PRU) to 75 mg daily (standard) or 150 mg daily (high clopidogrel dosing). The effects of high-dose clopidogrel were relatively modest (about 40% of the patients still had HPR). Therefore, the antiplatelet effects of high-dose clopidogrel was weak to influence clinical outcomes in an overall low risk population, as also demonstrated in the ELEVATE-TIMI 51 trial.^5,12

Further, the TRIGGER-PCI trial investigated the effects of a more potent active arm (prasugrel) compared to standard-dose clopidogrel in low-risk patients with HPR (>208 PRU) undergoing non-urgent PCI.¹³ This trial was prematurely terminated due to very low incidence of CV events.

Clinical Decision Making with PFT Results Recent American and European guidelines have included Class IIb recommendations to measure platelet function in high-risk patients if the results of testing may alter management.^15,16 However, current guidelines generally favor the use of new P2Y12 inhibitors for ACS and do not seem to leave space for platelet function monitoring and antiplatelet drug adjustment in these patients. Despite the lower on-treatment platelet reactivity during new P2Y12 inhibitor therapy, there is evidence that a relevant number of ACS patients still may have high-on-treatment platelet reactivity that is associated with increased MACE.¹⁷

Additionally, PFT might help to identify bleeding risk under chronic therapy with new antiplatelet agents and to adjust to less potent antiplatelet therapy to reduce bleeding events under long-term DAPT.¹⁸ Finally, the Society of Thoracic Surgeons gave a Class IIa recommendation that it is reasonable to make decisions about surgical delay based on tests of platelet inhibition, rather than arbitrary use of a specified period of surgical delay for patients on DAPT.¹⁹

The currently available data suggest that HPR is most predictive of event occurrence in high-risk PCI patients and some evidence suggests that short-term events are most closely related to HPR. In medically-managed ACS patients, disease-related clinical risk factors seem to play a more pronounced role than on-treatment platelet function. There is still a need to better define specific groups within this heterogeneous cohort of medically-managed ACS patients in which there is a clear pathophysiological rationale for platelet reactivity and cardiovascular outcomes (e.g., patients with proven CAD). Pre-selection of risk collectives for atherothrombotic events and choice of potent active arms will be crucial to further define the role of personalized antiplatelet therapy.

Despite the new guideline recommendations for use of new antiplatelet agents in ACS patients, platelet function testing may have a role to monitor: a) efficacy when clopidogrel is the chosen therapy, and b) safety of long-term use of new more potent drugs especially in low-risk patients and patients with high bleeding risk.

Finally, platelet reactivity should not be regarded as an absolute and sole prognostic marker but rather be evaluated in relation to patient risk, the timing of PCI and the presence of ACS. High on-treatment platelet reactivity has a high negative (~94%) but low positive predictive value. This means that you can well exclude high risk for atherothrombotic events in patients with low platelet reactivity but there are many patients with HPR without events. Therefore, additional risk estimation in these patients will be necessary. Future trials should evaluate the role of platelet function–guided approaches in pre-selected high risk patients with clearly defined platelet-associated outcomes and focus on the early phase after PCI. More differential approaches are warranted to use platelet function monitoring as a risk tool in combination with additional genetic and nongenetic risk factor stratification to predict short-term thrombotic and long-term bleeding risk.²⁰

References
1. Gurbel PA, Tantry US. Circulation. 2012;125:1276-1287.
2. Geisler T, et al. Eur Heart J. 2006;27:2420-5.
3. Bonello L, et al. J Am Coll Cardiol. 2010;56:919-33.
4. Geisler T, et al. Eur Heart J. 2010;31:59-66.
5. Price MJ, et al. Circulation. 2011;124:1132-7.
6. Stone GW, et al. Presented at: Transcatheter Cardiovascular Therapeutics 23rd and 24th Annual Scientific Symposium 2011 and 2012
7. Campo G, et al. J Am Coll Cardiol. 2010;56:1447-55.
8. Roe MT, et al. N Engl J Med. 2012 ;367:1297-309.
9. Gurbel PA, et al. JAMA. 2012;308:1785-94. 10. Wiviott SD, et al. Presented at the TCT 2012; October 24, 2012; Miami, FL.
11. Reny JL, et al. Circulation. 2012;125:3201-10.
12. Mega JL, et al. JAMA. 2011;306:2221-8.
13. Trenk D, et al. J Am Coll Cardiol. 2012;59:2159-64.
14. Collet JP, et al. N Engl J Med. 2012;367:2100-9.
15. Jneid H, et al. Circulation. 2012;126:875-910.
16. Hamm CW, et al. Eur Heart J. 2011;32:2999-3054.
17. Bonello L, et al. J Am Coll Cardiol. 2011;58:467-73.
18. Bonello L, et al. J Thromb Haemost. 2012;10:1999-2005.
19. Ferraris VA, et al. Ann Thorac Surg. 2012;94:1761–81
20. Geisler T, et al. J Thromb Haemost. 2008;6:54-61.

Tobias Geisler, MD, is associate professor at University Hospital of Tübingen, Germany. Paul A. Gurbel, MD, is director, and Udaya S. Tantry, PhD, is laboratory director at the Sinai Center for Thrombosis Research in Baltimore.

Keywords: Platelet Aggregation Inhibitors, Platelet Function Tests, Thiophenes, Ticlopidine, Piperazines, Blood Platelets, Risk Factors, Stents, Prevalence, Incidence, Renal Insufficiency, Thrombosis, Platelet Aggregation, United States, Diabetes Mellitus

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