Furberg 1994.

Study characteristics
Methods	Study design: randomised, double‐blind, placebo‐controlled trial Total duration of study: 5 years Details of any 'run‐in' period: "at the completion of visit 3, eligible participants received lovastatin placebo pills and open‐labelled warfarin pills (1 mg). Participants were masked to the identity of the placebo and were told to take one of each kind of pill daily for 21 to 28 days (until the next [baseline] visit) to rule out any reaction to either medication." Number of study centres and location: clinical centres at four academic institutions (Bowman Gray School of Medicine and the Universities of Iowa, Kentucky, and Tennessee) Study setting and date of study: outpatients of community clinics; May 1988 to June 1993
Participants	Number randomised: 919 participants Number lost to follow‐up/withdrawn: "lovastatin/LP or warfarin/WP were prematurely discontinued in 118 and 116 participants, respectively; 94 people stopped both medications. Blind breaks occurred in 11 people." Number analysed: 919 participants Number of interest: 919 participants Mean age: "mean age 61.7 years in lovastatin plus warfarin group, 61.9 years in lovastatin plus warfarin placebo, 62 years in lovastatin placebo plus warfarin and 61.3 years in lovastatin placebo plus warfarin placebo." Age range: 40 to 79 years old Gender: 474 men and 445 women Severity of condition: free of a history of MI, severe angina, stroke, or TIA Diagnostic criteria: "low‐density lipoprotein cholesterol values ranging from either 130 to 159 mg/dL (regardless of the number of coronary risk factors) or 160 to 189 mg/dL (with 1 coronary risk factor) with at least one carotid artery intima‐medial wall thickening > 1.5 mm (common or internal carotid artery) or > 1.6 mm (bifurcation) and less than 3.5 mm (common, internal, or bifurcation)" Smoking history: current smokers: 109, former smokers: 408 Inclusion criteria "40 to 79 years inclusive Serum LDL 130 to 159 mg/dL with any number of coronary risk factors Serum LDL 160 to 189 mg/dL with ~1 coronary risk factor Triglycerides ~400 mg/dL At least one B‐mode image measurement reflecting an intimal + medial wall thickness ~1.5 mm (common or internal carotid) or 1.6 mm (bifurcation) and ~3.5 mm" Exclusion criteria "Uncontrolled hypertension (DBP > 94 mmHg, SBP > 180 mmHg) History of definite MI, angina pectoris on chronic therapy, stroke or definite TIA Use of lipid‐lowering agents within the last year Regular use of anticoagulants ALT 1.2 times the upper limit of normal History of allergies or intolerance to lovastatin or warfarin Bleeding disorder or family history of bleeding disorders that contraindicates use of antithrombotic drugs Prothrombin time > 16.8 sec (equal to an INR > 2.0) during 1‐mg warfarin test dosing History of other serious competing medical conditions that might limit longevity or treatment Alcohol consumption > 14 drinks per week Personality unsuitable for participation Women who are pregnant or lactating or are of childbearing potential and are not practising birth control Plans to move or travel extensively during duration of study Participation in another research study Compliance < 80% to placebo and warfarin during run‐in and test dosing."
Interventions	Intervention: "warfarin was administered in a fixed 1 mg daily dose. The initially assigned dose of lovastatin was 20 mg per day. The goal was to lower the LDL cholesterol to a value of 90 to 110 mg/dL (2.31 to 2.85 mmol/L). The dosage of lovastatin was doubled if serum levels were above that range after an average 4.5 months of treatment." Comparison: placebo Concomitant medications: "all participants were encouraged to use open‐label aspirin (81 mg/day) unless there was a contraindication for its use."
Outcomes	Primary outcome: "change over time (i.e. the slope) during the course of treatment in the mean of maximum IMT across up to 12 preselected segments in the carotid arteries." Secondary outcome: "progression of the single maximum IMT measurement among the same preselected carotid artery segments." Time points reported: "regular clinic visits were scheduled every 6 weeks for the first 15 months and quarterly thereafter to permit safety monitoring. Fasting lipid profiles were obtained during follow‐up at 1.5, 3, 6, and 12 months and then annually. B‐mode ultrasonography was conducted semiannually. ALT and urine were examined at every visit. Drug adherence was assessed by pill count and participant report of usage. The annual visits involved a brief physical examination and dietary assessment."
Notes	Funding for trial: "this study was supported by grants from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (R01‐HL‐38194); Merck, Sharp and Dohme Research Laboratories, West Point, PA; and DuPont Pharmaceuticals, Wilmington, DE. Drugs were supplied by Merck, Sharp and Dohme (lovastatin), Du Pont Pharmaceuticals (warfarin), and Sterling Drug Company, NewYork, NY (aspirin)." Notable conflicts of interest of trial authors: no details given Protocol: NCT00000469
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The principal components of the randomization system were the computerised randomization list (devised in randomized blocks of 4 and 8) and the randomization program that confirmed participant eligibility and assigned the next identification number, which represented one of the four treatment groups"
Allocation concealment (selection bias)	Low risk	Quote: "All data collection and adjudication was done by investigators who were unaware of treatment allocation."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The medications were formulated to maintain blinding of the participants and investigators."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All data collection and adjudication was done by investigators who were unaware of treatment allocation."
Incomplete outcome data (attrition bias) All outcomes	Low risk	All exclusions reported with reasons and by study group
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	Low risk	No evidence of other bias