Harvard Atherosclerosis Reversibility Project (HARP)
Condition: Cardiovascular Diseases; Coronary Disease; Heart Diseases; Myocardial Ischemia
MeSH terms: Cardiovascular Diseases; Heart Diseases; Coronary Disease; Myocardial Ischemia; Ischemia
Study type: Interventional
Phase: Phase 2

Summary: 
      To determine by sequential coronary arteriography whether a lipid-lowering diet with and
      without lipid-lowering drugs could reverse coronary artery disease in normocholesterolemic
      patients. Also, to test whether fish oil supplements could improve human coronary
      atherosclerosis. Finally, to determine the effect of combination therapy with lipid-reducing
      drugs in patients with coronary heart disease and "normal" cholesterol levels. At least three
      clinical trials were conducted.
    

Detailed description: 
      BACKGROUND:

      The prognosis of patients with coronary heart disease is closely related to the degree of
      coronary luminal obstruction. In population studies, the incidence and severity of coronary
      atherosclerosis on angiography is correlated with diet and plasma lipoprotein cholesterol.
      Previous clinical trials had shown that treatments that lowered plasma concentrations of low
      density lipoprotein cholesterol benefited some hypercholesterolemic patients with coronary
      heart disease. No similar benefit had been demonstrated in normocholesterolemic patients who
      make up the majority of patients with coronary heart disease.

      DESIGN NARRATIVE:

      In the cholesterol-lowering agent trial, all patients received Step 1 dietary instruction
      before randomization and every three months thereafter. Randomization was stratified by
      medical or surgical treatment for coronary disease and the ratio of total to HDL cholesterol.
      A total of 39 patients were assigned to placebo and 40 to active treatment with pravastatin,
      nicotinic acid, cholestyramine, and gemfibrozil stepwise as needed to reach the specified
      goal (total cholesterol less than or equal to 4.1 mmol/L, ratio of LDL/HDL cholesterol less
      than or equal to 2.0). Lipid concentrations were measured every six weeks. Baseline
      angiograms were compared to angiograms taken at 30 months.

      In the fish oil trial, 41 patients were randomized to fish oil capsules containing 6 grams of
      n-3 fatty acids daily and 39 patients were randomized to olive oil placebo capsules for an
      average duration of 28 months. Each fish oil capsule contained 500 mg of n-3 polyunsaturated
      fatty acids composed of 240 mg of eicosapentaenoic acid, 160 mg of docosahexaenoic acid, and
      100 mg of mainly docosapentaenoic acid. Randomization was stratified by medical or surgical
      treatment for coronary disease and the ratio of total to HDL cholesterol. The primary outcome
      variable was change in minimal diameter of coronary artery lesions expressed as a continuous
      variable. During the initial hospital stay for catheterization, dietary instruction was
      provided to every patient according to the National Cholesterol Education Program (NCEP) Step
      1 guidelines. A seven-day diet record was collected at the randomization visit and every
      three months during the trial. Every twelve weeks, a research nurse reviewed with the
      patients side effects, diet, and concomitant medications and performed a pill count. Every 24
      weeks, the patients received an interval medical history and physical examination by a
      physician. A fasting blood sample was obtained for lipid analysis at the 12- and 24-week
      visits and every 24 weeks thereafter. If the total cholesterol level of any patient increased
      to 250 mg/dl (6.43 mmol/liter) or greater on two consecutive measurements, intensified
      dietary instruction was given, followed by drug therapy with cholestyramine or nicotinic acid
      or both as needed to lower total cholesterol to less than 250 mg/dl. Twenty-one patients did
      not complete the protocol due to death, refusal to undergo the second cardiac
      catheterization, development of medical conditions precluding participation, intolerance to
      the capsules, and a missing initial angiogram.

      In the combination therapy trial, patients were randomized to usual care or to stepped-care
      drug therapy with lipid-lowering agents including pravastatin, nicotinic acid,
      cholestyramine, and gemfibrozil to decrease total cholesterol levels to less than 160 mg/dl
      and the ratio of low density lipoprotein cholesterol to high density lipoprotein cholesterol
      to less than 2.0. Measurements included fasting serum lipoprotein profile, fasting
      apolipoprotein levels, and frequency of adverse effects. Patients were assessed every six
      weeks during drug titration and every three months thereafter for two -and-a-half years.

      The study completion date listed in this record was obtained from the "End Date" entered in
      the Protocol Registration and Results System (PRS) record.
    

Intervention name(s): pravastatin; niacin; cholestyramine; gemfibrozil; fatty acids, omega-3
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention MeSH terms: Niacin; Pravastatin; Gemfibrozil; Cholestyramine Resin
Allocation: Randomized
Primary purpose: Treatment