Study population

VERIFRENCHY was a multicentre prospective observational study that recruited patients in 20 high-volume percutaneous coronary intervention (PCI) centres in France. The study population included adults (≥ 18 years) with stable angina, silent ischaemia or non-ST-segment elevation acute coronary syndrome (ACS; unstable angina or non-ST-segment elevation myocardial infarction) undergoing planned PCI with stenting. Exclusion criteria were periprocedural glycoprotein IIb/IIIa inhibitors, bivalirudin treatment before PCI, contraindications to aspirin or clopidogrel, use of oral anticoagulation and lack of available clopidogrel response at inclusion. Written informed consent was obtained from all patients before the index procedure. The study was approved by the French Authorities (AFSSAPS [2008-A00411-54] and CPP [n° 2008-N2]).

Procedures

Eligible patients were screened at the time of the coronary angiogram. Patients were loaded with clopidogrel 600 mg ≥ two hours before PCI unless they had been on a maintenance clopidogrel dose of 75 mg for > one week. An intravenous loading dose of aspirin was given according to the investigators’ usual practices in patients in whom aspirin was started < one week before angiography. Patients were tested for both aspirin and clopidogrel response before stent implantation. A valid biological measure of clopidogrel/aspirin response was requested before inclusion in the study.

After stent implantation, aspirin (75–160 mg) and clopidogrel (75 mg) maintenance doses were recommended for one month after bare-metal stent (BMS) implantation and for one year after drug-eluting stent (DES) implantation or if the clinical presentation was an ACS. In this registry, we compared the rate of primary and secondary endpoints at one year according to treatment response to both clopidogrel and aspirin.

Data were collected prospectively on-site and analysed by the Peter Holmes Company . Blood samples were drawn both before PCI and 24 hours after PCI to measure troponin concentrations. Follow-up data were obtained by clinical examination at hospital discharge and by telephone contact at one month and one year after discharge.

Whole blood was obtained at the time of catheterization. Platelet function testing was performed with the VerifyNow assay after the decision was made to perform stenting, but before starting PCI . The selection of VerifyNow platelet inhibition (%PI) with a cut-off of ≤ 15% was based on data from Bouman et al., who demonstrated a good correlation between P2Y12 reaction unit values and %PI with plasma concentrations of active metabolite clopidogrel . High on-aspirin platelet reactivity (OAR) was defined as an aspirin reaction unit (ARU) ≥ 550, and normal OAR was defined as ARU < 550 . High on-clopidogrel platelet reactivity (OCR) was defined as %PI ≤ 15% and normal OCR as %PI > 15%, based on data from Godino et al. . Investigators were strongly encouraged not to modify antiplatelet therapy according to the results of platelet function tests.

Patients were also classified according to the VerifyNow %PI and ARU quartiles to assess bleeding events; the lowest platelet reactivity quartiles of clopidogrel and aspirin were compared with the other three quartiles.

Endpoints

Ischaemic endpoints were defined as definite and probable stent thrombosis, myocardial infarction (spontaneous and/or periprocedural), all-cause death, cardiovascular death and stroke. The main ischaemic composite endpoint was a combination of definite and probable stent thrombosis, cardiovascular death and spontaneous myocardial infarction at one year. The secondary composite ischaemic endpoint included the combination of definite and probable stent thrombosis, all-cause death, non-fatal myocardial infarction (spontaneous and periprocedural) and stroke.

Periprocedural myocardial infarction was defined as a postprocedural increase in troponin concentration > three times the 99th percentile upper reference limit in patients with normal baseline concentrations of troponin (type 4a ); in patients with an ACS and raised baseline troponin concentrations, the definition of a subsequent elevation ≥ 20% of the baseline value was applied . Spontaneous myocardial infarction was defined as ≥ 1 value of troponin > 99th percentile upper reference limit together with evidence of myocardial ischaemia (type 1) . Stent thrombosis included definite, probable and possible stent thrombosis . Ischaemic stroke was defined as focal loss of neurological function caused by an ischaemic event.

The main safety endpoint was defined according to the International Society of Thrombosis and Haemostasis definitions . Major bleeding was defined as: fatal bleeding; symptomatic bleeding in a critical area or organ (i.e. intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial), or intramuscular bleeding with compartment syndrome; and bleeding causing a fall in haemoglobin concentration of ≥ 20 g/L or leading to transfusion of ≥ two units of whole blood. Minor bleeding was defined as any clinically overt sign of haemorrhage that was actionable, but did not meet the criteria for major bleeding.

Statistical analysis

A power calculation was performed to determine the study sample size. Anticipating a 35% rate of high OCR and an annual stent thrombosis rate of 1.7% (α risk at 5% and error at 80%, bilateral test), 800 patients would be needed; allowing for loss to follow-up, a population of 1000 patients was chosen.

Continuous variables and categorical variables are expressed as mean ± standard deviations and counts and percentages, respectively. Student’s t test was used to compare continuous variables and the Chi ² test or Fisher’s exact test was used to compare categorical variables. Survival analysis was performed by the Kaplan–Meier method with a log-rank test-group comparison. A P value < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 20.0 (IBM Corp, Somers, NY, USA).