ClinicalTrials.gov processed this data on March 28, 2024Link to the current ClinicalTrials.gov record.https://clinicaltrials.gov/ct2/show/NCT0000046150R01HL036392NCT00000461Harvard Atherosclerosis Reversibility Project (HARP)National Heart, Lung, and Blood Institute (NHLBI)NIH
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.
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.
CompletedDecember 1986November 1992Phase 2InterventionalNoRandomizedTreatmentCardiovascular DiseasesCoronary DiseaseHeart DiseasesMyocardial IschemiaDrugpravastatinDrugniacinDrugcholestyramineDruggemfibrozilDrugfatty acids, omega-3
Men and women, normocholesterolemic, with 30 percent or greater narrowing of a coronary
artery lumen as revealed by angiography. (Cholesterol-Lowering Agent Trial).
Men and women with angiographically-documented coronary heart disease (Fish Oil Tr
All18 Years75 YearsNoFrank SacksBrigham and Women's HospitalSacks FM, Pasternak RC, Gibson CM, Rosner B, Stone PH. Effect on coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolaemic patients. Harvard Atherosclerosis Reversibility Project (HARP) Group. Lancet. 1994 Oct 29;344(8931):1182-6. doi: 10.1016/s0140-6736(94)90506-1.7934538Sacks FM, Stone PH, Gibson CM, Silverman DI, Rosner B, Pasternak RC. Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group. J Am Coll Cardiol. 1995 Jun;25(7):1492-8. doi: 10.1016/0735-1097(95)00095-l.7759696Sacks FM, Gibson CM, Rosner B, Pasternak RC, Stone PH. The influence of pretreatment low density lipoprotein cholesterol concentrations on the effect of hypocholesterolemic therapy on coronary atherosclerosis in angiographic trials. Harvard Atherosclerosis Reversibility Project Research Group. Am J Cardiol. 1995 Sep 28;76(9):78C-85C. doi: 10.1016/s0002-9149(99)80475-5.7572692Pasternak RC, Brown LE, Stone PH, Silverman DI, Gibson CM, Sacks FM. Effect of combination therapy with lipid-reducing drugs in patients with coronary heart disease and "normal" cholesterol levels. A randomized, placebo-controlled trial. Harvard Atherosclerosis Reversibility Project (HARP) Study Group. Ann Intern Med. 1996 Oct 1;125(7):529-40. doi: 10.7326/0003-4819-125-7-199610010-00001.8815751March 2005October 27, 1999October 27, 1999October 28, 1999March 15, 2016March 15, 2016March 16, 2016Cardiovascular DiseasesHeart DiseasesCoronary DiseaseMyocardial IschemiaIschemiaNiacinPravastatinGemfibrozilCholestyramine Resin