ESC: ABCB1 genotype increases CV risk with clopidogrel, but not prasugrel

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Patients with acute coronary syndrome who underwent PCI and carry both the ABCB1 and CYPC2C19 genotypes are at an increased risk for cardiovascular death, MI and stroke. However, ABCB1 genotypes seem to be independent of clinical outcomes when patients are treated with prasugrel, but increased risk when patients are treated with clopidogrel, according to the results of a substudy of the TRITON-TIMI 38 trial presented this week at the European Society of Cardiology (ESC) meeting in Stockholm, and simultaneously published in the Lancet.

For patients presenting with acute coronary syndromes undergoing PCI with stenting, dual-antiplatelet treatment of aspirin and clopidogrel is often the standard of care; however, the responses to clopidogrel vary in patients as some cannot  metabolize the drug due to the CYPC2C19 allele.

“[A] key protein involved in thienopyridine absorption is the efflux pump P-glycoprotein, which is encoded by ABCB1,” the authors wrote.

Because prasugrel (Effient, Daiichi-Sankyo/Eli Lilly), a thienopyridine, can achieve platelet inhibition in patients, Jessica L. Mega, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues set out to assess the effect of ABCB1 polymorphisms (3435C->T) on CV outcomes in patients treated with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) or prasugrel.

To do so, the researchers used previous data from the TRITON-TIMI 38 trial and identified 2,932 patients for genotyping who were treated with either a 300 mg loading dose of clopidogrel followed by 75 mg daily (1,471 patients) or a 60 mg loading dose of prasugrel followed by 10 mg daily (1,461 patients).

The mean follow-up of the study was 15 months and the researchers assessed primary endpoints of cardiovascular death, MI and stroke. The researchers also evaluated definite or probable rates of stent thrombosis.

Patients had an average age of 60.2 years, 28 percent of the study population were woman and 30 percent presented with STEMI.

Researchers screened patients for the 3435C->T variants and classified them as being either homozygous for the C allele (CC), heterozygous (CT) or homozygous for the T allele (TT). For the ABCB1 3435C->T gene, 27 percent of patients were classified as TT homozygotes, 50 percent were CT heterozygotes and 23 percent were CC homozygotes.

Mega and colleagues also assessed the combination of the genetic variants CYP2C19 and ABCB1 3435C->T and separated patients into two groups: those who had at least one reduced-function allele or no reduced function alleles.

Within the arm of patients who were treated with clopidogrel, the researchers found that instances of the 3435C->T genotype were significantly associated with risk of CV death, MI and stroke. Additionally, the researchers found that those patients classified as TT homoygotes had a 72 percent increased risk compared to those who were CT/CC patients.

Among the 3435 TT versus CT/CC patients, the researchers reported CV death as 1.63, non-fatal MI at 1.82 and stroke as 1.66.

Mega et al found that rates of stent thrombosis were the same for 3435 TT and CT/CC patients—1.3 percent.

“In a model containing both ABCB1 3435C?T genotype and CYP2C19 reduced-function allele carrier status in patients in the TRITON–TIMI 38 genetic substudy treated with clopidogrel, both variants were significant independent predictors of cardiovascular death, MI or stroke,” the authors wrote.

After the researchers split patients into four groups based on ABCB1 3435C->T genotype and CYP2C19 status, 53 percent of the 1,453 patients genotyped who did not carry at-risk genotypes in either gene saw lower rates of CV death, stroke and MI.

Of the patients who were carriers of CYP2C19, ABCB1 3435 TT homozygotes, or both, 47 percent of the 1,454 patients genotyped with reduced-function alleles, event rates were higher compared to patients without these reduced-function alleles.

According to the researchers, at 30 days, patients who did not carry either of the at-risk gene variants were at low risk, but patients who carried either the ABCB1 3435 TT homozygotes or CYP2C19 reduced-function alleles were at immediate risk. Additionally, those who carried both CYP2C19 reduced-function allele and ABCB1 3435 TT homozygotes were classified as high risk.

“There was no significant association between ABCB1 3435C->T genotype and risk of cardiovascular death, MI or stroke among patients in the TRITON-TIMI 38 genetic substudy who had been allocated to prasugrel,” the authors wrote.

In addition, Mega and colleagues found that for healthy patients treated with clopidogrel, ABCB1 3435 TT homozygotes had “a diminished pharmacodynamic effect,” and saw a reduction in platelet aggregation to a loading dose of clopidogrel that was 7.3 percentage points lower. However, after adjusting for the CYP2C19 genotype, these percentage points were 6.6 percent lower.

“There was no significant association between 3435C->T genotype and exposure to clopidogrel active metabolite concentrations,” the authors wrote. “In prasugrel-treated individuals, 3435C->T genotype was not significantly associated with platelet response or exposure to prasugrel’s active metabolite.”

"In conclusion, we found that ABCB1 3435 TT homozygotes had an increased risk of adverse CV outcomes during treatment with clopidogrel after an acute coronary syndrome and PCI.

“Thus, the association between ABCB1 polymorphisms and ischemic risk in patients treated with clopidogrel has been noted now in several pharmacological and clinical outcomes studies. As clinicians, professional societies and patients integrate information about genetic factors affecting the response to thienopyridines, the roles of both ABCB1 and CYP2C19 should be considered.”

In an accompanying Lancet editorial, Betti Giusti, MD, and Rosanna Abbate, MD, from the University of Florence-Careggi Hospital in Florence, Italy, suggested that the most “interesting” result of this trial was the fact that the ABCB1 polymorphism was an independent predictor of outcomes in patients undergoing PCI.

“The temptation to find the easier way by choosing the ‘superior’ drug on the basis of large trials in which participants with different risk profiles venture to be considered equal is not desirable,” wrote Giusti and Abbate.

“The issue is not to choose the lesser of the evils, but the better of the goods—by identifying the therapeutic strategy that, in consideration of individual’s characteristics, warrants the higher benefit/risk ratio.”

In addition, the authors suggested that the best evaluation should also take into account clinical determinants of platelet reactivity such as age, sex, body mass index and diabetes.

“Prospective studies evaluating different antiplatelet treatments tailored to individual characteristics of patients—genetic profile, residual platelet reactivity, drug–drug interactions, and traditional and procedural risk factors—are urgently needed to identify therapeutic strategies that will provide the best benefit for the single patient in this high-risk clinical setting,” the authors concluded.