Clinical trial NCT04990596: Mechanisms fo Clopidogrel Resistance in Older Adults (CEPAGE)
Official title: Mechanisms fo Clopidogrel Resistance in Older Adults
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Drug Resistance
Keywords: clopidogrel
primary or secondary prevention of cardiovascular events
older adults
clopidogrel resistance
Drug resistance
Antiplatelet resistance
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2021-08-04
Enrollment: 100
Sex: ALL
Minimum age (years): 50
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: patients from 50 to 100 years treated with clopidogrel 75 mg/d for at least 10 days for primary or secondary prevention of cardiovascular events

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.

Eligibility criteria: 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

Primary outcomes:
measure: PK/PD correlation - clopidogrel active metabolite concentration (pharmacokinetics PK in ) / platelet response phenotype(pharmacodynamics, PD)
timeFrame: Day 0
Secondary outcomes:
measure: Correlation of prodrug/active metabolite concentrations
timeFrame: Day 0
measure: Correlation between the area under the curve of aggregationat 10 μM ADP and the concentration of the active metabolite of clopidogrel
timeFrame: Day 0
measure: Correlation between the Platelet Reactivity Index of VASPphosphorylation and the concentration of the active metabolite of clopidogrel
timeFrame: Day 0
measure: Determination of factors influencing PK/PD response
timeFrame: Day 0
measure: Determination of factors influencing PK/PD response
timeFrame: Day 0
measure: Determination of factors influencing PK/PD response
timeFrame: Day 0
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Charles Foix
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou,
city: Paris
country: France
facility: Hôpital Lariboisière
city: Rennes
country: France
facility: CHU de RENNES
Study officials:
affiliation: CHU de Rennes - Service de Gériatrie
name: Dominique SOMME, MD, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Rennes - Service d'Hématologie Biologique
name: Isabelle GOUIN-THIBAULT, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Charles Foix - Court séjour Gériatrique
name: Eric PAUTAS, MD, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Pitié-Salpêtrière - Hématologie Biologique
name: Corinne FRERE, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Européen Georges Pompidou, Service de Gériatrie Aiguë,
name: Elena PAILLAUD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Européen Georges Pompidou - Service d'Hématologie Biologique,
name: Pascale GAUSSEM, MD, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Lariboisière - Service de Cardiologie
name: Jean-Guillaume DILLINGER, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Lariboisière - Hématologie Biologique
name: Virginie SIGURET, MD, Pr
role: PRINCIPAL_INVESTIGATOR
References: