PMID- 8815751 OWN - NLM STAT- MEDLINE DCOM- 19961010 LR - 20190619 IS - 0003-4819 (Print) IS - 0003-4819 (Linking) VI - 125 IP - 7 DP - 1996 Oct 1 TI - 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. PG - 529-40 AB - BACKGROUND: Combination drug therapy has been shown to decrease cholesterol levels in hyperlipidemic patients. However, its efficacy has not been well studied in patients previously considered to be normolipidemic, many of whom are now candidates for this therapy. OBJECTIVE: To determine the efficacy and tolerability of multidrug therapy designed to improve low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels in patients with coronary heart disease and average lipid levels. DESIGN: Randomized, placebo-controlled, 2.5-year trial comparing patients receiving usual care with patients receiving stepped-care drug therapy. INTERVENTION: Stepped-care therapy (pravastatin, nicotinic acid, cholestyramine, and gemfibrozil) to decrease total cholesterol levels to less than 4.1 mmol/L (160 mg/dL) and the ratio of LDL cholesterol to HDL cholesterol to less than 2.0. SETTING: 2 academic, urban, tertiary care hospitals. PATIENTS: 91 patients (80 men and 11 women) with coronary heart disease, a mean age of 60 years, total cholesterol levels less than 6.4 mmol/L (250 mg/dL) at baseline, and ratios of total cholesterol to HDL cholesterol greater than 4.0 at baseline. MEASUREMENTS: Fasting serum lipoprotein profile, fasting apolipoprotein levels, and frequency of adverse effects. Patients were assessed every 6 weeks during drug titration and every 3 months thereafter. RESULTS: Mean lipid levels at baseline were as follows: total cholesterol, 5.5 mmol/L (214 mg/dL); LDL cholesterol, 3.6 mmol/L (140 mg/dL); HDL cholesterol, 1.1 mmol/L (42 mg/dL); and triglycerides, 1.8 mmol/L (159 mg/dL). With pravastatin, changes in levels from baseline were -22% for total cholesterol, -32% for LDL cholesterol +8% for HDL cholesterol, and -15% for triglycerides (P < 0.001 for all comparisons). With the addition of 1.5 g of nicotinic acid, additional changes were -6% for total cholesterol (P < 0.002). -11% for LDL cholesterol, +8% for HDL cholesterol, and -10% for triglycerides (P < 0.001 for all comparisons). With 2.25 to 3 g of nicotinic acid, these changes were -7% for total cholesterol (P = 0.007), -14% for LDL cholesterol (P < 0.001), +6% for HDL cholesterol (P = 0.02), and -13% for triglycerides (P = 0.03). With cholestyramine, total cholesterol and LDL cholesterol levels were unchanged compared with the previous step; the change in HDL cholesterol level was -8% (P = 0.03); and the change in triglyceride level was +46% (P < 0.001). With gemfibrozil, total cholesterol level was unchanged; the additional change in LDL cholesterol level was +12% (P = 0.09); the change in HDL cholesterol level was +12% (P = 0.03); and the change in triglyceride level was -37% (P < 0.001). Apolipoprotein B levels decreased by 25% overall (P < 0.001); lipoprotein(a) levels did not change significantly. Adverse effects were primarily attributable to nicotinic acid or cholestyramine. In 18 of the 35 patients (50%) whose baseline LDL cholesterol levels were greater than 3.35 mmol/L (130 mg/dL), pravastatin decreased LDL cholesterol levels to 2.6 mmol/L (100 mg/dL) or less by 6 weeks; 70% of patients needed combination therapy to reach this National Cholesterol Education Program goal during the 2.5 years of the study. Adding nicotinic acid to pravastatin produced LDL cholesterol levels of 2.6 mmol/L or less in 15 more of these 35 patients, so that 94% (n = 33) of the patients receiving these two drugs reached this goal. CONCLUSIONS: To reach current goals for LDL cholesterol levels, most normolipidemic patients with coronary heart disease in this study needed combination therapy. Pravastatin with nicotinic acid and pravastatin with gemfibrozil are well-tolerated combinations that can maintain target LDL cholesterol levels, decrease triglyceride levels, and increase HDL cholesterol levels. Adding resin to these combinations produced no further benefit. FAU - Pasternak, R C AU - Pasternak RC AD - Cardiac Unit, Massachusetts General Hospital, Boston 02114, USA. FAU - Brown, L E AU - Brown LE FAU - Stone, P H AU - Stone PH FAU - Silverman, D I AU - Silverman DI FAU - Gibson, C M AU - Gibson CM FAU - Sacks, F M AU - Sacks FM LA - eng GR - HL34980/HL/NHLBI NIH HHS/United States GR - M01 RR02635/RR/NCRR NIH HHS/United States PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Ann Intern Med JT - Annals of internal medicine JID - 0372351 RN - 0 (Cholesterol, HDL) RN - 0 (Cholesterol, LDL) RN - 0 (Hypolipidemic Agents) RN - 0 (Placebos) RN - 0 (Triglycerides) SB - IM CIN - Ann Intern Med. 1997 Jun 1;126(11):916; author reply 917. PMID: 9163299 CIN - Ann Intern Med. 1997 Jun 1;126(11):916-7. PMID: 9163300 MH - Algorithms MH - Cholesterol, HDL/*blood MH - Cholesterol, LDL/*blood MH - Coronary Disease/blood/*complications MH - Drug Administration Schedule MH - Drug Therapy, Combination MH - Female MH - Humans MH - Hyperlipidemias/etiology/*prevention & control MH - Hypolipidemic Agents/administration & dosage/adverse effects/*therapeutic use MH - Male MH - Middle Aged MH - Placebos MH - Triglycerides/blood EDAT- 1996/10/01 00:00 MHDA- 1996/10/01 00:01 CRDT- 1996/10/01 00:00 PHST- 1996/10/01 00:00 [pubmed] PHST- 1996/10/01 00:01 [medline] PHST- 1996/10/01 00:00 [entrez] AID - 10.7326/0003-4819-125-7-199610010-00001 [doi] PST - ppublish SO - Ann Intern Med. 1996 Oct 1;125(7):529-40. doi: 10.7326/0003-4819-125-7-199610010-00001.