**6. Study drop out criteria**

Patients were over the age of 21, and able to provide informed consent and agreed to comply

**Group A** 

**Group B** 

**Clopidogrel 75mg po every 24 h** 

**Aspirin 75 mg po every 24 h** 

**Group C Aspirin75mg+Clopidogre**

Patients were excluded from enrolment in the study if any of the following criteria were met:

**Active treatment** 

**l 75mg po every 24 h** 


**Control days 1-10, 15 months 1, 3, 6 and 1 year after CABG** 

**Control days 1-10, 15, months 1,3,6 and 1 year** 

**Control days 1-10, 15, months 1, 3, 6 and 1 year after CABG** 

**after CABG** 


**(min 1 year) Follow up** 

with all protocol-specified procedures.

**Randomization** 

**Enrollment phase** 

**•** Active internal bleeding or risk of hemorrhagic diathesis

**•** severe hepatic failure with ALT or AST > 3x ULN

**•** Need for long-term anticoagulant or NSAID use **•** Failed PCI within 2 weeks prior to randomization

**•** Active participation in another clinical trial **•** Failure to comply with the hospital protocol

**•** Previous use of a GPIIb/IIIa antagonist within 7 days

**•** Q-wave myocardial infarction within 24 hours prior to randomization


**Figure 1.** Treatment protocol phases

**5. Non-eligibility criteria**

**•** Serum Creatinine ≥ 3.0 mg/dl

**•** Cardiogenic shock.

**1 day after CABG** 

294 Artery Bypass

The occurrence of adverse events (skin reactions, gastrointestinal symptoms, active in‐ ternal bleeding)

Failure to comply with the hospital protocol/ absence to follow-up

The protocol was approved by the institute management, and every patient signed the informed consent form.

The essential inclusion criteria (gender,mean age, comorbidities, number of grafts per patient, the type of the grafts (arterial or venous) and the mean left ventricular ejection fraction, left ventricular diastolic performance and left atrial dimensions (diameters and area), the duration of treatment and assessment criteria were similar in the three treatment groups (p<0.0001). All patients received standard therapy including beta blockers, IEC, statins throughout the study period. The patients with exclusive arterial revascularisation also received calcium channel blockers agents but their number was similar in the three groups of study.

Clinical and laboratory parameters were initially assessed, at baseline and at each visit until the end of the study period.

The clinical measurements included: NYHA class for heart failure, presence of angina pectoris, ventricular rhytm, patient compliance and quality of life.

Laboratory parameters included: the usual blood tests (platelet count, hemoglobin, hematocrit, aminotransferases, LDH, biochemistry cholesterol and tryglycerides levels), electrocardio‐ gram(with the evaluation of rhythm, frequence and ST-T elevation), 24 hours ECG Holter monitoring for silent ischemia, stress efort test at 1,3,6 months and 1 year postoperatively and when angina occurred (Bruce or Bruce modified protocol), echocardiography (with assessment of the LV dimensions, ventricular sistolic and diastolic performance, ventricular walls contractility - segmental kinetics, mitral regurgitation degree) and coronarography at 1 year when the other tests where positive for ischemia. Also, at each visit were recorded the occurrence of major and minor bleeding episodes, gastrointestinal symptoms, skin reactions, thrombocytopenia and lab tests abnormalities.

24 hours ECG Holter used a 12 channels monitoring with the evaluation of conduction or rhythm disturbances or occurrence of silent ischemia.

Treadmill stress test was done at 1, 3, 6 months and at 1 year postoperatively and used Bruce or Bruce modified protocol. If the stress test or Holter monitoring diagnosed ischemia at one follow up visit, this was the indication for performing coronarography.

Early development of graft occlusion was diagnosed based on clinical criteria and through electrocardiogram, Holter monitoring, thoracic and transesophageal echocardiography. The appearance of gastrointestinal bleeding was diagnosed using clinical evaluation, endoscopy and colonoscopy.

#### **6.1. Primary and secondary endpoints**

The looked at all-cause mortality and major cardiac events, namely cardiac mortality, myo‐ cardial infarction or need for target lesion revascularization. The most important endpoints used for the estimation of the medium term prognosis were:

randomised to receive Clopidogrel 75 mg daily or Aspirin 75 mg daily or Aspirin plus Clopidogrel 75mg daily one day after surgery and in the postoperative period for no less than 1 year.. The patients undergoing also venticular remodelling for aneurysms were not taken in

The baseline characteristics were similar in the three arms of the study (Table 1). Overall, the

Mean (SD) age (years) 62,3 (12) 62,5 (13) 62,4(12)

Age"/>70 years 13,85% 14,21% 14,43%

Women 25,94% 26,18% 26,62%

Family history of heart disease (%) 49,62% 50,12% 49,75%

Dislipidemia (%) 75,06% 75,81% 76,37%

Prior myocardial infarction (%) 33,50% 33,91% 34,58%

NYHA class "/>II 20,15% 20,70% 20,89%

Prior stroke (%) 6,29% 6,73% 6,96%

Peripheral arterial disease 9,82% 9,72% 10,45%

Atrial fibrillation 6,04% 6,48% 6,47%

Hypertension 65,49% 66,58% 64,92%

Diabetes mellitus 25,19% 25,43% 25,12%

Current smoker 26,45% 26,43% 25,87%

Re-intervention (previous coronary artery surgery) 8,82% 8,98% 8,95%

The medications used chronically by the patients at the time of randomization were similar in the Aspirin, Clopidogrel and Aspirin plus Clopidogrel treatment arms and are are listed in

**Group A – 397 pts**

The Antiagregant Treatment After Coronary Artery Surgery Depending on Cost – Benefit Report

**Group B- 401 pts**

**Group C-402 pts**

http://dx.doi.org/10.5772/54467

297

study populations were similar to those of previous trials on antiagregants.

our study.

**Table 1.** Baseline characteristics

Table 2

The primary endpoint (efficacy endpoint) was a composite outcome cluster of 30-day mortal‐ ity, myocardial infarction, in-hospital and at 1 year occurrence of graft occlusion (efficacy endpoints), total hospital stay and immobilization (measured in days), Intensive Care Unit length of stay and cost, quality of life. Quality of life was appreciated using a scale from one to ten calculated on the base of a questionnaire filled by the patients at each visit

The secondary endpoints at 30 days looked at in-hospital major peripheral or bleeding complications (including surgical bleeding complications, transfusion of at least two units of blood, intracranial bleeding, retroperitoneal bleeding, overt hemorrhage), neutropenia (<1.5 x 109 per litre), thrombocytopenia (<100 x 109 per litre), early discontinuation of the study drug due to a non-cardiac adverse event (including death of non-cardiac origin) (safety endpoint).

The data collected represented the fields of a database in the Visual Fox Pro computer program. Data were processed by means of computers, using the Excel, EpiInfo, Systat and SPSS programs for multivariate regression analysis and relative risk and correlation coefficient calculation

No confirmatory statistical hypothesis was pre-specified, but a detailed analysis plan was defined before the database was locked. This analysis plan was based on generating risk ratios and CIs (CI=confidence index) for the pairwise comparisons of primary interest. These comparisons were presented with the two - sided 95% CI of the relative risk and with normal p values. For the primary endpoints Kaplan-Meier curves were constructed and log-rank tests were done. For each endpoint, a two-sided 95% CI was also calculated and an overall Chi square test, comparing the three treatment groups was done [19, 21, 25].

The frequency of the primary efficacy plus safety endpoint for the Aspirin group as a reference group was 17,7%. On the basis of phase-II studies we assumed that the experimental groups with Clopidogrel and Aspirin plus Clopidogrel would result in better, or at least similar outcomes when compared with standard treatment. The sample size and power calculations were therefore based on non-inferiority of the experimental group versus the reference group. The study has 80% power to exclude, with 95% confidence (one-sided), a 1% higher rate of the primary endpoints compared with the reference group, provided the point estimate in the experimental treatment group was 1,7% lower for the efficacy endpoint and 2% lower for the efficacy and safety endpoint. [2-11, 13-18, 22]
