Clinical trial NCT02293928: Impact of Hybrid Coronary Revascularization on Antiplatelet Therapy
Official title: Impact of Hybrid Coronary Revascularization on Antiplatelet Effect of Aspirin and Clopidogrel
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Coronary Artery Disease
Keywords: Hybrid coronary revascularization
Antiplatelet therapy
Aspirin
Clopidogrel
Lead sponsor: Aarhus University Hospital Skejby
Sponsor class: OTHER
Collaborators: name: Danish Heart Foundation
name: Aase and Ejnar Danielsens Foundation
First posted: 2014-11-19
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with coronary artery disease scheduled for elective hybrid coronary revascularization. The study cohort is recruited from a prospective pilot study conducted to assess feasibility and safety of hybrid coronary revascularization combining minimally invasive off-pump coronary artery bypass grafting and percutaneous coronary intervention (PCI) performed three to five days later (Clinicaltrials.gov identifier: NCT01496664).

Brief summary: The effect of antiplatelet therapy is impaired among patients, who recently underwent on-pump coronary artery bypass grafting. The impact of hybrid coronary revascularization using minimal invasive surgical techniques on the antiplatelet effect of aspirin and clopidogrel remains unclear.

The aim of the study is to describe the impact of hybrid coronary revascularization on the effect of aspirin and clopidogrel. Furthermore, we will investigate whether high baseline platelet aggregation, high postoperative levels of platelet turnover and acute-phase response may contribute to the effect.

Detailed description: Objective:

The effect of antiplatelet therapy is impaired among patients, who recently underwent on-pump coronary artery bypass grafting. The impact of hybrid coronary revascularization using minimal invasive surgical techniques on the antiplatelet effect of aspirin and clopidogrel remains unclear.

We hypothesize that hybrid coronary revascularization is associated with a transiently reduced antiplatelet effect of aspirin and clopidogrel. We hypothesize that the reduced antiplatelet effect of aspirin and clopidogrel could be explained by increased platelet turnover with an increased fraction of immature platelets in the peripheral blood. Furthermore, we hypothesize that the reduced antiplatelet effect is associated with increased inflammatory markers in the early postoperative phase. We hypothesize, that high platelet aggregation prior to the intervention is associated with reduced effect of antiplatelet therapy following hybrid coronary revascularization.

Methods:

40 patients with coronary artery disease will be enrolled in this prospective cohort study (recruited from a prospective pilot study conducted to assess feasibility and safety of hybrid coronary revascularization combining minimally invasive off-pump coronary artery bypass grafting through an inferior J-hemisternotomy (JOPCAB) with percutaneous coronary intervention - Clinicaltrials.gov identifier: NCT01496664). Demographics and medical history are documented preoperatively. The predicted mortality is assessed by means of the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) I. Adverse cardiovascular events are recorded prospectively, including graft dysfunction, myocardial infarction, stroke, and pulmonary embolism.

Six blood samples are obtained from each patient:

* Pre-OP: in the outpatient setting while patients were on aspirin 75 mg daily
* Baseline: in the morning prior to surgery after eight to ten days of aspirin discontinuation (off-aspirin)
* Post-OP: on the first postoperative day when aspirin had been resumed
* Pre-PCI: on the day prior to PCI
* Post-PCI: on the first day after PCI following initiation of dual antiplatelet therapy
* 1-year follow-up: when patients were still on maintenance aspirin 75 mg and clopidogrel 75 mg Platelet function analyses are performed using Multiplate® Analyzer (Roche, Roche Diagnostics, Mannheim, Germany), VerifyNow® Aspirin, and VerifyNow® P2Y12 (Accumetrics Inc., San Diego, CA, USA). For Multiplate® Analyzer, arachidonic acid (1.0 mM) and adenosine diphosphate (6.4 and 20 uM) are used as agonists.

Complete blood counts, including immature platelet fraction (IPF), immature platelet count (IPC), and mean platelet volume (MPV), are performed using a Sysmex XE-5000 haematology analyzer (Sysmex, Kobe, Japan) with upgraded software (XE IPF Master, Sysmex) enabling flow cytometric detection of the IPF. Enzyme-linked immunosorbent assays are used according to the manufacturers' instructions to measure serum thromboxane B2 (Cayman Chemical, Ann Arbor, MI, USA) and thrombopoietin (R\&D Systems Europe, Abingdon, UK). Plasma C-reactive protein was measured by immunoprecipitation using the Cobas® 6000 (Roche, Basel, Switzerland). Von Willebrand factor (antigen) and coagulation factor VIII (functional) are measured using the ACL TOP (ILS Laboratories, Bedford, MA, USA).

Eligibility criteria: Inclusion Criteria:

* symptomatic multivessel coronary artery disease
* treatment with non-enteric coated aspirin 75 mg once daily

Exclusion Criteria:

* aspirin or clopidogrel intolerance
* conditions prohibitive of aspirin discontinuation prior to surgery
* use of anticoagulants or any drugs other than aspirin known to affect platelet function
* use of immunosuppressive drugs
* platelet count \<100 or \>450 x 109/l
* inability to give informed consent

Primary outcomes:
measure: Change in aspirin antiplatelet effect from preoperative to three days postoperative
timeFrame: 12-14 days
Secondary outcomes:
measure: Change on aspirin antiplatelet effect from 3 days postoperative to 1 year follow-up
timeFrame: 1 year
measure: Change on clopidogrel antiplatelet effect from first day after PCI to 1 year follow-up
timeFrame: 1 year
measure: Association between baseline platelet aggregation (off-aspirin) and aspirin antiplatelet effect
timeFrame: 12-14 days
measure: Correlation between acute phase reactants and platelet aggregation
timeFrame: 8-10 days preoperative until 1 year postoperative
measure: Correlation between platelet turnover and platelet aggregation
timeFrame: 8-10 days preoperative until 1 year postoperative
Other outcomes:
measure: Compliance to aspirin treatment at enrollment
timeFrame: 8-10 days preoperative
measure: Compliance to aspirin treatment at 1 year follow-up
timeFrame: 1 year
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
Study officials:
affiliation: Aarhus University Hospitak Skejby
name: Ivy S Modrau, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Modrau IS, Wurtz M, Kristensen SD, Hvas AM. Reduced Effect of Aspirin and Clopidogrel Following Hybrid Coronary Revascularization. Clin Appl Thromb Hemost. 2015 Oct;21(7):603-11. doi: 10.1177/1076029615573304. Epub 2015 Mar 9.