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Cardiovascular Pharmacology and Pharmacotherapy

Presenter abstract
Discussant report
All the Scientific resources on ESC Congress 365


By Jean-Philippe Collet
Other authors: Dr HULOT, France; Dr Cuisset, France; Dr Rangé, France; Dr Pouillot, France; Dr Henry, France; Dr Motreff, France; Dr Carrié, France; Dr Belle,France; Dr Van Belle, France; Dr O’Connor, France; Dr Abtan,France; Dr Kerneis, France; Dr Sabouret, France; Dr Saint-Etienne, France ; Dr Barthélémy, France ; Dr Beygui, France ; Dr Silvain, France ; Dr Vicaut,France ; Dr Gilles Montalescot, France; for the ARCTIC investigators
The ARCTIC study randomized 2440 patients scheduled for stent implantation to a strategy of platelet function monitoring with drug adjustment in patients who had a poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment.
No significant improvement in clinical outcomes with platelet function monitoring was observed. Prospective, multicenter evaluation of the effect over time of genetic variants affecting thienopyridine pharmacodynamics in this specific setting has been little explored.

DNA samples obtained from 1,420 patients were genotyped for CYP2C19 genes related to platelet reactivity. Patients were classified according to their clopidogrel predicted metabolic phenoytpe. Reduced metabolizers were identified as carriers of at least one loss-of-function allele (CYP2C19*2) and extensive metabolizers were wild type CYP2C19*1, carriers of at least one gain-of-function allele (CYP2C19*17) or carriers of both one gain and one loss-of-function allele (CYP2C19*2 and CYP2C19*17).
The primary study outcome defined as the composite of death, myocardial infarction, stent thrombosis, stroke or urgent revascularization 1 year after stent implantation and the primary safety outcome defined as the occurrence of major bleeding were evaluated according to the genetic metabolic profile and the strategy of platelet function testing.

The final results are presented at the meeting (see related slides on the ESC Congress 365).

The ARCTIC-GENE study was a prespecified substudy of the ARCTIC study (NCT00827411).

Discussant Report

Jurrien Ten Berg

It is well known that poor response to clopidogrel (high on treatment platelet reactivity [HOPR]) is a predictor of thrombotic events in patients undergoing PCI. It would be logical step to treat these patients with HOPR with stronger antiplatelet agents such as prasugrel to improve outcome. In the ARCTIC trial (N=2440) patients undergoing PCI were randomized to receive either conventional antiplatelet therapy (mostly 75 mg of clopidogrel), or to monitoring-guided antiplatelet therapy where dose-adjustments (mostly higher dose clopidogrel) were made based on platelet function testing.
As previously published, the primary endpoint (composed of death, myocardial infarction, stroke, stent thrombosis and urgent revascularization) showed no favourable outcome for the monitoring-guided strategy.
However, some methodological limitations should be considered e.g. it would be better to only study patients with HOPR, the majority of patients had stable coronary disease in whom the preventable stent thrombosis rate is very low (< 1%) and the predominant adjustment made was a higher dose of clopidogrel which does not affect the primary endpoint much as was demonstrated in the GRAVITAS. Because in this trial many different variables were introduced (on-table GPIIb/IIIa-inhibitor use, increasing and decreasing clopidogrel dose, switching to prasugrel), both during PCI and after two weeks, the interpretation of the study results is challenging. Because the primary endpoint is driven by peri-procedural infarction, it remains unclear how specific changes in antiplatelet therapy affect long-term outcome.
Another well known fact is that CYP2C19 gene polymorphisms contribute to HOPR and that carriers of the loss-of-function allele CYP2C19 *2 or *3 (especially when homozygous) have a higher event rate post stenting. In contrast, the gain-of-function CYP2C19*17 allele has been associated with enhanced inhibition of platelet aggregation in patients receiving clopidogrel therapy, leading to a greater risk of bleeding.
In the ARCTIC-GENE study (N=1294) patients were grouped into either a slow or a fast metabolizer genotype. Patients in the slow metabolizer group more often had HOPR. The difference (40% vs 30%) in HOPR is however small and the incidence of 30% HOPR in the fast metabolizer group demonstrates that many other factors contribute to HOPR. Slow metabolizers more often underwent dose adjustment (mostly on-table clopidogrel loading).
Thrombotic endpoints occurred similarly in both fast and slow metabolizer groups, which led to the conclusion by the researchers that “ARCTIC-GENE confirms that treatment monitoring does not improve outcome”.
However, one can also conclude that by adjusting antiplatelet therapy the event rate in the higher risk slow metabolizer group was reduced to that of the lower risk fast metabolizer group. A comparison of intervention versus control group, stratified by metabolizer group, would give important additional information.
Also analyzing homozygous *2 carriers alone, in which most benefit of adjusting antiplatelet therapy is expected, would add to the general picture.

Because both groups consisted of several drug metabolization genotypes, no conclusions can be drawn about an individual genotype. For instance, very poor metabolizers (such as *2/*2 homozygotes) possibly do benefit from dose-adjustments, but the favourable effects may be washed out by no effects in other genotypes (such as *1/non *17) in the same ‘slow metabolizers’ group.

Conclusively, in the ARCTIC study no substantial evidence was found supporting dose-adjustments of antiplatelet therapy based on platelet function measurement in patients undergoing PCI. However, ARCTIC-GENE might contain interesting data about the role of CYP2C19 genotyping in relation to HOPR and clinical outcome.





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.