Among patients who underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and who received dual antiplatelet therapy (DAPT) of aspirin and clopidogrel, high platelet reactivity was associated with all-cause mortality and other adverse events at both 1 and 5 years compared to low platelet reactivity, new study results show.

Seung-Jun Lee, MD, of Severance Cardiovascular Hospital, Jung-Joon Cha, MD, of Korea University Anam Hospital, Korea University College of Medicine, both in Seoul, South Korea, and colleagues, reported these findings from a real-world South Korean registry in a manuscript published Monday online and in the Nov. 28 issue of JACC: Cardiovascular Interventions.

The long-term implications of platelet reactivity after PCI are not clear, the authors wrote. PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated patients with coronary artery disease) is a multicenter, real-world registry of patients who underwent PCI with DES and received DAPT of aspirin and clopidogrel in South Korea.

The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), including all-cause death, myocardial infarction (MI), stent thrombosis or stroke. Key secondary endpoints were all-cause mortality, major bleeding and net adverse cardiac events (NACE), including MACCE and major bleeding.

Study results

The registry enrolled 11,714 patients between 2003 and 2018 and grouped them into tertiles according to P2Y12 reaction units (PRUs): high (≥253), intermediate (188-252) and low (<188). PRUs were measured using the VerifyNow assay.

At baseline, patients with high PRUs were older (high: 67.1 ± 10.3 years, intermediate: 64.4 ± 10.7, low: 61.7 ± 11.0; p<0.001) and more likely to be female (high: 43.9%, intermediate: 30.2%, low: 22.3%; p<0.001) and have cardiovascular comorbidities, including hypertension (high: 64.8%, intermediate: 60.5%, low: 55.3%; p<0.001), diabetes (high: 38.5%, intermediate: 35.2%, low: 30.2%; p<0.001) and chronic kidney disease (high: 27.0%, intermediate: 11.5%, low: 16.2%; p<0.001). Patients with low PRUs were more likely to be current smokers (high: 21.3%, intermediate 19.1%, low: 34.5%; p<0.001). There was also a significant difference among the groups in the percentage who presented with acute MI (high: 29.5%, intermediate: 26.0%, low: 30%; p<0.001).

The Kaplan-Meier estimate of the primary outcome was significantly higher in the high-PRU group at both 1 year (high: 4.1%, intermediate: 2.8%, low: 1.8%; p<0.001) and 5 years (high: 12.9%, intermediate: 11.1%, low: 7.0%; p<0.001).

This was also true for the key secondary outcomes of all-cause mortality and NACE, but major bleeding was similar among the three groups, both at 1 and 5 years.

Additionally, the authors said that the best PRU cutoff value, ≥252, had a strong correlation at 5 years to both MACCE (hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.11-1.74; P = 0.003) and all-cause death (HR: 1.42; 95% CI: 1.04-1.94; P = 0.026).

Finally, the authors wrote that the optimal cutoff value for aspirin reactivity, ≥414, was significantly associated with 5-year MACCE or all-cause death (p<0.001) for both.

Study limitations include that it was non-randomized and observational, meaning there might be selection bias the possibility of residual confounding even after multivariable adjustment or propensity-score matching, that selection bias in patients with acute coronary syndrome because patients using P2Y12 inhibitors other than clopidogrel were excluded.

The authors wrote that randomized controlled trials aiming to optimize antiplatelet treatment strategy by considering individual patients’ ischemic and bleeding risks according to platelet reactivity should be conducted.

Differences between East Asian, Western patients

In an accompanying editorial, Gregg W. Stone, MD, and Anton Camaj, MD, MS, of the Icahn School of Medicine at Mount Sinai, New York, said the PTRG-DES results should be interpreted in the context of the ADAPT-DES (Dual AntiPlatelet Therapy with Drug-Eluting Stents) study, which examined the relationships between VerifyNow PRU and aspirin reactivity and ischemic and bleeding outcomes at 1 and 2 years after PCI with DES in 8,582 consecutively treated all-comer US and Western European patients.

ADAPT-DES showed that the mean PRU in these Western patients was lower than that of the East Asian patients in PTRG-DES, as expected, but that MI and stent thrombosis rates were lower in the PTRG-DES patients than in the ADAPT-DES patients. Both studies reported a strong multivariable association between high PRU and risk of stent thrombosis and MI, but ADAPT-DES, unlike PTRG-DES, showed a higher risk of clinically relevant bleeding in high-PRU patients. The editorialists wrote that femoral access was used in nearly all ADAPT-DES patients, and the higher bleeding risk was driven by in-hospital groin hematomas and out-of-hospital arterial access-site bleeds, while PTRG-DES did not report that rate of radial access. However, Stone and Camaj wrote, radial access “is likely to have been substantially higher than in ADAPT-DES, which would reduce access-site related bleeding.”

Another difference between the two studies is that ADAPT-DES did not show an association between high platelet reactivity on clopidogrel and all-cause mortality. And a third difference was that aspirin reactivity was not associated with ischemic outcomes in ADAPT-DES but was associated with both MACCE and mortality, but not bleeding, in PTRG-DES.

The editorialists wrote that PTRG-DES shows that the so-called “East Asian paradox,” in which East Asian patients have a higher prevalence of loss-of-function CYP2C19*2 and *3 alleles than Western patients, leading to higher rates of high on-platelet reactivity and ischemic risk, yet a lower risk of thrombotic risk after PCI, “is alive and well and implies that different DAPT utilization approaches may be necessary for patients of different ancestries.”

They added that whether routine platelet function testing (PFT) at single or multiple time points to guide DAPT is superior to clinically driven DAPT protocol with less precise characterization of ischemic and bleeding risk profiles has not been proven, “although we can conclude that based on the differences between the PTRG-DES and ADAPT-DES studies these approaches are likely to be population-specific.”

“Finally,” the editorialists concluded, “whether even greater precision can be attained with genetic testing as either a standalone point-of-care assessment or in concert with PFT measurements to guide pharmacotherapy decisions deserves further investigation.”

Sources:

Lee S-J, Cha J-J, Jeong Y-H, et al. Platelet Reactivity and Clinical Outcomes After Drug-Eluting Stent Implantation: Results From the PTRG-DES Consortium. JACC Cardiovasc Interv. 2022;15:2253–2265.

Stone GW, Camaj A. Platelet Reactivity Testing: East Meets West. JACC Cardiovasc Interv. 2022;15:2266–2269.

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