The methods of the study have been previously reported.4
Briefly, consecutive patients with stable coronary artery disease visiting the outpatient department of the cardiology department were screened for inclusion. The history of patients had to include one of the following: myocardial infarction, significant coronary artery lesions (> 60%) on coronary angiography, percutaneous coronary intervention, or coronary bypass surgery. Patients had to be stable with no invasive vascular procedures scheduled. Patients were eligible when they had been taking statin for at least three months. The main exclusion criteria were age below 18 years, history of low vitamin B12 concentration, treatment for hyperhomocysteinaemia, severe renal failure or any other treatment for renal disease, known hepatic disease, signs and symptoms of severe heart failure (New York Heart Association functional class IV), or any other serious illness that would exclude the patient from follow up of at least three years.
The patients were randomly assigned to receive open label folic acid 0.5 mg once daily or to standard care. In addition, during the study statin treatment was intensified when necessary. At least one of four goals was meticulously pursued: firstly, a decrement of low density lipoprotein (LDL) cholesterol of 30% (compared with concentrations before the initiation of statin treatment); secondly, LDL cholesterol concentration of < 3 mmol/l; thirdly apolipoprotein B concentration of < 1 g/l; and fourthly, a decrement of apolipoprotein B concentrations of 30% compared with pre-statin concentrations. Persistent nicotine use was discouraged at regular intervals. Patients were followed up for a maximum of five years. During the whole study clinical events were carefully registered. Visits for laboratory examinations were planned at three, six, and 12 months and every six months thereafter. The study was conducted in accordance with the Declaration of Helsinki as revised in 1996. This study was performed in a rural area in the vicinity of the city of Goes, called the Bevelanden (province of Zeeland, the Netherlands), from 1998 to 2003. The local ethics committee approved the study protocol before the start of the study. The primary end point was a composite of vascular events. These events were defined as vascular death (sudden death, fatal recurrent ACS, fatal stroke, and other cardiovascular deaths), non-cardiovascular death, recurrent ACS, cerebrovascular accident, and transient ischaemic attack. ACS was defined according to contemporary criteria, which include an increase of troponin of > 0.2 µg/l (with a typical rise and fall) with at least one of the following: ischaemic symptoms, development of pathological Q waves on the ECG, and ECG changes indicative of ischaemia. All clinical events were adjudicated by an independent end point monitoring committee, unaware of treatment arm.