Harvard Atherosclerosis Reversibility Project - HARP

Description:

Lipid-lowering therapy for primary prevention in normocholesterolemic patients.

Hypothesis:

Lipid-lowering therapy ameliorates coronary atherosclerosis in patients with raised concentrations of low-density-lipoprotein (LDL) cholesterol. The study is designed to determine whether a similar benefit can be obtained in normocholesterolemic patients.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 91
Mean Follow Up: 125 weeks
Mean Patient Age: 58
Female: 12
Mean Ejection Fraction: not given

Patient Populations:

Nonsmokers aged 30 to 75 years.
Angiographically documented stenoses (>30%) of a major coronary artery.
Total cholesterol level between 4.7 and 6.5 mmol/L (180 and 250 mg/dL).
A ratio of total cholesterol to HDL cholesterol greater than 4.0.
Women had to be postmenopausal or surgically sterile.

Exclusions:

Taking hypolipidemic drugs.
Insulin-dependent diabetes mellitus.
Other endocrine diseases or secondary causes of hyperlipidemia.
Symptomatic congestive heart failure.
Ejection fraction <30%.
Other debilitating, chronic, noncardiac diseases.

Primary Endpoints:

Total cholesterol level of 4.1 mmol/L (160 mg/dL) or less, ratio of LDL to HDL of less than 2.0

Drug/Procedures Used:

Stepped Care:
1. Pravastatin, 40 mg/d, given at night.
2. If goal not reached after 6 weeks, add nicotinic acid, 750 mg, bid.
3. If goal not reached after 6 weeks, and nicotinic acid is tolerated, increase dosage of nicotinic acid to 3 g/d over.

Concomitant Medications:

Aspirin, beta-blockers, ACE inhibitors, calcium blockers

Principal Findings:

Pravastatin, 40 mg/d decreased total cholesterol levels by 22%, decreased LDL cholesterol by 32%, decreased triglyceride levels by 15%, and increased HDL cholesterol levels by 8% (P <0.001 for all comparisons). Pravastatin also decreased the ratio of total cholesterol to HDL cholesterol by 28% (P <0.001) and the ratio of LDL cholesterol to HDL cholesterol by 37% (P <0.001).

Nicotinic acid, 1.5 g/d, was added to pravastatin for 40 of 44 patients in the control group. Nicotinic acid caused additional mean reductions of 6% in total cholesterol levels (P <0.002), and 10% in triglyceride levels (P <0.001), and it caused an additional increase in HDL cholesterol levels of 8% (P <0.001). Nicotinic acid (1.5 g/d) and pravastatin (40 mg/d) combined produced changes of -26% in total cholesterol levels, -39% in LDL cholesterol levels, -23% in triglyceride levels, +17% in HDL cholesterol levels, -33% in the ratio of total cholesterol to HDL cholesterol, and -46% in the ratio of LDL cholesterol to HDL cholesterol (P <0.001 for all comparisons).

When the dose of nicotinic acid was increased to 2.25 to 3 g/d in combination with pravastatin in 23 patients, further reductions were seen. Total cholesterol levels were reduced by an additional 7% (P = 0.007), LDL cholesterol levels were reduced by an additional 14% (P <0.001), and triglyceride levels were reduced by an additional 13% (P = 0.03). Levels of HDL cholesterol increased by an additional 6% (P = 0.02). The total effect of nicotinic acid (2.25 to 3 g/d) and pravastatin (40 mg/d) combined produced changes of -29% in total cholesterol levels, -44% in LDL cholesterol levels, -26% in triglyceride levels, +20% in HDL cholesterol levels, -41% in the ratio of total cholesterol to HDL cholesterol, and -53% in the ratio of LDL cholesterol to HDL cholesterol (P <0.001 for all comparisons).

Cholestyramine, 4 to 24 g, was added to pravastatin and nicotinic acid in 21 patients. Surprisingly, the addition of this resin partially reversed the action of the previous steps. The mean triglyceride level increased by 46% (P <0.001), and the mean HDL cholesterol level decreased by 8% (P = 0.03) relative to the levels achieved at the previous step (nicotinic acid, to 3 g/d in combination with pravastatin, 40 mg/d). The LDL cholesterol level did not change.

Twelve patients required gemfibrozil, 600 to 1200 mg/d. In contrast to the lack of overall benefit produced by the addition of cholestyramine, the addition of gemfibrozil increased HDL cholesterol levels by 12% (P = 0.03). Triglyceride levels markedly decreased by 37% (P <0.001) relative to the levels achieved at the previous step. LDL cholesterol level increased by 12% (P = 0.09).
There was no significant difference in coronary atherosclerosis during follow-up between the active treatment group and placebo groups: the mean minimum diameter narrowed significantly, but to the same extent in both groups (change baseline to 2.5 years 0.14 [SD 0.42] and 0.15 [SD 0.41] mm, respectively, both p <0.001). Similarly, the change in percentage stenosis did not differ between the groups (2.1 [SD 10.6] vs. 2.4 [SD 10.3] %). By multiple regression analysis, the adjusted difference between the groups was 0.04 mm (95% CI, -0.04 to 0.12 mm) increase in minimum diameter and a 0% (-1.7 to 1.7) change in percentage stenosis. The groups differed significantly in plasma lipids (% change in active minus % change in placebo group: -28% total cholesterol, -41% LDL-cholesterol, 13% HDL-cholesterol, -26% triglycerides, -31% apolipoprotein B, all p <0.001).

Interpretation:

The combination of pravastatin, 40 mg, and nicotinic acid, 1.5 to 3.0 g, was particularly effective:
LDL cholesterol reduced by 39% to 44%.
increased HDL cholesterol levels by 17% to 20%.
decreased the ratio of LDL cholesterol to HDL cholesterol by 46% to 53%.

The National Cholesterol Education Program (NCEP) guidelines for the secondary prevention of cardiovascular disease recommend the use of drug therapy:
to decrease LDL cholesterol levels to 2.6 mmol/L (100 mg/dL) or less in patients whose LDL cholesterol levels are greater than 3.25 mmol/L (130 mg/dL).
As an option for patients with LDL cholesterol levels greater than 2.6 mmol/L (100 mg/dL).

The HARP study determined the number and types of medications needed to achieve the NCEP goal.

The stepped-care algorithm of the HARP study provides a clinical approach that leads to drug selection and the use of a minimum of drugs at tolerable doses to achieve the NCEP target goal.

Intensive pharmacological treatment of normocholesterolemic patients has significant effects on plasma lipid concentrations but no angiographically measurable benefit on the coronary arteries.

References:

1. Lancet 1994;344:1182-86. Final results
2. Ann Intern Med 1996;125:529-40. Lipid levels

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Statins

Keywords: Cholestyramine Resin, Cholesterol, Coronary Artery Disease, Gemfibrozil, Pravastatin, Nicotinic Acids, Constriction, Pathologic, Hypercholesterolemia, Triglycerides, Regression Analysis, Primary Prevention


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