Mechanisms fo Clopidogrel Resistance in Older Adults (CEPAGE) (CEPAGE)

Mechanisms fo Clopidogrel Resistance in Older Adults

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.

Study Overview

• Status: Recruiting
• Conditions: Drug Resistance
• Intervention / Treatment: Biological: additional blood sample

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.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Joaquim PRUD'HOMM, MD; Phone Number: +33 2 99 28 41 10; Email: joaquim.prud'homm@chu-rennes.fr
• Study Contact Backup: Name: Isabelle GOUIN-THIBAULT, MD, PhD; Phone Number: +33 2 99 28 95 63; Email: isabelle.gouin@chu-rennes.fr

Study Locations

• France
  • Paris, France
    • Not yet recruiting
    • Hôpital Charles Foix
    • Contact: Eric PAUTAS, Pr
  • Paris, France
    • Recruiting
    • Hôpital Européen Georges Pompidou,
    • Contact: Elena PAILLAUD, MD
  • Paris, France
    • Recruiting
    • Hopital Lariboisiere
    • Contact: Jean-Guillaume DILLINGER, MD
  • Rennes, France
    • Recruiting
    • CHU de Rennes
    • Contact: Dominique SOMME, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• 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

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Age Group 50 to 59; Inclusion criteria : age 50-100 years old,; in consultation or hospitalization in one of the participating centres,; treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug,; myeloproliferative syndrome,; platelet count < 100 gigas/liter,; acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer,; dialysis.	Biological: additional 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.
Age Group 60 to 69; Inclusion criteria : age 50-100 years old,; in consultation or hospitalization in one of the participating centres,; treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug,; myeloproliferative syndrome,; platelet count < 100 gigas/liter,; acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer,; dialysis.	Biological: additional 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.
Age Group 70 to 79; Inclusion criteria : age 50-100 years old,; in consultation or hospitalization in one of the participating centres,; treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug,; myeloproliferative syndrome,; platelet count < 100 gigas/liter,; acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer,; dialysis.	Biological: additional 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.
Age Group 80 to 89; Inclusion criteria : age 50-100 years old,; in consultation or hospitalization in one of the participating centres,; treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug,; myeloproliferative syndrome,; platelet count < 100 gigas/liter,; acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer,; dialysis.	Biological: additional 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.
Age Group 90 to 100; Inclusion criteria : age 50-100 years old,; in consultation or hospitalization in one of the participating centres,; treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug,; myeloproliferative syndrome,; platelet count < 100 gigas/liter,; acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer,; dialysis.	Biological: additional 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK/PD correlation - clopidogrel active metabolite concentration (pharmacokinetics PK in ) / platelet response phenotype(pharmacodynamics, PD)	Correlation PK (concentration of active metabolite of clopidogrel) / PD (%maximum aggregation at 10 μM ADP) as a function of age	Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of prodrug/active metabolite concentrations	Ratio of prodrug/active metabolite concentrations as a function of age	Day 0
Correlation between the area under the curve of aggregationat 10 μM ADP and the concentration of the active metabolite of clopidogrel	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	Day 0
Correlation between the Platelet Reactivity Index of VASPphosphorylation and the concentration of the active metabolite of clopidogrel	Correlation between the Platelet Reactivity Index of VASP phosphorylation and the concentration of the active metabolite of clopidogrel in relation to age	Day 0
Determination of factors influencing PK/PD response	clinical data: gender	Day 0
Determination of factors influencing PK/PD response	clinical data: body mass index in kg/m^2	Day 0
Determination of factors influencing PK/PD response	clinical data: Cumulative Illness Rating Scale-Geriatric	Day 0

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Principal Investigator: Dominique SOMME, MD, Pr, CHU de Rennes - Service de Gériatrie; Principal Investigator: Isabelle GOUIN-THIBAULT, MD, PhD, CHU de Rennes - Service d'Hématologie Biologique; Principal Investigator: Eric PAUTAS, MD, Pr, Hôpital Charles Foix - Court séjour Gériatrique; Principal Investigator: Corinne FRERE, MD, CHU Pitié-Salpêtrière - Hématologie Biologique; Principal Investigator: Elena PAILLAUD, MD, Hôpital Européen Georges Pompidou, Service de Gériatrie Aiguë,; Principal Investigator: Pascale GAUSSEM, MD, Pr, Hôpital Européen Georges Pompidou - Service d'Hématologie Biologique,; Principal Investigator: Jean-Guillaume DILLINGER, MD, Hôpital Lariboisière - Service de Cardiologie; Principal Investigator: Virginie SIGURET, MD, Pr, Hôpital Lariboisière - Hématologie Biologique

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2021
• Primary Completion (Estimated): July 12, 2025
• Study Completion (Estimated): January 12, 2026

Study Registration Dates

• First Submitted: May 6, 2021
• First Submitted That Met QC Criteria: July 26, 2021
• First Posted (Actual): August 4, 2021

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 24, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: older adults; clopidogrel; Drug resistance; primary or secondary prevention of cardiovascular events; clopidogrel resistance; Antiplatelet resistance
• Other Study ID Numbers: 35RC19_9831_CEPAGE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No