Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia

Plasma cholesterol and other lipoproteins play a significant role in the development of atherosclerosis and subsequent coronary heart disease (CHD). This 1 year study was designed to confirm the efficacy and safety of atorvastatin (Lipitor) compared to pravastatin, a marketed agent for low density lipoprotein cholesterol (LDL-C) reduction in hypercholesterolemic patients. Patients were recruited at 26 centers in six European countries. After a 6 week placebo baseline phase, patients were randomized to receive atorvastatin 10 mg or pravastatin 20 mg daily. The dose could be doubled at week 16, if LDL-C levels remained ≥3.4 mmol/l (135 mg/dl). Atorvastatin significantly lowered LDL-C from baseline by 35% compared with 23% for pravastatin (P<0.05). A total of 72% of atorvastatin patients attained the LDL-C target level of <3.4 mmol/l, compared to 26% of pravastatin patients. Atorvastatin also significantly reduced TC, TG and apo B (P<0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. Atorvastatin 10 and 20 mg once daily is superior to pravastatin 20 and 40 mg once daily in treating patients with hypercholesterolemia.     

Efficacy and tolerability of ezetimibe 10 mg/day coadministered with statins in patients with primary hypercholesterolemia who do not achieve target LDL-C while on statin monotherapy: A Canadian, multicentre, prospective study--the Ezetrol Add-On Study

BACKGROUND: For patients who have above-target low-density lipoprotein cholesterol (LDL-C) levels while on statin monotherapy, coadministration of a cholesterol absorption inhibitor with the statin may decrease serum LDL-C levels and improve overall lipid profiles. OBJECTIVES: To assess the effectiveness and safety of ezetimibe 10 mg/day coadministered with a statin in patients with primary hypercholesterolemia who have higher than recommended LDL-C levels while on statin monotherapy. METHODS: A six-week, prospective, multicentre study of eligible patients who had above-target LDL-C levels while on monotherapy with any statin, regardless of dose, for a minimum of four weeks. All patients were treated for six weeks with 10 mg ezetimibe daily coadministered with their current statins. RESULTS: A total of 1141 patients were screened, 953 (83.5%) fulfilled the study inclusion criteria and 837 (87.8%) completed the study. Reasons for withdrawal included: lost to follow-up (50 patients [5.2%]); protocol violations (45 patients [4.7%]); adverse events (19 patients [2.0%]); and withdrawal of consent (two patients [0.2%]). After six weeks of treatment, statistically significant (P = 0.001) mean reductions were observed in LDL-C (30.05%), total cholesterol (20.84%), triglycerides (10.16%), apolipoprotein B (19.84%) and the total cholesterol to high-density lipoprotein cholesterol ratio (19.88%). At six weeks, 674 patients (80.5%) achieved target LDL-C levels. Fifty predominantly mild, nonserious adverse events related to ezetimibe were reported by 32 patients (3.4%). Frequently reported adverse events included constipation (n = 7 [0.7% of patients]), diarrhea (n = 4 [0.4%]) and dizziness (n = 4 [0.4%]). CONCLUSION: Ezetimibe coadministered with statins is effective in reducing LDL-C in patients who do not attain target LDL-C levels while on statin monotherapy.     

Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.

AIMS: This randomized, double-blind, placebo-controlled, parallel-group study evaluated the safety and efficacy of ezetimibe 10 mg/day in patients with primary hypercholesterolemia. METHODS AND RESULTS: Following dietary stabilization, a 2-12-week washout period, and a 4-week, single-blind, placebo lead-in period, 827 patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =3.36 mmol/l (130 mg/dl) to < or =6.47 mmol/l (250 mg/dl) and triglycerides < or =3.95 mmol/l (350 mg/dl) were randomized 3:1 to receive ezetimibe 10 mg or placebo orally once daily in the morning for 12 weeks. The primary efficacy endpoint was percentage reduction in direct plasma LDL-C. Ezetimibe reduced direct LDL-C by a mean of 17.7% from baseline to endpoint, compared with an increase of 0.8% with placebo (P<0.01). Response to ezetimibe was generally consistent across all subgroups analyzed. Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, high-density lipoprotein(2)-cholesterol and lipoprotein(a), and elicited a trend toward lower triglyceride levels. Ezetimibe did not alter the serum concentrations of lipid-soluble vitamins or significantly affect baseline or stimulated cortisol production. Ezetimibe was well tolerated, with a safety profile similar to that of placebo. CONCLUSIONS: Ezetimibe, which significantly reduces LDL-C and favorably affects other lipid variables, may provide a well tolerated and effective new option for lipid management in the future.     

Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia

This multicenter, randomized, double-blind, placebo-controlled clinical study assessed the efficacy and safety of ezetimibe administered with lovastatin in primary hypercholesterolemia. After dietary stabilization, a 2- to 12-week washout period, and a 4-week single-blind placebo lead-in period, 548 patients with low-density lipoprotein (LDL) cholesterol > or =145 mg/dl (3.75 mmol/L) and < or =250 mg/dl (6.47 mmol/L) and triglycerides < or =350 mg/dl (3.99 mmol/L) were randomized to one of the following, administered daily for 12 weeks: ezetimibe 10 mg; lovastatin 10, 20, or 40 mg; ezetimibe 10 mg plus lovastatin 10, 20, or 40 mg; or placebo. The primary efficacy variable was percentage decrease in direct LDL cholesterol from baseline to end point for pooled ezetimibe plus lovastatin versus pooled lovastatin alone. Ezetimibe plus lovastatin significantly improved concentrations of LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides compared with lovastatin alone (p <0.01). The coadministration of ezetimibe provided an incremental 14% LDL cholesterol decrease, a 5% HDL cholesterol increase, and a 10% decrease in triglycerides compared with pooled lovastatin alone. Ezetimibe plus lovastatin provided mean LDL cholesterol decreases of 33% to 45%, median triglyceride decreases of 19% to 27%, and mean HDL cholesterol increases of 8% to 9%, depending on the statin dose. The coadministration of ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable efficacy to high-dose lovastatin (40 mg) across the lipid profile (LDL cholesterol, HDL cholesterol, and triglycerides). Ezetimibe plus lovastatin was well tolerated, with a safety profile similar to both lovastatin alone and placebo. The coadministration of ezetimibe and lovastatin may offer a new treatment option in lipid management of patients with hypercholesterolemia.     

西立伐他汀治疗原发性高胆固醇血症随机对照研究

目的：比较不同剂量的西立伐他汀（ｃｅｒｉｖａｓｔａｔｉｎ）治疗国人原发性高胆固醇血症的疗效、安全性及耐受性。方法采用多中心,随机、双盲、安慰剂对照,平行组试验,所有入选停止其他降脂治疗且饮食控制达美国心脏协会Ⅰ级（ＡＨＡ－ＳＴＥＰ－Ｉ）或其相应标准,满４周后,接受单盲安慰剂治疗５周（Ａ期）。安慰剂期后,４７０例患随机接受西立伐他汀０．１ｍｇ（ｎ＝１１９）、０．２ｍｇ（ｎ＝１１７）、０．３ｍｇ（     

Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia.

AIMS: To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO) in patients with mixed hyperlipidaemia. METHODS AND RESULTS: This was a multicentre, randomized, double-blind, placebo-controlled, parallel arm trial in patients with mixed hyperlipidaemia [LDL-cholesterol (LDL-C), 3.4-5.7 mmol/L (2.6-4.7 mmol/L for patients with type 2 diabetes); triglycerides (TG), 2.3-5.7 mmol/L] and no history of coronary heart disease (CHD), CHD-equivalent disease (except for type 2 diabetes), or CHD risk score>20%. A total of 625 patients was randomized in a 1:3:3:3 ratio to one of four daily treatments for 12 weeks: placebo; EZE 10 mg; FENO 160 mg; FENO 160 mg plus EZE 10 mg (FENO+EZE). The primary endpoint compared the LDL-C lowering efficacy of FENO+EZE vs. FENO alone. LDL-C, non-HDL-cholesterol (non-HDL-C), and apolipoprotein B were significantly (P<0.001) reduced with FENO+EZE when compared with FENO or EZE alone. TG levels were significantly decreased and HDL-C was significantly increased with FENO+EZE and FENO treatments when compared with placebo (P<0.001). Coadministration therapy reduced LDL-C by 20.4%, non-HDL-C by 30.4%, TG by 44.0%, and increased HDL-C by 19.0%. At baseline, >70% of all patients exhibited the small, dense LDL pattern B profile. A greater proportion of patients on FENO+EZE and FENO alone treatments shifted from a more atherogenic LDL size pattern to a larger, more buoyant, and less atherogenic LDL size pattern at study endpoint than those on placebo or EZE. All three active therapies were well tolerated. CONCLUSION: Coadministration of EZE with FENO provided a complementary efficacy therapy that improves the atherogenic lipid profile of patients with mixed hyperlipidaemia.     

A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia

Pitavastatin (p-INN) is a novel and fully synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, with a cholesterol-lowering action stronger than that of other statins currently in use. A 12-week, multi-center, randomized, double-blind, controlled study was conducted to confirm the efficacy and safety of pitavastatin compared with pravastatin, an agent for using to reduce low density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. Patients were recruited at 43 institutes in Japan. Following more than 4 weeks run-in period, 240 patients were randomized to receive 2 mg of pitavastatin or 10 mg of pravastatin daily. At 12 weeks post-randomization, the pitavastatin group showed significantly lower LDL-C levels by -37.6% from baseline compared with -18.4% in the pravastatin group (P<0.05). Pitavastatin also significantly lowered total cholesterol (TC) by -28.2% compared with -14.0% of pravastatin (P<0.05). The LDL-C target level of <140 mg/dl was attained in 75% of the patients treated with pitavastatin, compared with 36% of those in the pravastatin group (P<0.05). Pitavastatin also significantly reduced triglycerides (TG), apo B, C-II and C-III, compared with pravastatin, and increased HDL-C, apo A-I and A-II, to the same extent of pravastatin. Safety was assessed by monitoring adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. These results indicated that pitavastatin was more effective than pravastatin, and both drugs were well-tolerated in the treatment of hypercholesterolemia.     

Erratum to 'Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial' [European Heart Journal 2003; 24(8): 717-728]

The publisher regrets that     

Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin. Methods and Results- Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LDL cholesterol (LDL-C) from statin-40 baseline to the end point for patients receiving statins alone (statin-80) versus patients receiving ezetimibe plus atorvastatin or simvastatin at either dose (ezetimibe plus statin-40/80). Ezetimibe plus statin-40/80 significantly reduced LDL-C levels compared with statin-80 (-20.7% versus -6.7%, P=0.007). In the high-dose statin cohorts, ezetimibe plus statin-80 reduced LDL-C by an additional 20.5% (P=0.0001) versus statin-80. Similar significant reductions in LDL-C concentrations were observed for patients with genotype-confirmed HoFH (n=35). Ezetimibe was safe and well tolerated. CONCLUSIONS: Ezetimibe coadministered with atorvastatin or simvastatin in patients with HoFH produced clinically important LDL-C reductions compared with best current therapy. Ezetimibe provides a new, complementary pharmacological approach for this high-risk population.     

Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial

The hepatotoxic potential of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in patients with underlying chronic liver disease remains controversial. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that compared pravastatin (80 mg) to a placebo administered once daily to hypercholesterolemic subjects greater than 18 years of age with at least a 6-month history of compensated chronic liver disease and with a low-density lipoprotein cholesterol (LDL-C) level greater than or equal to 100 mg/dL and a triglyceride (TG) level lower than 400 mg/dL. The efficacy was determined by the percentage change in LDL-C [along with the total cholesterol (TC), high-density lipoprotein cholesterol, and TG] from the baseline to week 12. The safety was analyzed by the proportion of subjects who developed at least 1 alanine aminotransferase (ALT) value greater than or equal to 2 times the upper limit of normal for those with normal ALT at the baseline or a doubling of the baseline ALT for those with elevated ALT at the baseline during 36 weeks of treatment. A total of 630 subjects were screened, and 326 subjects were randomized; nonalcoholic fatty liver disease was present in 64%, and chronic hepatitis C was present in 23%. In the intent-to-treat population, pravastatin (80 mg/day) significantly lowered the mean LDL-C, TC, and TG values at week 12 and at other times (weeks 4, 8, 24, and 36) in comparison with the placebo. The incidence of subjects who met the primary prespecified ALT event definition was lower in the pravastatin group at all times over the 36 weeks of therapy in comparison with the placebo group, although the difference was not statistically significant. No differences were seen on the basis of the baseline ALT values or among the different liver disease groups. CONCLUSION: High-dose pravastatin (80 mg/day) administered to hypercholesterolemic subjects with chronic liver disease significantly lowered LDL-C, TC, and TGs in comparison with the placebo and was safe and well tolerated. The concern over an increased potential for statin-induced hepatotoxicity in patients with chronic liver disease appears to be lessened on the basis of these results.     

Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. I. A dose-response study

This multicenter, double-blind, placebo-controlled, dose-response study was conducted in patients with primary hypercholesterolemia to examine the effects of pravastatin, a selective inhibitor of HMG-CoA reductase, on plasma lipids and lipoproteins. A total of 306 patients on cholesterol-lowering diets received twice daily doses of 5 mg, 10 mg, 20 mg pravastatin, or placebo for 12 weeks. Marked reductions in low density lipoprotein (LDL) cholesterol and total cholesterol were observed after 1 week of treatment; maximum lipid-lowering effects occurred at 4 weeks and were sustained for the duration of the trial. At week 12, pravastatin treatment resulted in dose-dependent mean reductions from baseline in LDL cholesterol of 17.5%, 22.9%, and 30.8% for the 3 doses tested (P less than or equal to 0001 compared with baseline and placebo). The reduction in LDL cholesterol was log-linear with respect to dose; each doubling of dose reduced LDL cholesterol an additional 6.5%. Dose-dependent reductions in total cholesterol from 12.9% to 23.3% also occurred (P less than or equal to 0.001). Triglycerides decreased by as 15.4% (P less than or equal to 0.001) and high-density lipoprotein (HDL) cholesterol increased approximately 7% (P less than or equal to 0.01), but these effects were not dose-dependent. No patient receiving pravastatin was discontinued during the 12-week trial. Transient episodes of rash and headache occurred. Slight increases in mean serum levels of ASAT and ALAT occurred, and 2% of both placebo- and pravastatin-treated patients reported myalgia although there was no clinically significant elevation of creatine kinase. These data indicate that pravastatin favorably affects all lipid parameters and is well tolerated.     

Efficacy and safety of cerivastatin in the treatment of primary hypercholesterolemia: a multicentre, randomized, double-blind study.

Objective: To assess the efficacy and safety of cerivastatin in Chinese with primary hypercholesterolemia. Methods: The multicentre, randomized, double-blind, placebo-controlled, parallel group trial was conducted in 3 hospitals. After a 5-week single-blind run-in period (period A), 470 patients were randomized to receive cerivastatin 0.1mg (n=119), 0.2mg (n=     

Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. II. Once-daily versus twice-daily dosing

This 8-week multicenter, placebo-controlled trial compared the efficacy and safety of the HMG-CoA reductase inhibitor, pravastatin, when administered either as single doses of 40 mg in the morning (AM) or evening (PM) or 20 mg twice daily (bid) in 196 diet-stabilized outpatients with primary type II hypercholesterolemia. Mean reductions in total and low-density lipoprotein (LDL) cholesterol concentrations were observed in all pravastatin groups after 1 week and were sustained throughout the study (P less than or equal to 0.001 versus baseline and placebo). At week 8, mean reductions from baseline in the pravastatin treatment groups were 23-27% for total cholesterol and 30-34% for LDL cholesterol. LDL cholesterol was reduced greater than or equal to 15% by pravastatin in all patients in the group treated with 40 mg PM and in 88 and 96% in those receiving 20 mg bid and 40 mg AM, respectively. High density lipoprotein cholesterol was elevated (up to 8%) and triglycerides were reduced (up to 25%) by all pravastatin regimens (P less than or equal to 0.05). Pravastatin was well tolerated and was associated with a low incidence of adverse events. No patient withdrew from the study due to a pravastatin-related adverse event. Once-daily pravastatin is a safe and effective treatment for patients with primary hypercholesterolemia and has a favorable safety profile.     

Efficacy and safety of a potent new selective cholesterol absorption inhibitor,ezetimibe, in patients with primary hypercholesterolemia

The efficacy and safety of ezetimibe, a new cholesterol absorption inhibitor, was evaluated in this randomized, double-blind, placebo-controlled trial of 892 patients with primary hypercholesterolemia. After > or =2 weeks on the National Cholesterol Education Program (NCEP) Step I or a stricter diet and a 4- to 8-week single-blind placebo lead-in, patients with low-density lipoprotein (LDL) cholesterol 130 to 250 mg/dl and triglycerides < or =350 mg/dl were randomized 3:1 to receive ezetimibe 10 mg or placebo orally each morning for 12 weeks. The primary efficacy end point was the percent reduction in direct plasma LDL cholesterol from baseline to end point. A total of 434 men and 458 women (ages 18 to 85 years) received randomized treatment (666 ezetimibe 10 mg, 226 placebo). Demographics and baseline characteristics were similar between treatment groups. Ezetimibe significantly reduced direct LDL cholesterol by a mean of 16.9%, compared with an increase of 0.4% with placebo (p <0.01). Subgroup analysis indicated that response to ezetimibe was generally consistent across all subgroups, regardless of risk-factor status, gender, age, race, or baseline lipid profile. Ezetimibe effects on LDL cholesterol occurred early (2 weeks) and persisted throughout the 12-week treatment period. Compared with placebo, ezetimibe 10 mg also significantly improved calculated LDL cholesterol, apolipoprotein B, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and HDL(3) cholesterol (p <0.01). Ezetimibe was well tolerated. There were no differences in laboratory or clinical safety parameters, or gastrointestinal, liver, or muscle side effects from that of placebo. Ezetimibe 10 mg/day is well tolerated, reduces LDL cholesterol approximately 17%, and improves other key lipid parameters.     

Efficacy and safety of atorvastatin and pravastatin in patients with hypercholesterolemia

This 1-year, double-blind, active-controlled, multicenter study compared the efficacy and safety of atorvastatin to pravastatin and evaluated their ability to achieve target low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. Patients were stratified to risk factor groups based upon European Atherosclerosis Society (EAS) guidelines before randomization to atorvastatin 10 or 20 mg or pravastatin 20 or 40 mg once daily. Target LDL-C levels for patients with mild/moderate risk and severe risk were <130 mg/dl (3.4 mmol/l) and <115 mg/dl (3.0 mmol/l), respectively. If needed to achieve target levels both drugs were uptitrated within the approved dose range. Mean changes from LDL-C levels were 39% for atorvastatin patients compared to 29% for pravastatin-treated patients (p<0.0001). The number of patient responders (those reaching LDL-C goals) was higher (p<0.0001) for atorvastatin patients (91% at any study visit and 51% at the last study visit) than for pravastatin patients (48% and 20%, respectively). The daily atorvastatin dose used by most patients after the titration phase was 10 mg and the respective pravastatin dose was 40 mg. Both drugs were well-tolerated and had similar adverse event profiles. Atorvastatin, in the approved dose range, will allow a greater number of patients to reach established LDL-C treatment goals with single drug therapy.