Myocardial Infarction, Percutaneous Coronary Intervention
Conditions
Keywords
Myocardial infarction, Percutaneous coronary intervention, Clopidogrel, Genetics, Platelet Function
Brief summary
To determine whether higher as compared with lower maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele.
Detailed description
Clopidogrel blocks the P2Y12 ADP receptor on platelets and has been shown to reduce cardiovascular events in acute coronary syndrome (ACS) patients.However, inter-patient variability in the pharmacodynamic response to clopidogrel is well recognized, and patients with lesser degrees of platelet inhibition in response to clopidogrel have been shown to be at increased risk of cardiovascular events. One potential source of this variability is the metabolism of clopidogrel, which is a pro-drug requiring biotransformation to become an active antiplatelet compound. Cytochrome P-450 (CYP) enzymes play a role in the metabolism, and carriers of reduced-function genetic variants in CYP2C19 (\ 30% of the population) have lower active clopidogrel metabolite levels, diminished platelet inhibition, and higher rates of adverse cardiovascular events as compared with non-carriers in the setting of treatment with standard maintenance doses of clopidogrel. Aim: To determine whether higher as compared with lower maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele. Hypotheses: The primary hypothesis is that subjects who carry a reduced-function CYP2C19 allele will have improvement in platelet inhibition with higher maintenance doses of clopidogrel.The secondary hypothesis is that higher maintenance doses of clopidogrel in carriers of a reduced-function CYP2C19 allele will result in similar platelet inhibition as compared to a standard maintenance dose of clopidogrel in non-carriers.
Interventions
DRUGClopidogrel
Clopidogrel 75 mg daily, 150 mg daily, 225 mg daily, and 300 mg daily based on genotype
Sponsors
Bristol-Myers Squibb
Sanofi
The TIMI Study Group
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
(major): 1. Between 18 and 75 years of age, inclusive. 2. Have an indication for the use of clopidogrel defined as either spontaneous MI \[hospitalized with final diagnosis of MI, excluding periprocedural or definite secondary MI (e.g., due to anemia or hypertensive emergency)\] or PCI within the past 6 months. 3. Clinically stable and at least 4 weeks following the MI or PCI.
Exclusion criteria
(major): 1. Conditions that alter platelet function. 2. Conditions that increase bleeding risk.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | Approximately every 2 weeks for 8 weeks | The outcome measurement was on-treatment PRI determined through flow cytometric assessment of phosphorylation status of VASP. |
Countries
United States
Participant flow
Recruitment details
335 patients from 32 sites were enrolled from October 2010 until September 2011.
Pre-assignment details
335 patients enrolled, 2 patients not genotyped 333 patient allocated to initial treatment with 75 mg and 150 mg clopidogrel
Participants by arm
| Arm | Count |
|---|---|
| CYP2C19*2 Non-Carriers | 247 |
| CYP2C19*2 Carriers | 86 |
| Total | 333 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Initial Treatment With 75 mg and 150 mg | No follow-up sample | 10 | 4 |
Baseline characteristics
| Characteristic | CYP2C19*2 Non-Carriers | CYP2C19*2 Carriers | Total |
|---|---|---|---|
| Age, Continuous Mean Age | 60.8 years STANDARD_DEVIATION 9.9 | 58.6 years STANDARD_DEVIATION 9.7 | 60.2 years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 61 Participants | 23 Participants | 84 Participants |
| Sex: Female, Male Male | 186 Participants | 63 Participants | 249 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 82 | 0 / 82 | 0 / 82 | 0 / 82 | 0 / 233 | 0 / 233 |
| serious Total, serious adverse events | 1 / 82 | 5 / 82 | 0 / 82 | 0 / 82 | 24 / 233 | 16 / 233 |
Outcome results
Primary
Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI)
The outcome measurement was on-treatment PRI determined through flow cytometric assessment of phosphorylation status of VASP.
Time frame: Approximately every 2 weeks for 8 weeks
Population: Non-carriers did not receive clopidogrel 225 mg or 300 mg
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| CYP2C19*2 Carriers | Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | Clopidogrel 75 mg | 71.0 % of PRI |
| CYP2C19*2 Carriers | Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | Clopidogrel 150 mg | 62.4 % of PRI |
| CYP2C19*2 Carriers | Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | Clopidogrel 225 mg | 54.0 % of PRI |
| CYP2C19*2 Carriers | Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | Clopidogrel 300 mg | 50.1 % of PRI |
| CYP2C19*2 Non-Carriers | Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | Clopidogrel 75 mg | 57.5 % of PRI |
| CYP2C19*2 Non-Carriers | Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | Clopidogrel 150 mg | 46.9 % of PRI |