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After percutaneous coronary intervention (PCI), African Americans are more likely than white patients to have high on-treatment platelet reactivity and worse short-term outcomes. The reactivity disadvantage is partly attributable to increased prevalence of a genetic variation affecting clopidogrel activation, but ‘race,’ which sums up a host of other genetic, clinical, and lifestyle factors, also plays an independent role.

The findings were published online May 28, 2013, ahead of print in the American Heart Journal.

Investigators led by Ron Waksman, MD, of MedStar Washington Hospital Center (Washington, DC), evaluated on-treatment platelet reactivity in 289 consecutive patients at their hospital who underwent elective or urgent PCI and were enrolled in a prospective registry. Platelet function was tested 6 to 24 hours after the procedure using the VerifyNow P2Y12 and aspirin assays (Accumetrics; San Diego, CA) as well as vasodilator-stimulated phosphoprotein  phosphorylation (VASP) analysis (FACSCalibur flow cytometer, BD Biosciences; San Jose, CA). Patients were also assessed for the presence of the CYP2C19*2 loss-of-function allele, which reduces the availability of the clopidogrel active metabolite.

Almost Half of African Americans Carry a Loss-of-Function Allele

Among African Americans, who constituted 21% of the study population (n = 61), 38% carried 1 CYP2C19*2 allele and 5% carried 2 such alleles, while among white patients (n = 228), 26% were heterozygous and 2% were homozygous with regard to the *2 allele. Because of the low prevalence of *2 alleles, the researchers dichotomized patients into *2 carriers vs. noncarriers, with African Americans more likely than white patients to be carriers (43% vs. 29%; P = 0.04). 

After clopidogrel loading, African Americans showed higher mean residual platelet reactivity compared with whites for both VerifyNow P2Y12 reaction units (PRU; 207 ± 110 vs. 160 ± 102; P = 0.002) and VASP platelet reactivity index (PRI; 49 ± 26 vs. 38 ± 26; P = 0.004). In addition, African Americans experienced higher rates of high on-treatment platelet reactivity using conventional cut-off points for both assays (table 1).

Table 1. High On-Treatment Platelet Reactivity by Race

On the other hand, mean VerifyNow aspirin response units (ARU) and rates of ARU ≥ 550 were similar between the races.

A gene-dose interaction was seen between platelet reactivity and *2 allele carrier status, with PRU values increasing along with the number of loss-of-function alleles in both African Americans (P < 0.03) and whites (P < 0.006).

In linear regression analysis, African American race and CYP2C19*2 status had independent effects on both the PRU value (P = 0.007 and P = 0.0003, respectively) and PRI (P = 0.008 and P = 0.02, respectively), with no interaction between the factors.

Gene, ‘Race’ Independent Predictors of High Reactivity

 Multivariate analysis identified correlates of high on-treatment platelet reactivity for PRU ≥ 208:

• African American race (OR 2.03; 95% CI 1.08-3.81)
• Carrier of CYP2C19*2 allele (OR 2.07; 95% CI 1.22-3.53)
• Age (OR  1.03; 95% CI 1.01-1.06)

and for VASP PRI > 50%:

• African American race (OR 2.25; 95% CI 1.18-4.26)
• Clopidogrel loading (OR 2.21; 95% CI 1.27-3.85)
• BMI (OR 1.05; 95% CI 1.01-1.10)

At 1-year follow-up, available for 67% of the overall cohort, African Americans had a fourfold higher rate of MACE, a composite of death, Q-wave MI, and TLR, compared with whites (12.5% vs. 3.2%; P = 0.03), driven by higher rates of revascularization (12.8% vs. 1.9%; P = 0.009) and MI (7.7% vs. 0.6%; P = 0.03). According to the authors, there were too few ischemic events attributable to platelet reactivity, such as MI and stent thrombosis, to perform a meaningful race- or gene-based analysis.

In a telephone interview with TCTMD, Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), called the study “provocative,” but he noted several aspects that warrant caution in interpreting the results. For example, he said, the frequency of CYP2C19*2 loss-of-function allele observed in African Americans is higher than has been previously reported and may be an anomaly due to small numbers in the registry.

Another source of uncertainty, he commented, is that the blood samples used to determine platelet reactivity were drawn over an 18-hour period following PCI, during which reactivity would be expected to decline. Thus, any discrepancy in the timing of sampling between whites and African Americans could potentially have skewed the findings regarding differences in platelet reactivity.

Perhaps more important, he said, the researchers failed to investigate whether African American and white patients were similarly compliant with their antiplatelet regimen. The question becomes all the more important in light of the large difference in MACE between the groups, he added.

Noting that the CYP2C19*2 genotype has been found to account for only 12% of the variability in clopidogrel response (Shuldiner AR, et al. JAMA 2009;302;849-857), the authors acknowledge that the “majority of factors, both genetic and nongenetic, influencing clopidogrel response remain unexplained.”

Dr. Gurbel also pointed to other biological contributors to adverse outcomes after stenting, citing an earlier study showing greater platelet-fibrin clot strength and thus higher thrombogenicity in African Americans, especially women (Gurbel PA, et al. Blood Coagulation and Fibrinolysis. 2008;19:268-275). 

A Case for Functional Platelet Testing?

The study once again questions the adequacy of a ‘one size fits all’ approach to antiplatelet therapy, Dr. Gurbel said. “These data suggest that if you give consecutive patients [the same dose of] clopidogrel, you’re going to have a lot of people with high on-treatment reactivity. We need to pay attention to the individual patient, and now we have African American race as another risk factor for poor response.

“We should be measuring to make sure [the antiplatelet regimen provides] an adequate pharmacodynamic effect,” Dr. Gurbel asserted, especially after a complex stent procedure. In particular, in ACS patients, “before they go home, we should make sure that their platelet function is [adequately] inhibited,” he added.

The authors conclude that “[i]n the face of rapidly changing pharmacotherapy for both acute and long-term PCI care, careful selection of antiplatelet agents should be considered in the [African American] population at higher risk of ischemic complications.”

Study Details

All patients received a 600-mg loading dose of clopidogrel at least 6 hours before, or a 75-mg maintenance dose for at least 5 days before, platelet reactivity testing. In addition, patients received 325 mg aspirin 6 to 24 hours before testing. After PCI, aspirin was prescribed indefinitely and clopidogrel for at least 1 month in patients receiving BMS for elective PCI and for 12 months in those receiving DES and in all ACS patients.  

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