ESC: Brilinta may best Plavix, eliminate need for genetic testing
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“In patients treated with clopidogrel (Bristol-Myers Squibb) after an ACS event or stenting, or both, the presence of any loss-of-function CYP2C19 allele (*2,*3,*4,*5,*6,*7 and *8) is associated with an increased risk of ischemic events and stent thrombosis, whereas the presence of any gain-of-function CYP2C19 allele (*17) is associated with a raised risk of bleeding,” the authors wrote.
In March, the FDA placed black box warnings on clopidogrel after learning that some patients may not be able to properly metabolize the drug.
While the authors wrote that ticagrelor (AstraZeneca) has been shown to provide a more “pronounced and consistent” platelet inhibition, “no genetic determinants of the ticagrelor response are known, although ticagrelor absorption might be affected by ABCB1 polymorphisms.”
To better understand the effects of the aforementioned genotypes on outcomes between those administered clopidogrel and those administered ticagrelor, Lars Wallentin, MD, PhD, from Uppsala University in Uppsala, Sweden, and colleagues used data from the PLATO (PLATelet inhibition and patient Outcomes) trial in which 10,285 patients were genetically assessed for CYP2C19 gain-of-function alleles and loss-of-function alleles, to evaluate rates of CV death, stroke and MI.
The PLATO trial assessed the aforementioned primary outcomes in patients with or without STEMI who were treated with either 90 mg of ticagrelor twice daily (5,137 patients) or 75 mg of clopidogrel once daily (5,148 patients).
Researchers stratified the patients into six groups to represent their phenotypes (CYPC219): extensive (*1/*1), intermediate (*1/*2-*8), poor, (*2-*8/*2-*8), poor or rapid heterozygote (*2-*8/*17), rapid heterozygote (*1/*17) and ultra rapid (*17/*17).
Among the patients administered 90 mg of ticagrelor twice daily, 1,849 had extensive CYPC219, 894 were intermediate, 121 were classified as poor, 369 had poor or rapid heterozygote, 1,437 were rapid heterozygote, 269 were classified as ultra rapid and 199 were missing these data, the researchers reported. These same rates for patients administered 75 mg of clopidogrel were 1,862, 935, 125, 328, 1,386, 268 and 244.
Additionally, for the ABCB1 genotype, researchers stratified patients into three categories: high (C/C), intermediate (C/T) and low (T/T).
Wallentin and colleagues reported that rates of CV death, MI and stroke were lower in each of the six genotype stratified groups when ticagrelor was used as therapy, as were rates of stent thrombosis.
While 30-day event rates for patients with loss-of-function alleles differed in those administered ticagrelor and clopidogrel, 4.1 percent versus 5.7 percent, these rates for patients without any loss-of-function alleles were equal—3.8 percent. After 31 days, these event rates were similar for patients with a loss-of-function allele, but were lower for patients administered ticagrelor without any loss-of-function allele.
When assessing primary endpoints of CV death, stroke and MI in patients genotyped for the ABCB1 gene, the researchers found that these rates were similar for ticagrelor and clopidogrel, 1.2 percent versus 1.3 percent, respectively.
Additionally during the study, researchers combined the data from for CYP2C19 and ABCB1 polymorphisms. For patients with any loss-of-function CYP2C19 allele or a high-expression ABCB1 phenotype, event rates were 8.6 percent for ticagrelor versus 11.2 percent for clopidogrel. These same rates for patients without any loss-of-function alleles were 8.9 percent and 9.5 percent, respectively.
“Treatment with ticagrelor versus clopidogrel in a large population with acute coronary syndromes was associated with lower rates of CV death and MI, similar rates of total major bleeding and higher rates of major bleeding related to non-CABG irrespective of CYP2C19 and ABCB1 polymorphisms,” the authors wrote.
“The results of our study clearly show the absence of interaction between the occurrence of any CYP2C19 loss-of-function allele and the superiority of ticagrelor over clopidogrel for all efficacy events tested.”
The researchers acknowledged that the interactions between polymorphisms and the effects of clopidogrel may be time dependent as higher event rates were reported in patients with loss-of-function alleles compared to those without CYP2C19 loss-of-functions alleles at 30 days, but not thereafter.
Wallentin and colleagues wrote that the trial did leave room for limitations including the fact that the majority of the patient population was white and that trial did not include all of the genetic polymorphisms that could affect the outcomes of ticagrelor, such as CYP3A4 or CYP3A5 alleles.
In an accompanying Lancet editorial, Betti Giusti, MD, and Rosanna Abbate, MD, from the University of Florence-Careggi Hospital in Florence, Italy, wrote, "The issue of the optimal dose of clopidogrel and/or the personalization of alternative antiplatelet therapeutic strategies aimed at reducing ischemic events and minimization of bleedings is open.
“[T]he relevance of obtaining adequate ‘residual platelet reactivity’ on antiplatelet treatment is now well founded and the crucial goal is now to identify the clinical, environmental, procedural and genetic determinants of the increased risk of major adverse cardiovascular events and of bleedings in these high-risk patients.”
Additionally, Giusti and Abbate offered that just because ticagrelor’s efficacy was not influenced by either CYP2C19 or ABCB1 polymorphisms, does not mean that other polymorphisms wouldn’t affect its pharmacodynamics.
AstraZeneca funded the study.