HATS 2001Low.

Methods	The HDL‐Atherosclerosis Treatment Study (HATS). Randomised, double‐blind, placebo‐controlled trial with two‐by‐two factorial design.
Participants	Country: United States and Canada. Number of participants randomised: 160, mean age 53 years, 13 % female. Inclusion criteria: men (younger than 63 years of age) and women (younger than 70 years of age) with clinical coronary disease (defined as previous myocardial infarction, coronary interventions, or confirmed angina) and with at least three stenoses of at least 30 percent of the luminal diameter or one stenosis of at least 50 percent. All had low levels of HDL cholesterol (35 mg per decilitre [0.91 mmol per litre] or lower in men and 40 mg per deciliter [1.03 mmol per litre] in women), LDL cholesterol levels of 145 mg per deciliter (3.75 mmol per litre) or lower, and triglyceride levels below 400 mg per decilitre (4.52 mmol/L). Exclusion criteria: lipid levels outside of the specified ranges, coronary bypass surgery, severe hypertension, recent gout, or liver, thyroid, or kidney disease, or uncontrolled diabetes.
Interventions	Patients were randomly assigned to receive: group 1: simvastatin (10 mg to 20 mg) plus niacin (500 mg to 4 g), (n = 33); group 2: antioxidant vitamins, 800 IU of vitamin E (as d‐alpha‐tocopherol), 1000 mg of vitamin C, 25 mg of natural beta‐carotene, and 100 µg of selenium; group 3: simvastatin plus niacin plus antioxidants (n = 40). group 4: all placebos (n = 34); for three years. Simvastatin therapy began at 10 mg per day for patients with an LDL cholesterol level of 110 mg per decilitre (2.84 mmol per litre) or lower on screening and 20 mg per day for those with an LDL cholesterol level higher than 110 mg per decilitre. The dose was increased by 10 mg per day in patients whose LDL cholesterol level was higher than 90 mg per decilitre (2.33 mmol per litre) in any sample during the first year of the study and was reduced by 10 mg per day if the LDL cholesterol level fell below 40 mg per decilitre (1.03 mmol per litre) at any time during the study. During treatment, patients receiving the matching placebo were given 10 mg of simvastatin if their LDL cholesterol level was 140 mg per decilitre (3.62 mmol per litre) or higher; the target level was 130 mg per decilitre (3.37 mmol per litre) or lower. The dose of slow‐release niacin was increased linearly from 250 mg twice daily to 1000 mg twice daily at four weeks. Patients whose HDL cholesterol levels had not increased by at least 5 mg per decilitre (0.13 mmol per litre) at 3 months, at least 8 mg per decilitre (0.21 mmol per litre) at 8 months, and at least 10 mg per decilitre at 12 months were switched to crystalline niacin the dose of which was gradually increased to 3 g per day or, at most, 4 g per day in order to meet the target levels. Niacin "placebo" tablets (taken at a dose of 50 mg twice daily) were active, provoking flushing without affecting lipid levels.
Outcomes	The primary outcome measures were: arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularisation).
Notes	Compliance with the trail regimens, measured by means of pill counts, ranged between 80 percent and 95 percent. The mean doses of simvastatin and niacin taken by patients were 13 ± 6 mg per day and 2.4 ± 2.0 g per day, respectively. Plasma vitamin concentrations increased significantly in 75 patients who received active vitamin therapy. Vital status was ascertained at 38 months for all 160 patients enrolled. Follow‐up information for 159 patients was complete, including records of events from the patient's physicians. The active agents and placebos were provided by: Simvastatin (Zocor, Merck, West Point, Pa.) slow‐release niacin (Slo‐Niacin, Upsher‐Smith, Minneapolis) crystalline niacin (Niacor, Upsher‐Smith).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)	Low risk	Allocation was controlled by a central and independent randomisation unit, so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias) All outcomes	Low risk	The trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)	Low risk	Pre‐defined, or clinically relevant and reasonably expected outcomes are reported on.
Other bias	Low risk	The trial appears to be free of other components that could put it at risk of bias.