Genotype Guided Comparison of Clopidogrel and Prasugrel Outcomes Study
This study is designed to compare the effectiveness of clopidogrel in CYP2C19 extensive metabolizers (EM) with prasugrel in adults recently hospitalized for acute coronary syndrome (ACS) with primary, delayed, or planned percutaneous coronary intervention (PCI).
This is a prospective, non-randomized, open-label, non-inferiority comparative effectiveness outcomes trial comparing clopidogrel EMs (confirmed by CYP2C19 genotype) with prasugrel in ACS patients. The antiplatelet drug clopidogrel is a commonly prescribed therapy in patients following ACS, stroke, PCI with or without stent placement, and in patients with peripheral artery disease. However, recent research suggests that in vitro anti-platelet response to clopidogrel may be limited or lost in up to 30% of treated individuals, and may be associated with inferior clinical outcomes.
The antiplatelet effect of clopidogrel requires conversion of the parent compound to an active thiol. This active thiol metabolite inhibits adenosine diphosphate (ADP)-induced platelet aggregation by blocking the platelet P2Y12 receptor, resulting in a reduction of ADP-mediated platelet aggregation. Conversion of clopidogrel to its active metabolite is a relatively inefficient process during which 85% of the pro-drug is converted to an inactive metabolite by esterases, and the remaining 15% is oxidized to the active form by cytochrome P-450 (CYP) enzymes.
The variability of clopidogrel response is associated with variability in CYP enzyme genetic expression and activity, primarily CYP2C19 which is principally responsible for the conversion of clopidogrel into its active metabolite. CYP2C19 is genetically polymorphic, with alleles that produce both reduced and enhanced drug metabolism. These polymorphisms include the loss-of-function alleles CYP2C19 *2, *3,*4 and *5 and the ultra-rapid metabolizer CYP2C19 *17.
Subjects carrying the wild-type allele for CYP2C19 (*1/*1 or extensive metabolizers, EM) are able to efficiently metabolize clopidogrel and have the greatest exposure to the active metabolite, as well as the highest levels of platelet inhibition following clopidogrel exposure. Intermediate metabolizers (IM), those individuals carrying one reduced function allele (e.g.*1/*2, *1/*3, etc), have their circulating active drug metabolite level reduced by over 30% compared to EMs resulting in a 25% reduction in platelet inhibition. These results are consistent with other studies also demonstrating that individuals carrying the CYP2C19*2 allele have decreased levels platelet aggregation inhibition following clopidogrel administration as compared to the *1/*1 wild type.
A series of recent articles have explored the effect of genetic polymorphisms in CYP2C19 on the anti-platelet activity of clopidogrel as well as clinical outcomes following PCI. Collett, et al. examined 259 patients <45 years of age who were treated with clopidogrel following a MI. Carriers for the CYP2C19*2 allele had an increased incidence of death, MI and urgent coronary revascularization (p=0.0005, HR = 3.69). Simon, et al. examined 2,208 patients that presented with acute MI and received clopidogrel therapy and found individuals that carried one or more CYP2C19 loss-of-function allele(s) had higher rates of cardiovascular events than non-carriers. The risk of death, non-fatal MI or cardiovascular stroke at 1 year after PCI was 3.58 times greater in patients carrying two loss-of-function alleles compared to wild-type patients. Trenk, et al., associated elevated platelet activity and poor clinical outcomes in patients with the*2 allele in 797 patients followed for one year after PCI.
Prasugrel is a third generation thienopyridine, and appears to have increased antiplatelet efficacy compared to clopidogrel. Like clopidogrel, prasugrel is a pro-drug that requires metabolic activation. However, esterases that are known to inactivate clopidogrel act on prasugrel to prime it for activation by a single CYP-dependant oxidation step. This more direct pathway results in a more efficient activation pathway of prasugrel.
The efficacy of prasugrel and clopidogrel have been compared head-to-head in the TRITON-TIMI 38 study. This trial enrolled 13,608 ACS patients scheduled for PCI and compared prasugrel (60-mg loading dose and then 10-mg daily maintenance dose) against clopidogrel (300-mg/75-mg), both in combination with aspirin. Results indicated that prasugrel reduced the combined rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (12.1% for clopidogrel vs. 9.9% for prasugrel) at 15 months post-ACS. These favorable effects on cardiovascular events were offset by an increased rate of serious bleeding (1.4%, vs. 0.9% in the clopidogrel group) and fatal bleeding (0.4% vs. 0.1%). Overall mortality did not differ between the two treatment groups.
A genetic substudy subsequently published by Mega, et al. examined the association between CYP2C19 genotypes and cardiovascular outcome in a subset of 1,477 clopidogrel-treated subjects enrolled in the TRITON-TIMI 38 study. This study demonstrated that carriers of one or more reduced-function CYP2C19 alleles had a 53% increase in the composite primary efficacy outcome compared with non-carriers (12.1% vs 8.0%, p=0.01) over 15 months of follow-up. In contrast, outcomes in a subset of prasugrel-treated patients were similar across CYP2C19 genotypes. Unfortunately, the in-trial response to clopidogrel among the genetic substudy participants differed from that of the overall clopidogrel study cohort, thus preventing direct comparisons of clopidogrel to prasugrel as a function of CYP2C19 genotype
In May, 2009 the FDA approved a modification of the Plavix label to include what it termed pharmacogenetic data. This label modification affirms the impact of the CYP2C19 genotype on the pharmacokinetics of clopidogrel's active metabolite and, most importantly, confirmed the effect of reduced anti-platelet response with a higher rate of cardiovascular events in IM and PM populations.
On July 10, 2009 the FDA approved prasugrel to reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in patients with unstable angina or NSTEMI who are to be managed with PCI, and in patients with STEMI managed with primary or delayed PCI.
Currently, both clopidogrel and prasugrel are available to prescribers for patients with ACS managed by primary or delayed PCI. However, the event rate for clopidogrel extensive metabolizers alone has never been directly compared to prasugrel in this population. We hypothesize that the reported cardiovascular event rate in ACS patients is influenced by the relative inability of the CYP2C19-determined intermediate and poor metabolizer populations to metabolically activate, and thus derive benefit from, clopidogrel. As a result the true event rate for clopidogrel, when measured in the estimated 70%-75% of the ACS population that is able to fully metabolize this drug, will closely approximate that observed for prasugrel.
Observational Model: Cohort, Time Perspective: Prospective
Acute Coronary Syndrome
Medco Health Solutions, Inc
Enrolling by invitation
Medco Health Solutions, Inc.
Results (where available)
- Source: http://clinicaltrials.gov/show/NCT00995514
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Abnormal balloon- or sac-like dilatation in the wall of CORONARY VESSELS. Most coronary aneurysms are due to CORONARY ATHEROSCLEROSIS, and the rest are due to inflammatory diseases, such as KAWASAKI DISEASE.
Acute Coronary Syndrome
An episode of MYOCARDIAL ISCHEMIA that generally lasts longer than a transient anginal episode but that does not usually result in MYOCARDIAL INFARCTION.
Coronary Vessel Anomalies
Malformations of CORONARY VESSELS, either arteries or veins. Included are anomalous origins of coronary arteries; ARTERIOVENOUS FISTULA; CORONARY ANEURYSM; MYOCARDIAL BRIDGING; and others.
Coronary-subclavian Steal Syndrome
A complication of INTERNAL MAMMARY-CORONARY ARTERY ANASTOMOSIS whereby an occlusion or stenosis of the proximal SUBCLAVIAN ARTERY causes a reversal of the blood flow away from the CORONARY CIRCULATION, through the grafted INTERNAL MAMMARY ARTERY (internal thoracic artery), and back to the distal subclavian distribution.
Complete blockage of blood flow through one of the CORONARY ARTERIES, usually from CORONARY ATHEROSCLEROSIS.
The purpose of the study is to procure blood samples from patients who present to the Emergency Department with suspected ACS (Acute Coronary Syndrome).
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