A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events

Context Most trials that address lipid management focus on reducing low-density lipoprotein (LDL) cholesterol levels rather than increasing high-density lipoprotein (HDL) cholesterol levels. Contribution In this double-blind trial, 143 military retirees with low HDL cholesterol levels and coronary artery disease were randomly assigned to placebo or aggressive HDL cholesterolincreasing therapy with gemfibrozil, niacin, and cholestyramine for 30 months. All participants received diet and exercise counseling. Compared with the placebo group, the treated group had a 20% decrease in total cholesterol level; a 36% increase in HDL cholesterol level; less focal coronary stenosis; fewer total cardiovascular events; and more flushing, skin rashes, and abdominal symptoms. Cautions The small trial had limited ability to assess clinical outcomes. The Editors Large epidemiologic studies have repeatedly demonstrated that cardiovascular risk increases proportionally with increasing total cholesterol and low-density lipoprotein (LDL) cholesterol levels and decreasing high-density lipoprotein (HDL) cholesterol levels (1, 2). Although many studies have documented that statins, drugs that primarily reduce LDL cholesterol levels, significantly reduce the risk for cardiovascular events (3-7), prospective studies that examine the clinical effects of increasing HDL cholesterol levels have been more limited. The Coronary Drug Project first reported evidence of a mortality benefit in patients treated with niacin; however, the difference was seen long after withdrawal of the study drug, making the mechanism of benefit less clear (8). The Helsinki Heart Study (9) examined the use of gemfibrozil in primary prevention. Coronary events were reduced by 34%, but the increase in HDL cholesterol level was modest (only 11%). The Bezafibrate Infarction Prevention Trial failed to show a reduction in cardiovascular events in the composite population, although a recent reanalysis of the data suggests an improved outcome in patients experiencing a greater increase in HDL cholesterol level (10). The Veterans Affairs HDL Intervention Trial (VA-HIT) (11) demonstrated a modest reduction in coronary events when gemfibrozil was used in patients with normal levels of LDL cholesterol and low levels of HDL cholesterol. The authors ascribed most of the reduction in clinical events to the improvement in HDL cholesterol, although the overall improvement was only approximately 6% with drug therapy. More recently, a combination of a statin (simvastatin) with niacin was found to favorably modify both HDL cholesterol and LDL cholesterol levels and reduce cardiovascular events compared with both placebo therapy and underlying treatment with antioxidants in a cohort of 160 patients with coronary disease (12). Despite a significant increase in mean HDL cholesterol levels, the overwhelming treatment effect in this study was the reduction in LDL cholesterol level (42% in the treatment group). The most suggestive evidence of benefit from an increase in HDL cholesterol level has come from trials assessing the effect on coronary stenosis. Trials of quantitative angiography after monotherapy with fibrates (13), as well as combinations of medications that both reduce LDL cholesterol levels and increase HDL cholesterol levels (14-18), have shown an attenuation in angiographic progression. Nissen and colleagues (19) recently took this theory a step further by demonstrating that an infusion of a recombinant form of HDL, apolipoprotein A-I Milano, can lead to regression of angiographic stenosis as assessed by intravascular ultrasonography. We undertook the Armed Forces Regression Study (AFREGS) in 1993 to determine whether coronary atherosclerosis, assessed by quantitative coronary angiography and clinical coronary events, would improve when combination drug therapy focused on increasing HDL cholesterol levels in a sample of patients with fairly normal LDL cholesterol levels and low HDL cholesterol levels. A pilot study by Whitney and colleagues (20) showed the feasibility of this trial design, and the safety of using these drugs in combination has been previously established (21). Methods Patients Participants living within a 150-mile radius of Wilford Hall Medical Center in San Antonio, Texas, who could provide written informed consent were eligible for enrollment. We recruited men and women younger than 76 years of age who had established or suspected coronary artery disease (positive results on an exercise treadmill test or classic angina) and did not have unstable symptoms. We allowed LDL cholesterol levels up to 4.1 mmol/L (160 mg/dL) with HDL cholesterol levels less than 1.0 mmol/L (40 mg/dL) after adherence to the American Heart Association (AHA) step II diet for at least 6 months. We set no lower limit to either HDL cholesterol or LDL cholesterol level. Each patient was required to have measurable stenosis between 30% and 80% of the luminal diameter within the coronary tree by caliper inspection. Patients with stenosis greater than 80% were eligible if they had a favorable prognosis based on functional testing (ability to exercise for >9 minutes on a full Bruce protocol exercise treadmill test). Exclusions included a major vascular event (myocardial infarction, cerebrovascular accident, coronary artery bypass grafting, or other coronary catheterbased intervention) within 6 months, a history of congestive heart failure (other than in the setting of myocardial infarction), or a left ventricular ejection fraction less than 0.4 on ventriculography. Other exclusion criteria included alcohol or substance abuse within the past year, uncontrolled arrhythmias, resistant hypertension, diabetes, uncontrolled gout, uncontrolled thyroid disease, liver or gall bladder disease, renal dysfunction (creatinine concentration > 176.8 mol/L [>2.0 mg/dL] or proteinuria greater than 2+ by dipstick or 500 mg/24 h), uncontrolled peptic ulcer disease, or pancreatic disorders. In addition, we excluded patients taking any lipid-modifying medications within 4 weeks of randomization, heparin or coumarin-type anticoagulants, long-term oral corticosteroid therapy, or other immunosuppressive agents. We also excluded patients if they had hypersensitivity to or history of intolerance that required cessation of therapy for any component of gemfibrozil, nicotinic acid, cholestyramine, aspirin, or nitrates. Other exclusion criteria were the potential for childbearing, technically inadequate coronary arteriography for stenosis quantification, or any serious condition that we thought would compromise participation in the study or preclude survival for the duration of the study. We thoroughly informed participants of the details of the study. Each patient voluntarily enrolled and signed an informed consent statement that the Wilford Hall Medical Center Institutional Review Board reviewed and approved. From screening laboratory records, we identified 1290 participant candidates and invited them to participate (Figure 1). Of the 847 patients who attended the introductory briefing, 671 met LDL cholesterol and HDL cholesterol entry criteria on fasting lipid analysis. Of the 269 participants who eventually provided informed consent, 55 subsequently withdrew for personal reasons, most commonly citing a fear of cardiac catheterization, and an additional 27 met an exclusion criterion. Of the 187 participants who completed the 6-month lifestyle modification phase and underwent coronary angiography, 44 were excluded after initial coronary arteriography; 27 had extensive coronary disease necessitating revascularization (percutaneous coronary intervention in 3 patients and coronary artery bypass grafting in 24 patients), and 17 had insignificant coronary disease on angiography. Thus, we eventually randomly assigned 143 patients (11% of those initially contacted) to either pharmacologic therapy or placebo. Figure 1. Flow of patients through the study. Protocol After inclusion and exclusion criteria were met, a 6- to 8-month run-in period was performed to ensure that patients could adhere to the prescribed diet. During this phase, all patients received diet counseling from a study dietitian, exercise guidance from an exercise specialist, and smoking cessation advice. All study participants committed to attending a bimonthly food show for training in the AHA step II diet, with reinforcing presentations from the dietitian, exercise specialist, and cardiologist that discussed cardiac risk factor modification. We randomly assigned each participant by using a computer-generated randomization schedule. The central pharmacy held the code, and the information was not shared with physicians or patients until the completion of the protocol. Patients were randomly assigned to 1 of 2 treatment groups: pharmacologic therapy with gemfibrozil, niacin, and cholestyramine or conventional therapy. The goal of therapy was to increase HDL cholesterol level by at least 25%. The study was double-blind and placebo-controlled. The pharmaceutical company prepared all medications and placebos, and the central pharmacy dispensed them at 30-day intervals. The pharmacologic therapy group began receiving gemfibrozil, 600 mg twice per day. Short-acting niacin was added in the third month at a dosage of 250 mg/d and was titrated to 3000 mg/d as tolerated. Cholestyramine was added in the sixth month, and the dosage was titrated to 16 g/d as tolerated. The conventional therapy group was maintained on the AHA step II diet and applicable matching placebos for the duration of the investigation. If LDL cholesterol levels exceeded 4.14 mmol/L (160 mg/dL) during the trial, cholestyramine was administered in an open-label fashion. Participants visited 1 clinic on a monthly basis for the duration of the study. At each monthly visit, clinicians measured vital signs and weight, counted unused study drugs, reviewed changes in medications or medical status, provided ne