December 24, 2008 (Paris, France) – Acute-MI patients who possess the genetic variant linked previously with variability in the antiplatelet response to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) are at an increased risk of death, recurrent MI, and urgent coronary revascularization when placed long-term on the antiplatelet regimen [1].
"Our study shows a strong relation between the presence of the CYP2C19*2 allelic variant and recurrent thrombotic coronary events in clopidogrel-treated patients predominantly of European ancestry who survived a myocardial infarction before 45 years of age," write lead investigator Dr Jean-Philippe Collet (INSERM, Paris, France) and colleagues in a paper published online December 23, 2008 in the Lancet.
In their paper, the group explains that variability in the gene that encodes the cytochrome P450 2C19 enzyme is thought to contribute to the effectiveness of clopidogrel as an antiplatelet agent. This enzyme is active in the biochemical pathway that converts clopidogrel into an active metabolite, and the loss-of-function polymorphism, known as CYP2C19*2, is associated with reduced clopidogrel responsiveness.
In addition to this study, Dr Tabassome Simon (Université Pierre et Marie Curie, Paris, France) and colleagues also examine the subsequent risk of cardiovascular events among acute-MI patients with the CYP2C19 alleles receiving clopidogrel [2].
Publishing findings from the French Registry of Acute ST-Segment Elevation and Non-ST-elevation Myocardial Infarction (FAST-MI) study online December 22, 2008 in the New England Journal of Medicine, the investigators show that patients carrying any two of the CYP2C19 loss-of-function alleles, which included CYP2C19*2, CYP2C19*3, CYP2C19*4, or CYP2C19*5, were at a significantly greater risk of death, MI, or stroke.
A third study, from the Thrombolysis in Myocardial Infarction (TIMI) study group, showed that, among clopidogrel-treated subjects, carriers of the reduced-function CYP2C19 alleles had a more than 50% increased risk in the primary end point of death from cardiovascular causes, MI, or stroke, when compared with noncarriers, as well as a threefold increase in the risk of stent thrombosis [3].
Speaking with heartwire, Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA), who was not part of any of the studies, called the results "major findings in cardiovascular medicine," especially since clopidogrel is the second-most-prescribed drug in the world.
"At this moment in time in cardiovascular medicine, this is perhaps the most striking, practical, pharmacogenetic relationship demonstrated," said Topol. "It has practical implications for managing patients and for patients getting a stent and clopidogrel. At least one-third, if not more, depending on ancestry, are at considerably higher risk for stent thrombosis, and this information isn't being taken into account."
The CYP2C19 variant is extremely common, occurring in 30% of individuals of European ancestry, 40% of individuals of African ancestry, and in more than 50% of individuals of Asian ancestry, noted Topol.
Loss-of-Function Alleles and Clopidogrel Resistance
In the FAST-MI paper, Simon and colleagues report their findings based on data from 2208 patients with an acute MI treated with clopidogrel. In addition to CYP2C19, the researchers also assessed the relationship between variants of genes modulating clopidogrel absorption, such as ABCB1, as well as genes modulating metabolic activation and biologic activity, and the risk of cardiovascular events during one year of follow-up.
During the follow-up period, there were 225 deaths and 94 nonfatal MIs or strokes. Patients with two variant alleles of ABCB1 had a significantly greater risk of death from any cause, nonfatal stroke, or MI at one year compared with individuals with the ABCB1 wild-type genotype.
Among patients carrying any two variants of CYP2C19, there was a doubling in the risk of cardiovascular events at one year compared with individuals without any of the loss-of-function alleles.
Predictors of death from any cause, nonfatal MI, or stroke among patients
Subgroup | All patients, n=2208 (95% CI) |
ABCB1 alleles | |
CC (wild-type) | 1.00 |
CT | 1.51 (1.09–2.10) |
TT | 1.72 (1.20–2.47) |
Any CYP2C19 loss-of-function alleles (*2, *3, *4, and *5) | |
No variant alleles | 1.00 |
1 variant allele | 0.69 (0.51–0.93) |
2 variant alleles | 1.98 (1.10–3.58) |
Any CYP2C19 loss-of-function alleles (*2, *3, *4, and *5) among PCI patients | |
No variant alleles | 1.00 |
1 variant allele | 0.78 (0.50–1.21) |
2 variant alleles | 3.58 (1.71–7.51) |
This increased risk was even more pronounced among those who underwent PCI during hospitalization. Among these 1535 PCI patients, the rate of cardiovascular events among those with two CYP2C19 loss-of-function alleles was 3.5 times greater than among those without the genetic polymorphism.
Analysis From TRITON-TIMI-38
The TIMI study group also gets in on the clopidogrel-genetics action in the study by Dr Jessica Mega (Brigham and Women's Hospital, Boston, MA), which is also published online December 22, 2008 in the New England Journal of Medicine.
In an analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON–TIMI) 38, the researchers tested the association between functional genetic variants in cytochrome P450 genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects.
Carriers of at least one CYP2C19 loss-of-function allele had a 30% relative reduction in plasma exposure to the active metabolite of clopidogrel when compared with noncarriers. In addition, these carriers also had a significant 9% absolute reduction in maximal platelet aggregation in response to clopidogrel.
In terms of cardiovascular outcomes among clopidogrel-treated subjects, carriers had a more than 50% increased risk in the primary end point of death from cardiovascular causes, MI, or stroke compared with noncarriers, as well as a threefold increase in the risk of stent thrombosis.
Lancet Study Also Published
In the Lancet study, the researchers assessed whether the CYP2C19*2 polymorphism is associated with clinical outcomes of acute-MI patients treated long-term with clopidogrel. Using data from the large Appraisal of Risk Factors in Young Ischemic Patients Justifying Aggressive Intervention (AFIJI) registry, they identified 259 patients younger than 45 years who survived a first MI and were exposed to clopidogrel for at least one month. All patients underwent genetic testing for the CYP2C19*2 polymorphism.
After a median exposure of 1.07 years, the primary end point, a composite of death, nonfatal MI, and urgent revascularization, occurred more frequently in carriers vs noncarriers of CYP2C19*2. In total, there were 11 events in individuals without the CYP2C19*2 allele and 15 events in those heterozygous and homozygous for CYP2C19*2.
Main effects of CYP2C19*2 polymorphism on cardiovascular outcomes
Outcomes | Adjusted hazards ratio (95% CI) | p |
Death, nonfatal MI, urgent revascularization (primary end point) | 5.38 (2.32–12.47) | <0.0001 |
Definite stent thrombosis (secondary end point) | 6.04 (1.75–20.80) | 0.004 |
MI | 5.57 (1.94–16.01) | 0.001 |
Urgent revascularization | 3.24 (0.69–15.09) | 0.13 |
"The magnitude of the detrimental effect of the CYP2C19*2 genetic variant was unexpected in view of the clinical benefits that were recorded with clopidogrel in previous studies that used similar clinical end points," write Collet and colleagues.
The group notes that at the last follow-up visit, 213 patients were still receiving a maintenance dose of 75 mg per day of clopidogrel, and nearly all of these were receiving low-dose aspirin in combination. They note that it is unknown whether higher doses of clopidogrel would override the detrimental effect of the loss-of-function CYP2C19*2 polymorphism, but this warrants further investigation.
Speaking with heartwire, Topol noted there are inconsistencies across the three studies, mainly in that the TRITON-TIMI-38 analysis and the study by Collet and colleagues documented a higher risk of cardiovascular events among carriers, with threefold and sixfold increases in the risk of stent thrombosis, respectively.
In contrast, carriers of the gene included in the FAST-MI analysis appeared to be at lower risk. "It's a very peculiar finding," said Topol.
Overall, however, Topol said the findings, taken together to include ABCB1 and CYP2C19, as well as the reduced-function CYP2B6 allele that appears to affect the amount of active metabolite in the TRITON-TIMI analysis, suggest that multiple genes are at work.
"There are other things lurking besides this very important CYP2C19, and probably with larger samples and more events you'd have enough power to pick up CYP2B6 and further demonstrate the importance of ABCB1," said Topol.
The findings also need to be independently replicated before being extrapolated to older patients or those of non-European ancestry, write Collet and colleagues. The results, however, raise the question of whether or not the prognostic information associated with the CYP2C19*2 genotype can be used to guide management of these patients.
In an editorial accompanying the Lancet study [4], Dr Robert Storey (University of Sheffield, UK) called the degree of risk associated with the variant "remarkable," partly because the conversion of clopidogrel to its active metabolite can be achieved through several cytochrome P450 enzymes. Other mechanisms should be explored and further testing carried out to determine whether having the CYP2C19*2 variant is associated with other genetic determinants of risk, he writes.
Regarding the possibility of genotyping patients with acute coronary syndrome to identify CYP2C19*2 carriers for risk stratification, Storey believes the concept is attractive, but several factors are likely to dampen enthusiasm. "The results of such an analysis would be unlikely to be available at the time of starting clopidogrel and during the high-risk phases of an acute coronary syndrome," he writes. Other drugs, he notes, including prasugrel, are currently in development and could potentially provide solutions to the problems of variability in the response to clopidogrel.
Regarding genotyping patients to identify the CYP2C19 variant, Topol said he thinks genotyping could be incorporated into daily practice. If two million patients are getting stents annually, then some 700 000 individuals are at increased for stent thrombosis based on their genetics.
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου