Drug Resistance
Conditions
Keywords
clopidogrel, primary or secondary prevention of cardiovascular events, older adults, clopidogrel resistance, Drug resistance, Antiplatelet resistance
Brief summary
A clopidogrel resistance rate of 40-50% has been found in the population over 70 years of age, whereas biological resistance, associated with an increased risk of cardiovascular events, is observed in about 20-30% of younger patients. One hypothesis is that the active metabolite is less available in resistant patients. Indeed, 85% of the absorbed clopidogrel undergoes inactivation by esterases. Then the remaining fraction undergoes two steps of metabolisation to the active thiol metabolite by CYP450, essentially the isoform 2C19. In older adults, increased esterase activity and/or decreased CYP450 2C19 activity may lead to a decreased concentration of the active metabolite. Multiple chronic conditions and polypharmacy encountered in older individuals are associated with basal platelet hyperactivity, and may also contribute to a poor response to clopidogrel. No data on the relationship between platelet response and circulating metabolite levels, or on the determinants of response to clopidogrel, are currently available in the geriatric population. Therefore, we propose to analyse the relationship between age and platelet and extra-platelet mechanisms potentially involved in the variability of response to clopidogrel.
Detailed description
This study is a prospective observational multi-centre study. The main objective is assessing the pharmacokinetics (PK) and pharmacodynamics (PD) correlation of clopidogrel action in older adults, i.e. correlation between clopidogrel active metabolite concentration (PK) and platelet response phenotype (PD). The primary outcome is the correlation between the concentration of active metabolite of clopidogrel (PK) over the percentage of maximum aggregation at 10 μM ADP (PD) as a function of age. Inclusion criteria are: age 50-100 years old, hospitalization in one of the 4 participating centres, treatment with clopidogrel 75 milligrammes per day, for at least 10 days. The statistical analysis is a multiple linear regression model with the introduction of an interaction term. The first variable of interest (explanatory) is the concentration of the metabolite. A linear regression model will be used to estimate the proportion of variance explained. The analyses will be conducted with SAS version 9.4 (SAS Institute Inc., Cary, N.C., USA). Results will be published in an international scientific review.
Interventions
BIOLOGICALadditional blood sample
One sample per patient will be taken 1 to 3 hours after clopidogrel administration. Four additional tubes of 3 mL each will be collected for the study, for a total volume of 12 mL.
Sponsors
Rennes University Hospital
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
50 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Consecutive patients per 10-year age range, (20 patients per age range from 50 to 100 years included) : * in consultation or hospitalization in one of the participating centres, * treatment with clopidogrel 75 mg/d for at least 10 days for primary or secondary prevention of cardiovascular events. * who have received the information and have not expressed their opposition to participate in the study and who have given their written consent for the performance of genetic examinations and the realization of a biocollection * affiliated to French social security system
Exclusion criteria
: * treatment with another antithrombotic agent, * myeloproliferative syndrome, * platelet count \< 100 G/L, * acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer, * under dialysis, * no participation in another clinical study, * deprived of liberty
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK/PD correlation - clopidogrel active metabolite concentration (pharmacokinetics PK in ) / platelet response phenotype(pharmacodynamics, PD) | Day 0 | Correlation PK (concentration of active metabolite of clopidogrel) / PD (%maximum aggregation at 10 μM ADP) as a function of age |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of prodrug/active metabolite concentrations | Day 0 | Ratio of prodrug/active metabolite concentrations as a function of age |
| Correlation between the area under the curve of aggregationat 10 μM ADP and the concentration of the active metabolite of clopidogrel | Day 0 | Correlation between the area under the curve of aggregation at 10μM ADP and the concentration of the active metabolite of clopidogrelas a function of age |
| Correlation between the Platelet Reactivity Index of VASPphosphorylation and the concentration of the active metabolite of clopidogrel | Day 0 | Correlation between the Platelet Reactivity Index of VASP phosphorylation and the concentration of the active metabolite of clopidogrel in relation to age |
| Determination of factors influencing PK/PD response | Day 0 | clinical data: gender |
Countries
France
Contacts
PRINCIPAL_INVESTIGATORDominique SOMME, MD, Pr
CHU de Rennes - Service de Gériatrie
PRINCIPAL_INVESTIGATORIsabelle GOUIN-THIBAULT, MD, PhD
CHU de Rennes - Service d'Hématologie Biologique
PRINCIPAL_INVESTIGATOREric PAUTAS, MD, Pr
Hôpital Charles Foix - Court séjour Gériatrique
PRINCIPAL_INVESTIGATORCorinne FRERE, MD
CHU Pitié-Salpêtrière - Hématologie Biologique
PRINCIPAL_INVESTIGATORElena PAILLAUD, MD
Hôpital Européen Georges Pompidou, Service de Gériatrie Aiguë,
PRINCIPAL_INVESTIGATORPascale GAUSSEM, MD, Pr
Hôpital Européen Georges Pompidou - Service d'Hématologie Biologique,
PRINCIPAL_INVESTIGATORJean-Guillaume DILLINGER, MD
Hôpital Lariboisière - Service de Cardiologie
PRINCIPAL_INVESTIGATORVirginie SIGURET, MD, Pr
Hôpital Lariboisière - Hématologie Biologique
Outcome results
None listed