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PLATO genetic substudy: Impact of CYP2C19 and ABCB1 single nucleotide polymorphisms (SNPs) on outcomes with ticagrelor and clopidogrel in acute coronary syndrome - a PLATO genetic substudy

Acute Coronary Syndromes (ACS)

Lars Wallentin, FESC
Presenter | see Discussant report Webcasts become available 24h after the presentation
Wallentin, Lars
Open presentation slides

List of Authors:

Lars Wallentin, Stefan James, Robert F Storey, Martin Armstrong, Bryan Barratt, Jay Horrow, Steen Husted, Hugo Katus, Gabriel Steg, Richard Becker


Introduction: Ticagrelor, an oral reversible directly acting P2Y12 receptor inhibitor was, in the PLATO trial, shown to provide a 16% relative reduction of the primary composite of cardiovascular (CV) death, myocardial infarction (MI), and stroke without an increase in the primary safety outcome PLATO major bleeding, when compared to clopidogrel. The CYP2C19 genotype is the main genetic determinant of pharmacokinetic and pharmacodynamic response to clopidogrel, although it might explain only 12% of the observed variability. It has also been associated with difference in clinical outcomes. ABCB1 genotype, affecting clopidogrel absorption and efflux has also been associated with changes in outcomes.
The present study explored the hypothesis that ticagrelor was superior to clopidogrel across all CYP2C19 and/or ABCB1 genotypes and that clopidogrel and not ticagrelor outcomes were affected by CYP2C19 and/or ABCB1 genotype polymorphisms.

Methods: The PLATO trial randomized 18,624 patients with acute coronary syndrome (ACS) to ticagrelor 180 mg loading dose and 90 mg b.d. maintenance dose versus clopidogrel 300 - 600 mg loading dose and 75 mg maintenance dose for 6 – 12 months (median 9 months). DNA samples were obtained after consent from 10,285 patients (5137 and 5148 from the ticagrelor and clopidogrel arms, respectively) and genotyped for the CYP2C19 wildtype (*1), loss of function (LOF) alleles *2, *3, *4, *5, *6, *7 & *8, plus the gain of function (GOF) *17 and ABCB1 (MDR1/P-Gp) C3435T SNP. For CYP2C19 , the statistical approach specified a guided decision for the most appropriate genotype groupings for each composite endpoint. For all outcomes, a grouping of with and without LOF alleles was used in between arms comparisons, except for total major bleeding where GOF carriers we treated as a separate group. Treatment by genotype subgroup interactions were evaluated by Cox regression accounting for the following covariates: ethnicity, gender, proton pump inhibitor (PPI)-use, aspirin dose, smoking, and diabetes.

Results: Baseline demographics and primary and secondary efficacy results comparisons confirmed that the genetic cohort was representative of the entire PLATO population. Genotype allele frequencies and predicted phenotypes were as expected. For Cyp2C19 the treatment effect of ticagrelor over clopidogrel on the primary efficacy outcome did not vary significantly by genotype grouping (interaction p=0.4628). Ticagrelor demonstrated similar event rates for the genotype groups (8.6% and 8.8% per year), whereas for clopidogrel the event rate was numerically greater for subjects with one or more LOF alleles (11.2% per year) compared with subjects with no LOF alleles (10.0% per year). The absolute risk reduction with ticagrelor was more marked for subjects with any LOF allele. Kaplan-Meier curves indicated an early, within the first weeks after randomisation, separation of event rates for subjects with one or more LOF alleles, while for other patients the separation did not appear until more than 30 days after randomisation.
For clopidogrel, the genotype group carrying any GOF allele had a numerically increased rate of total major bleeding, compared to *1/*1. No treatment by CYP2C19 genetic group interactions were observed for bleedings. For ABCB1 genetic groups (low, intermediate, and high expression) the primary efficacy composite, ticagrelor event rates (8.1 to 9.0 % per year) were consistently lower than with clopidogrel concerning low (9.9% per year), intermediate (9.3%) and high expression (11.5% per year) groups.
There were no relationships between ABCB1 genotype and bleeding rates. There were no significant interactions between tested treatments and any of the outcomes.

Conclusion: Ticagrelor was superior to clopidogrel for prevention of CV death, MI and stroke regardless of the CYP2C19 and ABCB1 genotypes known to affect the response to clopidogrel. The benefit of ticagrelor over clopidogrel with regard to ischemic events seemed to appear earlier in subjects with a genetically predicted low response to clopidogrel.

Kurt Huber, FESC
Discussant | see Presenter abstract Webcasts become available 24h after the presentation
Huber, Kurt
Open presentation slides


Genetic profiling has become of increasing interest to eventually detect poor responders to clopidogrel therapy. Multiple studies have shown that disorders in the CYP2C19 gene are associated with a higher adverse atherothrombotic event rate in patients under dual antiplatelet therapy after PCI and stenting, including stent thrombosis. Less frequent and inconsistent for results are reports about genetic disorders in genes related to absorption of the drug (ABCB1).
Clopidogrel is an ADP receptor inhibitor prodrug. After intestinal absorption (ABCB1 gene), the majority (85%) of the prodrug is metabolized and inactivated by esterases and only the remaining 15% of clopidogrel is transformed into the intermediate 2-oxo-clopidogrel metabolite by 3 isoenzymes (CYP1A2, CYP2B6 and CYP2C19). This intermediate non-active metabolite is further hydrolyzed into the highly unstable active thiol derivative R-130964 by involvement of 4 isoenzymes (CYP2B6, CYP2C9, CYP2C19 and CYP3A4) and inhibits platelet aggregation through an irreversible blockage of the ADP P2Y12 receptors on the platelet surface. In contrast, ticagrelor metabolism is not affected by such genetic variabilities.

The current presentation of Wallentin and co-workers focused on genetic disorders influencing absorption as well as metabolism by investigating loss-of-function (LOF)-genes (probably associated with atherothombotic complications) as well as genes associated with an increased metabolism of clopidogrel and therefore possibly related to bleeding complications in a huge PLATO genetic substudy in more than 10,000 patients with acute coronary syndromes, referred for angiography and PCI, and randomly treated with clopidogrel or ticagrelor. Objectives were to investigate if CYP2C19 and/or ABCB1 polymorphisms influences primary (CV death, MI and stroke) and secondary efficacy outcomes as well as safety outcomes when comparing treatments with ticagrelor versus clopidogrel in PLATO.

While genetic variants in the ABCB1 gene had no statistical impact on different clinical endpoints, the presence of any LOF allele in the CYP2C19 gene was associated with a higher combined endpoint rate in clopidogrel but not ticagrelor treated patients, which was statistically different after 30 days but lost significance after 1 year (clopidogrel: 11.2 vs. 10.0%; ticagrelor: 8.6 vs. 8.8%). The presence of any LOF allele, however, was not responsible for the statistical benefit of ticagrelor over clopidgrel (interaction p-value 0.46). In addition, ticagrelor vs. clopidogrel bleeding comparisons were unaffected by CYP2C19 and ABCB1 genotypes, whereas with clopidogrel carriers of CYP2C19 GOF allele had a tendency for higher bleeding rates.

In this elegant and important investigation, Wallentin et al were able to confirm earlier results from smaller trials with respect to the importance of disorders in the CYP2C19 gene. From these data, it might be concluded that personalized therapy targeting patients who carry these genetic variants might help to improve clinical outcome after stent implantation. However, for the clinical role of genetic profiling, multiple unknown factors still remain: While in the majority of trials CYP2C19 genetic polymorphisms have been shown to reduce clopidogrel metabolism and its clinical effectiveness while other genetic variants (with few exceptions) remained less important, there are no prospective studies demonstrating a clinical benefit to personalizing antiplatelet therapy based on genotyping.
Commercially available genetic tests that can determine CYP2C19 genotype (and other) variants are not routinely reimbursed and point of care assays (e.g. for patients with ACS) are lacking at the moment. Moreover, it is important to point out that CYP2C19 polymorphisms account for only approximately 12% of variability in clopidogrel platelet response, the positive predictive value of CYP2C19 loss-of-function polymorphisms for cardiovascular events in patients with ACS undergoing PCI is low, approximately 12% to 20% and other clinical factors and risk constellations might be of greater clinical importance.

Finally, it is unknown whether a specific genetic polymorphism is capable of influencing outcome for the individual patient. Accordingly, genetic profiling should not be recommended for routine use at present but will remain of increased scientific interest.


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Clinical Trial Update I
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.