Moderately Inhibited P2Y₁₂ Reaction Units May Be Key to Optimal Therapeutic Window of Antiplatelet Effect

An increase in P2Y₁₂ reaction units (PRU) was associated with a monotonic increase in stent thrombosis (ST), while the lowest PRU quintile was associated with more bleeding risks. The findings pointed to a possible “optimal therapeutic window of platelet inhibition,” according to an observational study of the ADAPT-DES (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents) trial.

Researchers sought to determine whether an ideal level of platelet reactivity (PR) exists to optimize safety and efficacy.

In the original ADAPT-DES study, platetlet function testing was conducted following clopidogrel loading after implantation of drug-eluting stent (DES). The primary end point was determined as definite or probable ST.

In the present study, the mean PRU was 188 ± 97 and after categorized into quintiles from lowest to highest PRU (most to least inhibited), the PRU cutoff values defined quintiles as <95, 95 to 159, 160 to 215, 216 to 275, and >275, and the median PRUs were 57, 130, 187, 244, and 317, respectively. Those with higher PRU were older, more likely to be female, and have higher BMIs. Diabetes, hypertension, congestive heart failure, previous revascularization, and renal insufficiency were more prevalent in these patients. Platelet counts were highest in patients with the lowest PRU, but these patients also experienced the highest rate of clinically relevant bleeding (11.2%).

Across all quintiles of PRU, there was a monotonic increase in definite or probable ST incidence from 0.7% to 1.8% (P=.025). The 2 highest PRU quintiles experienced greater increases of myocardial infarction incidences. The all-cause mortality monotonically increased in the higher PRU quintiles, with the highest rate in the highest quintile (P=.006).

Higher PRU remained independently associated with 2-year definite or probable ST, with a stepwise reduction in ST risk from the fifth quintile (Q5) to the first quintile (Q1) (hazard ratio [HR] in Q5 vs Q1 as referent: 2.32; 95% confidence interval [CI]: 1.17-4.59; P=.02).

“The present findings of an increasing and independent association between greater levels of PRU and ST within ADAPT-DES study demonstrate the potential utility of PRU as a risk factor for adverse ischemic events after DES,” the researchers wrote. “…however, a relationship between increasing PRU and mortality was observed only in unadjusted analyses and not after multivariable adjustment for differences in baseline and procedural characteristics between patients with high vs low PR.”

Researchers offered 2 possible explanations for this disconnect: a lack of power and the “offsetting effects of bleeding and ischemia.” Because there were nearly 8500 patients in the study, but no trend toward increased hazard of mortality, other influences may be at work (eg, comorbidities such as diabetes, acute coronary syndrome, and more widespread atherosclerosis).

Regarding the offsetting effects of bleeding and ischemia, “present and previous studies have now clearly documented an association between profound inhibition of PRU and bleeding events, which in numerous studies have also been found to strongly correlate with subsequent mortality,” researchers observed.

“Whether personalizing antiplatelet effects to balance the offsetting risk of ischemic and bleeding events can optimize overall outcomes for PCI patients remains to be shown prospectively, but there has been a renewed interest in this approach with the more widespread availability of more potent oral antiplatelet therapies, particularly in the context of the increasing complexity of current day PCI.”

Reference

Kirtane AJ, Parikh PB, Stuckey TD, et al. Is there an ideal level of platelet P2Y₁₂-receptor inhibition in patients undergoing percutaneous coronary intervention? “Window” analysis from the ADAPT-DES study. JACC Cardiovasc Interv. 2015;8(15):1978-1987.