European Heart Journal (2003) 24, 717–728 Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial Lorenzo Melani a*, Richard Mills b, David Hassman c, Robert Lipetz d, Leslie Lipka a, Alexandre LeBeaut a, Ramachandran Suresh a, Pabak Mukhopadhyay a, Enrico Veltri a, for the Ezetimibe Study Group 1 a Schering-Plough Research Institute, Kenilworth, NJ, USA Coastal Carolina Research Center, Mount Pleasant, SC, USA c Comprehensive Clinical Research, Berlin, NJ, USA d Encompass Clinical Research, Spring Valley, CA, USA b KEYWORDS Ezetimibe; Pravastatin; Hypercholesterolemia; Cholesterol absorption inhibitor; Coadministration; LDL-cholesterol Aims To evaluate the efficacy and safety of ezetimibe 10 mg administered with pravastatin in patients with primary hypercholesterolemia. Methods and results After dietary stabilization, 2–12 week screening/washout period, and 4-week, single-blind, placebo lead-in period, 538 patients with baseline LDL-C ≥3.8 to ≤6.5 mmol/l and TG ≤4.0 mmol/l were randomized to one of eight possible treatments administered daily for 12 weeks: ezetimibe 10 mg; pravastatin 10, 20, or 40 mg; ezetimibe 10 mg plus pravastatin 10, 20, or 40 mg; or placebo. The primary efficacy endpoint was percent reduction in LDL-C from baseline to study endpoint for ezetimibe 10 mg plus pravastatin (pooled doses) compared to pravastatin alone (pooled doses) and ezetimibe alone. The combined use of ezetimibe and pravastatin resulted in significant incremental reductions in LDL-C and TG compared to pooled pravastatin alone (p<0.01). Coadministration therapy reduced LDL-C by 34–41%, TG by 21–23%, and increased HDL-C by 7.8–8.4%, depending on the dose of pravastatin. The combined regimen was well tolerated, with a safety profile similar to pravastatin alone and placebo. Conclusions When coadministered with pravastatin, ezetimibe provided significant incremental reductions in LDL-C and TG and was well tolerated with a safety profile similar to pravastatin alone. © 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved. Introduction * Corresponding author. Tel.: +1-908-740-7405; fax: +1-908-740-4070 1 Members of the Ezetimibe Study Group are listed in the acknowledgments. E-mail address: [email protected]orp.com (L. Melani). The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most potent and commonly prescribed drugs for the treatment of hypercholesterolemia. However, despite widespread use of statins in clinical 0195-668X/03/$ - see front matter © 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S0195-668X(02)00803-5 Downloaded from by guest on October 15, 2014 Received 8 October 2002; accepted 16 October 2002 718 Methods Patients This study was conducted in 52 clinical centers across the United States. Institutional review board approval was obtained at each study center and all patients provided written informed consent. A total of 538 patients (238 men and 300 women) participated in the study. Adult men or women with primary hypercholesterolemia were eligible for inclusion. Lipid entry criteria included plasma LDL-C concentration ≥3.8 to ≤6.5 mmol/l, as calculated by the Friedewald equation,12 and TG levels ≤4.0 mmol/l. Prohibited concomitant illnesses and procedures included congestive heart failure (defined as New York Heart Association Class III or IV heart failure),13 uncontrolled cardiac arrhythmias, history of unstable or severe peripheral artery disease (within 3 months of study entry), unstable angina pectoris, myocardial infarction, coronary bypass surgery, or angioplasty (within 6 months of study entry), uncontrolled or newly diagnosed (within 1 month of study entry) diabetes mellitus, active or chronic hepatic hepatobiliary disease, known impairment of renal function, known coagulopathy, and unstable endocrine disease. Individuals receiving immunosuppressant drugs or corticosteroids were not eligible to participate in this study. Study design This multicenter, double-blind, randomized, placebo-controlled, balanced-parallel-group, 2×4 factorial study consisted of three phases (Fig. 1). During the initial 2- to 12-week screening/washout period, all lipid-altering drugs were discontinued, and patients were instructed to follow an NCEP Step I diet throughout the trial.14 The subsequent 4 weeks constituted the single-blind, placebo lead-in period. Blood samples were collected to assay for qualifying lipid values at Visit 2 (Q1; Week −4) and Visit 3 (Q2; Week −2). Patients with mean plasma LDL-C values at Q1 and Q2 of at least 3.8 mmol/l and not more than 6.5 mmol/l, with no single value less than 3.8 mmol/l or greater than 6.5 mmol/l were eligible to continue in the study. At Visit 4 (Week 0), qualifying patients were randomized to receive one of eight possible treatments administered orally at bedtime once daily for 12 consecutive weeks: ezetimibe 10 mg (Merck/ Schering-Plough Pharmaceuticals, Inc., Kenilworth, NJ); pravastatin 10, 20, or 40 mg (Bristol-Myers Squibb Company, Inc., Princeton, NJ); ezetimibe 10 mg plus pravastatin 10, 20, or 40 mg; or placebo. Balanced randomization across treatment groups was accomplished using a single computergenerated randomization schedule with treatment codes in blocks of eight. Downloaded from by guest on October 15, 2014 practice, a large proportion of at-risk patients do not achieve low-density lipoprotein cholesterol (LDL-C) goals as recommended by the European Second Joint Task Force1 and the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines.2 The combined use of statins with other lipid-lowering therapies is an attractive treatment option for patients who require reductions in LDL-C that cannot be achieved with statin monotherapy. Yet, the coadministration of statins with other lipid-lowering agents (e.g. fibric acid derivatives, bile acid sequestrants, and niacin) is often limited by an increased risk of side effects, intolerance, patient noncompliance, and drug interactions.3–7 Ezetimibe is a novel cholesterol-lowering drug that inhibits the absorption of dietary and biliary cholesterol across the intestinal wall without affecting the absorption of triglycerides (TG) and fat-soluble vitamins.8–10 By comparison, statins block the endogenous synthesis of cholesterol in the liver via inhibition of HMG-CoA reductase.11 Because ezetimibe and statins have distinct and potentially complementary mechanisms of action, it was hypothesized that the combined use of these agents may produce incremental antihypercholesterolemic effects. A study in hypercholesterolemic men demonstrated that coadministration of ezetimibe with pravastatin produced no alteration in pharmacokinetic profiles of either drug (data on file). The purpose of the present study was to evaluate the efficacy and safety profile of ezetimibe 10 mg coadministered with pravastatin (10, 20, or 40 mg) for 12 consecutive weeks in patients with primary hypercholesterolemia. The primary hypothesis was that coadministration therapy (ezetimibe 10 mg plus pravastatin pooled across all doses) would provide additional LDL-C-lowering effects compared to pravastatin alone (pooled across all doses). Secondary objectives were to evaluate the change from baseline for additional lipid-related variables. Additionally, the proportion of patients reaching NCEP ATP II (guidelines in clinical use during study conduct) and ATP III (guidelines issued before study closed) LDL-C goals with various treatments was examined. L. Melani et al. Efficacy and safety of ezetimibe 719 Downloaded from by guest on October 15, 2014 Fig. 1 Schematic of study design. Blood samples for routine lipid measurements (direct LDL-C, calculated LDL-C, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and TG) were collected at Weeks −4, −2, 0, 2, 4, 8, and 12. Baseline for these lipid parameters was defined as the mean of the last three available measurements prior to and including Week 0. Samples for HDL-C subfractions, apolipoproteins, and lipoprotein(a) (Lp(a)) were measured at Weeks 0 and 12. Baseline was defined as the last available value through Week 0. Evaluation of safety was accomplished through reports of patients and investigators and results from specific tests and measurements (laboratory tests, electrocardiograms, physical examinations, and vital signs). Patients completed 3-day diet diaries between prespecified visits. Diary entries were analyzed by Professional Nutrition Systems, Inc. (Overland Park, KS), the central diet analysis center. Laboratory methods Medical Research Laboratories (Highland Heights, KY) performed all clinical laboratory assays. Laboratory assays included fasting blood chemistry, hematology, coagulation tests, and urinalysis. All qualifying lipid determinations, as well as lipid profiles after Visit 1 were blinded to the investigators and study sponsor beginning with the first qualifying lipid value. LDL-C concentration was measured directly by ultracentrifugation (beta-quantification) and also calculated by the Friedewald equation:12 LDL-C⫽ TCK(TG/5)KHDL-C. Concentrations of TC and TG 720 were quantified enzymatically with the Hitachi 747 analyzer (Roche Diagnostics Corporation, Indianapolis, IN). HDL-C was determined enzymatically after selective removal of LDL-C and very low-density lipoprotein cholesterol (VLDL-C) by heparin and manganese chloride precipitation. The HDL3-C subfraction was quantified enzymatically following separation by ultracentrifugation, and the HDL2-C subfraction was calculated as follows: HDL2-C⫽HDL-CKHDL3-C. Non-HDL-C was calculated using the following equation: non-HDL-C⫽TCKHDL-C. Apolipoprotein A-I (apo A-I) and apolipoprotein B (apo B) were determined by fixed-rate nephelometry. Lp(a) was quantified by competitive enzyme-linked immunosorbent assay. Statistical analysis The incremental effect of ezetimibe across all pravastatin dose groups was evaluated with an ANOVA model using a test of interaction via contrast statement. If the interaction was not statistically significant at p≤0.05, then the average effect across all doses of pravastatin was considered the best estimate of the incremental ezetimibe effect. Additional secondary efficacy analyses with respect to LDL-C reduction were performed using an ANOVA model. These analyses included the comparison of ezetimibe monotherapy versus placebo, ezetimibe plus individual doses of pravastatin versus the corresponding pravastatin dose, and ezetimibe plus individual doses of pravastatin versus the next higher and the second higher pravastatin dose. Additional key secondary efficacy endpoints were evaluated using the same model. These endpoints included mean change and percent change from baseline in LDL-C as calculated by the Friedewald equation, TC, TG, HDL-C, the ratios of direct LDL-C:HDL-C and TC:HDL-C at study end and various time points, as well as nonHDL-C, Apo A-I, Apo B, HDL2-C, HDL3-C, and Lp(a) at study end. Finally, the percent of patients achieving NCEP ATP II and ATP III target levels for direct LDL-C at study end was assessed using logistic regression with baseline percent LDL-C difference from target as a covariate. All patients were included in the goal attainment analysis irrespective of baseline LDL-C levels. Results Patient characteristics Of the 1722 patients enrolled in this study, 538 (31%) met the eligibility criteria and were randomized to treatment. A total of 492 (91%) patients completed the double-blind treatment phase, while 46 (9%) discontinued study treatment early because of an adverse event (19 patients), noncompliance with protocol (6 patients), patient request (17 patients), or lost to follow-up (4 patients) (Fig. 2). The reasons for withdrawal and study discontinuation rates were similar across treatment groups. The treatment groups were comparable with regard to baseline lipid parameters and demographics (Table 1). The intention-to-treat population consisted of 300 women and 238 men, 20–86 years of age, with hypercholesterolemia characterized by plasma concentrations of direct LDL-C from 3.4 to 6.3 mmol/l. Mean baseline plasma concentrations of direct LDL-C ranged from 4.4 to 4.7 mmol/l across treatment groups. Of the 538 Downloaded from by guest on October 15, 2014 The primary endpoint was the percent change in direct LDL-C (measured by beta-quantification) from baseline to study end (last available postbaseline LDL-C measurement) for the intention-to-treat population. The primary hypothesis was that the coadministration of ezetimibe with pravastatin (pooled across all doses: 10, 20, 40 mg) would result in a significantly greater reduction in direct LDL-C compared to pravastatin monotherapy (pooled across all doses: 10, 20, 40 mg) and ezetimibe monotherapy. The primary efficacy analysis was performed using a two-way analysisof-variance (ANOVA) model that extracted effects due to dose (pravastatin 0, 10, 20 and 40 mg), treatment (ezetimibe, placebo), and treatmentby-dose interaction. The comparisons (pooled ezetimibe 10 mg plus pravastatin [10, 20, 40 mg] versus pooled pravastatin [10, 20, 40 mg], and pooled ezetimibe 10 mg plus pravastatin [10, 20, 40 mg] versus ezetimibe 10 mg) were performed using contrast statements under the model to evaluate the primary hypothesis. Consistency of the treatment effect across subgroups (sex, age [<65, ≥65 years], and race [Caucasian, non-Caucasian]), treatment-by-factor (defining such subgroups) interactions were evaluated for the primary variable in the intention-to-treat population using an ANOVA model including factors for treatment, dose, treatment-by-dose, subgroup, and treatment-bysubgroup interaction. With the planned sample size of approximately 520 patients (65 patients per treatment group), a difference of ≥5 percentage points in direct LDL-C reduction could be detected between any two individual treatment groups with 80% power and a significance level of p<0.05 (two-tailed), assuming a standard deviation of 10. L. Melani et al. Efficacy and safety of ezetimibe 721 patients who were randomized to treatment, 37 (7%) had known coronary heart disease (CHD), and 309 (57%) had risk factors or a history of cardiovascular disease. Overall, approximately 40% (216/ 538) of patients had a known family history of CHD, 31% (165/538) had a history of hypertension, 5% (28/538) had a history of diabetes mellitus, and 1% (8/538) had peripheral vascular disease. Efficacy data The coadministration of ezetimibe plus pravastatin (pooled across all doses) was significantly more effective than pravastatin alone (pooled across all doses) at reducing plasma levels of direct LDL-C from baseline to endpoint, as evidenced by a mean percentage change of −38% for coadministration versus −24% for pravastatin alone (p<0.01) (Table 2). Similarly, coadministration of ezetimibe plus pravastatin (pooled) was more effective than ezetimibe alone at reducing direct LDL-C (−38% versus −19%; p<0.01). Mean percentage changes in direct LDL-C from baseline to endpoint ranged from approximately −20% to −29% for individual doses of pravastatin monotherapy (pravastatin 10, 20, or 40 mg) versus −34% to −41% for coadministration therapy (Fig. 3A). The incremental mean percentage reductions in direct LDL-C resulting from the coadministration of ezetimibe with each dose of pravastatin (ezetimibe plus pravastatin 10 mg, ezetimibe plus pravastatin 20 mg, and ezetimibe plus pravastatin 40 mg) were statistically significant (p≤0.01) when compared with each corresponding dose of pravastatin monotherapy (pravastatin 10, 20, or 40 mg alone). Coadministration of ezetimibe plus pravastatin 10 mg produced a larger mean percentage reduction in direct LDL-C compared to the highest dose of pravastatin monotherapy (−34% for ezetimibe plus pravastatin 10 mg versus −29% for pravastatin 40 mg; p≤0.05). The incremental reduction in LDL-C concentrations resulting from coadministration of ezetimibe with pravastatin occurred as early as Week 2 and was maintained throughout the Downloaded from by guest on October 15, 2014 Fig. 2 Trial profile. Number of patients who were randomized, who completed the studies, and who discontinued prematurely, are shown for the placebo, ezetimibe monotherapy, pooled pravastatin monotherapy, and pooled coadministration treatment groups. 722 Table 1 Baseline summary of patient demographics and lipid parameters Characteristic Placebo (n=65) Ezetimibe (n=64) Pooled pravastatina (n=205) Ezetimibe+pooled pravastatina (n=204) Mean age (year) (range) Number of patients (%) ≥65 years 53.4 (32–76) 11 (17%) 52.0 (26–75) 10 (16%) 55.1 (23–84) 53 (26%) 56.9 (20–86) 50 (25%) Race Caucasian Black Hispanic Asian Pacific Islander Other 52 (80%) 6 (9%) 1 (2%) 6 (9%) 0 0 60 (94%) 3 (5%) 1 (2%) 0 0 0 174 (85%) 12 (6%) 15 (7%) 3 (1%) 1 (<1%) 0 176 (86%) 11 (5%) 10 (5%) 5 (2%) 0 2 (<1%) Gender Male Female 31 (48%) 34 (52%) 23 (36%) 41 (64%) 101 (49%) 104 (51%) 83 (41%) 121 (59%) Baseline lipid values (mean, SD) mmol/l Direct LDL-C Calculated LDL-C HDL-C TG 4.6 4.6 1.3 1.8 4.6 4.7 1.3 2.0 4.6 4.6 1.3 2.0 4.6 4.6 1.3 2.0 Family history of CHD Patient history of CHD History of hypertension History of diabetes mellitus History of peripheral vascular disease Current smoker Currently physically active 27 (42%) 2 (3%) 15 (23%) 2 (3%) 0 10 (15%) 38 (58%) 24 (38%) 2 (3%) 20 (31%) 1 (2%) 1 (2%) 15 (23%) 33 (52%) 87 (42%) 16 (8%) 64 (31%) 14 (7%) 2 (<1%) 31 (15%) 107 (52%) 78 (38%) 17 (8%) 66 (32%) 11 (5%) 5 (2%) 22 (11%) 126 (62%) Washout information HMG-CoA reductase inhibitor Fibrate Nicotinic acid Other 15 (23%) 1 (2%) 0 1 (2%) 14 (22%) 0 2 (3%) 2 (3%) 62 (30%) 1 (<1%) 4 (2%) 17 (8%) 63 (31%) 1 (<1%) 6 (3%) 15 (7%) (0.5) (0.5) (0.3) (0.7) (0.6) (0.6) (0.3) (0.7) (0.6) (0.6) (0.3) (0.7) (0.5) (0.5) (0.3) (0.7) CHD=coronary heart disease; Direct LDL-C=low-density lipoprotein cholesterol measured by ultracentrifugation; calculated LDL-C=low density lipoprotein cholesterol calculated by the Friedewald equation; HDL-C=high-density lipoprotein cholesterol; TG=triglycerides. Pooled pravastatin=pravastatin pooled across all doses (10, 20, and 40 mg). L. Melani et al. Downloaded from by guest on October 15, 2014 a Efficacy and safety of ezetimibe Table 2 Least-square mean percentage change from baseline to endpoint (Week 12) in plasma concentrations of various lipid-related variables Variable (mmol/l) Direct LDL-C Calculated LDL-C TC TG HDL-C Apo Bc Non-HDL-C HDL2-C HDL3-C Apo A-Ic Lipoprotein(a)d Direct LDL-C:HDL-C TC:HDL-C Placebo (n=65) Ezetimibe (n=64) Pooled pravastatin (n=205) Ezetimibe+pooled pravastatin (n=204) Difference B/E % Change (SE) B/E % Change (SE) B/E % Change (SE) B/E % Change (SE) P valuea P valueb 4.6/4.6 4.6/4.6 6.8/6.8 1.8/1.8 1.3/1.3 1.7/1.6 5.5/5.5 0.5/0.5 0.9/0.8 1.6/1.5 1.2/1.2 3.6/3.6 5.3/5.3 1.3 (1.6) −0.6 (1.5) 0.2 (1.2) 2.0 (3.8) 2.0 (1.5) −2.2 (1.8) −0.1 (1.4) 10.4 (4.7) −1.6 (2.8) −1.1 (1.5) 10.9 (7.0) 0.1 (1.7) −1.2 (1.4) 4.6/3.7 4.7/3.7 6.9/6.0 2.0/1.9 1.3/1.4 1.7/1.4 5.6/4.6 0.5/0.5 0.9/0.9 1.6/1.6 1.1/1.1 3.7/2.9 5.5/4.6 −18.7 (1.6) −19.6 (1.5) −13.2 (1.2) −2.1 (3.8) 4.1 (1.5) −14.8 (1.8) −17.2 (1.4) 13.8 (4.6) 0.5 (2.7) 2.5 (1.5) 15.0 (6.9) −21.8 (1.7) −16.0 (1.4) 4.6/3.5 4.6/3.4 6.8/5.6 2.0/1.8 1.3/1.4 1.7/1.3 5.5/4.3 0.5/0.5 0.8/0.9 1.6/1.6 1.1/1.1 3.7/2.6 5.5/4.3 −24.3 (0.9) −25.2 (0.9) −17.2 (0.6) −7.6 (2.1) 6.7 (0.8) −20.0 (1.0) −22.7 (0.8) 17.0 (2.6) 5.4 (1.6) 3.6 (0.9) −2.7 (3.9) −28.6 (0.9) −21.7 (0.8) 4.6/2.8 4.6/2.8 6.8/5.0 2.0/1.6 1.3/1.4 1.7/1.2 5.5/3.5 0.5/0.6 0.9/0.9 1.6/1.7 1.1/1.2 3.6/2.1 5.4/3.6 −37.7 (0.9) −38.6 (0.9) −27.1 (0.6) −17.6 (2.1) 8.1 (0.8) −30.2 (1.0) −35.6 (0.8) 17.0 (2.6) 4.0 (1.6) 3.8 (0.9) 2.2 (3.9) −41.7 (0.9) −32.0 (0.8) <0.01 <0.01 <0.01 <0.01 NS <0.01 <0.01 NS NS NS NS <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.02 <0.01 <0.01 NS NS NS NS <0.01 <0.01 B=baseline; E=endpoint; TC=total cholesterol; TG=triglyceride; Apo=apolipoprotein; NS=not significant (p>0.05). Not every patient had an endpoint measurement for every variable; n ranged from 53 to 65 for the placebo group, 56 to 64 for the ezetimibe group, 174 to 205 for the pooled pravastatin group, and from 173 to 204 for the coadministration group. a Ezetimibe+pooled pravastatin versus pooled pravastatin. Ezetimibe+pooled pravastatin versus ezetimibe. c g/l. d µmol/l. b 723 Downloaded from by guest on October 15, 2014 724 L. Melani et al. Downloaded from by guest on October 15, 2014 Fig. 3 Percentage change in direct LDL-C (A), calculated LDL-C (B), HDL-C (C), and TG (D) concentrations from baseline to endpoint. EZE5ezetimbe 10 mg; Prava5pravastatin. duration of the study (Fig. 4). The overall increase in LDL-C-lowering effect resulting from the coadministration of ezetimibe and pravastatin was generally consistent across all subgroups, irrespective of risk-factor status, gender, age, race, and baseline lipid profile (data not shown). Ezetimibe plus pravastatin (pooled) also significantly improved the following secondary efficacy variables compared to pravastatin alone (pooled) (Table 2): calculated LDL-C, TG, TC, apo B, nonHDL-C, direct LDL-C:HDL-C, and TC:HDL-C (p< 0.01). Fig. 3 summarizes the changes in LDL-C (direct and calculated), HDL-C, and TG concentrations across the individual treatment groups. Coadministration of ezetimibe with pravastatin significantly reduced direct (Fig. 3A) and calculated (Fig. 3B) LDL-C at all pravastatin doses (p<0.01) and TG (Fig. 3D) at pravastatin doses of 10 and 20 mg (p<0.05). The combined regimen also produced greater but not significant increases in HDL-C at the 10 and 40 mg doses (Fig. 3C). Overall, 47% (96/204) of patients receiving coadministration therapy achieved a ≥40% reduction in direct LDL-C concentrations at endpoint compared with 8% (17/203) of patients receiving pravastatin monotherapy. Of those patients with baseline LDL-C levels above established NCEP ATP III goals, 71% (144/204) receiving coadministration therapy and 48% (97/203) receiving pravastatin monotherapy attained target LDL-C levels by study end (Table 3). The differences in the proportion of patients achieving either NCEP ATP II or III goals between the pooled treatment groups (ezetimibe plus pooled pravastatin and pooled Efficacy and safety of ezetimibe Fig. 4 Mean percent change from baseline in plasma concentrations of direct LDL-C over time and at endpoint. pravastatin alone) were statistically significant (p<0.01). Adverse events resulting in treatment discontinuation (19/538, or 4% of the total population) or interruption (38/538, or 7% of the total population) were generally no more common or severe in any of the eight treatment groups. Treatment-related adverse events were reported for 15% (31/205) of patients receiving pravastatin monotherapy and 17% (35/204) of patients receiving coadministration therapy. The type and incidence of non-laboratoryrelated adverse events were generally comparable between the pooled treatment groups. Adverse events causing discontinuation were reported for 4% (9/204) of patients on coadministration therapy versus 1% (3/205) of patients in the pravastatin monotherapy group. None of the types of adverse events resulting in treatment discontinuation were more common in any of the treatment groups. Serious adverse events were rare and occurred with similar frequency in both treatment groups. No patient died during the study. Overall, three patients demonstrated asymptomatic consecutive or presumed consecutive elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) activity greater than or equal to three times the upper limit of normal (ULN) (Table 4). Two of these patients were in the coadministration treatment arm (ezetimibe plus pravastatin 20 mg, ezetimibe plus pravastatin 40 mg) and one was in the pravastatin monotherapy arm (pravastatin 40 mg). The patient receiving ezetimibe plus pravastatin 40 mg had elevated ALT levels at baseline (patients with elevations up to 2× ULN at baseline were eligible for randomization) and discontinued from the study because of elevations in hepatic enzyme activity. The other patient on coadministration therapy (ezetimibe plus pravastatin 20 mg) with AST and/or ALT elevations ≥3× ULN completed the study. No cases of hepatitis, jaundice, or other signs of liver dysfunction were reported in this study. Clinically important elevations in creatine phosphokinase (CPK) values ≥10× ULN or >5× ULN and <10× ULN with muscle symptoms were observed in three patients, none of whom were in the coadministration group. Two patients (one in the pravastatin 10 mg group and one in the pravastatin 40 mg group) experienced CPK elevations >10× ULN without associated muscle symptoms. A third patient (ezetimibe monotherapy) reported symptoms of myalgia and had CPK elevations between 5 and less than 10× ULN. All three of these patients completed the study. In all cases, physical exercise was considered by the investigator to be a possible contributing factor to the increased CPK activity. Results of other laboratory tests, vital signs, electrocardiograms, and cardiopulmonary examinations did not suggest any clinically important differences between the coadministration and pravastatin monotherapy groups. Discussion Efficacy of coadministration of ezetimibe and pravastatin The results of this study demonstrate that coadministration of ezetimibe plus pravastatin (pooled across 10, 20, and 40 mg doses) produced greater reductions in LDL-C than either pravastatin (p< 0.01) or ezetimibe (p<0.01) monotherapy. The combined regimen (ezetimibe 10 mg plus pravastatin 10, 20, or 40 mg) also produced significant LDL-C reductions compared with each corresponding and higher dose of pravastatin alone (p<0.01). Moreover, the coadministration of ezetimibe with pravastatin 10 mg provided greater LDL-C reductions compared to pravastatin 40 mg (−34% versus −29%, respectively; p<0.05). A further enhancement of the LDL-C-lowering effect was obtained when ezetimibe was combined with pravastatin 40 mg, resulting in a mean percentage change from baseline of approximately −41% compared to only −29% with pravastatin 40 mg monotherapy. Overall 47% of patients receiving coadministration therapy experienced a ≥40% reduction in Downloaded from by guest on October 15, 2014 Safety data 725 726 Table 3 L. Melani et al. Achievement of NCEP ATP II and ATP III LDL-C goals at endpoint Placebo (n=62) Ezetimibe (n=63) Pooled pravastatina (n=203) Ezetimibe+pooled pravastatina (n=204) NCEP ATP II14 Below goal at Below goal at Below goal at Below goal at baseline endpoint endpoint only baseline only 9 (15%) 13 (21%) 7 (11%) 3 (5%) 11 (17%) 41 (65%) 30 (48%) 0 28 (14%) 131 (65%) 104 (51%) 1 (<1%) 26 (13%) 174 (85%) 148 (73%) 0 NCEP ATP III2 Below goal at Below goal at Below goal at Below goal at baseline endpoint endpoint only baseline only 9 (15%) 14 (23%) 8 (13%) 3 (5%) 10 (16%) 38 (60%) 28 (44%) 0 25 (12%) 121 (60%) 97 (48%) 1 (<1%) 23 (11%) 167 (82%) 144 (71%) 0 a Pooled pravastatin=pravastatin pooled across all doses (10, 20, and 40 mg). Table 4 Number (%) of patients with adverse events CPK ≥5×ULN At least 10×ULN Ezetimibe (n=64) Pooled (n=205) 37 (57%) 7 (11%) 5 (8%) 45 (70%) 6 (9%) 2 (3%) 129 (63%) 31 (15%) 3 (1%) 134 (66%) 35 (17%) 9 (4%) 0 0 0 0 1 (<1%)c 1 (<1%)c 1 (<1%) 1 (<1%) 0 0 1 (2%) 0 1 (<1%) 2 (<1%) 1 (<1%) 0 ULN=upper limit of normal; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase. a Pooled pravastatin=pravastatin pooled across all doses (10, 20, and 40 mg). Patients were considered to have two consecutive postbaseline elevations if their last record was ≥3× ULN, or if a measurement of ≥3× ULN during treatment or ≤2 days after the end of treatment was followed by a measurement of <3× ULN that was taken >2 days following the last dose of study medication. c One patient receiving pravastatin 40 mg monotherapy experienced coincident elevations in ALT and AST. b LDL-C, compared to 8% of patients on pravastatin monotherapy. Coadministration of the two lipid-lowering therapies produced maximal or nearmaximal incremental reductions in LDL-C relative to statin monotherapy within the first 2 weeks of treatment and this effect was maintained throughout the 12-week treatment period. The efficacy results of this trial in conjunction with the results of three similarly designed studies with simvastatin, atorvastatin, and lovastatin demonstrate that ezetimibe is effective in enhancing the lipid-modifying effects of statins.15–17 In addition to the LDL-C-lowering effects, coadministration therapy also produced favorable effects on other lipid-related variables, including significant reductions in TC, TG, and apo B compared to pravastatin (p<0.01) or ezetimibe alone (p<0.01). Indicators of risk for CHD, such as LDL:HDL-C and TC:HDL-C and non-HDL-C, also showed significant improvement with the coadministration of ezetimibe plus pravastatin compared with pravastatin and ezetimibe monotherapy (p<0.01). Finally, the combined use of ezetimibe and pravastatin produced greater, but not statistically significant increases in HDL-C levels. Analyses were performed to evaluate the proportion of patients achieving NCEP ATP II or ATP III-defined LDL-C goals with combination therapy. The results of these analyses showed that a significantly greater proportion of patients receiving ezetimibe plus pravastatin coadministration therapy were able to reach their treatment goals compared to those who received pravastatin therapy alone. This study was conducted while the NCEP ATP II guidelines were still in clinical use. The current NCEP-ATP III guidelines were issued before Downloaded from by guest on October 15, 2014 All adverse events Treatment-related adverse events Discontinuation due to adverse event Liver function tests ALT≥3× ULN (consecutive)b AST≥3× ULN (consecutive)b pravastatina Ezetimibe+pooled pravastatina (n=204) Placebo (n=65) Efficacy and safety of ezetimibe the study was completed. These results suggest that coadministration therapy may have the potential to increase the number of patients achieving recommended lipid levels, and thus further studies are warranted. Safety of coadministration of ezetimibe and pravastatin In summary, the coadministration of ezetimibe and pravastatin offers a promising new lipid management strategy for patients with hypercholesterolemia. The combined use of these agents provides complementary lipid-lowering effects to statins with no apparent increased risk of adverse events. In clinical practice, the combination regimen may prove a useful treatment for patients who are either unable to reach LDL-C target concentrations with statins alone, or are at increased risk for side effects with more potent doses of statin monotherapy. In addition, the need for less frequent dose titration with combination therapy may lead to improved patient compliance and help more patients achieve their LDL-C goals. Acknowledgements The authors wish to thank Dr Amy O. JohnsonLevonas from Merck Research Laboratories for assistance in preparing this manuscript for publication. This study was conducted by ScheringPlough Research Institute, Kenilworth, New Jersey, USA, on behalf of Merck/Schering-Plough Pharmaceuticals, North Wales, Pennsylvania, USA. The Ezetimibe Study Group consisted of the following investigators. Nicola Abate, MD, Dallas, TX; Robert Ambruster, MD, Tucson, AZ; Robert E. Broker, MD, Simpsonville, SC; Robert Benjamin Chadband, MD, Birmingham, AL; Mukul S. Chandra, MD, Louisville, KY; Linda Crouse, MD, Kansas City, MO; Adnan Dahdul, MD, Springfield, MA; Z. A. Dalu, MD, St. Louis, MO; Eugene DuBoff, MD, Denver, CO; Steven L. Duckor, MD, Orange, CA; William T. Ellison, MD, Greer, SC; Walter Gaman, MD, Irving, TX; Richard Gilmore, MD, Lake Charles, LA; Raul E. Goana, Sr., MD, San Antonio, TX; Salah El Hafi, MD, Houston, TX; Regina C. Hamlin, MD, Fresno, CA; David R. Hassman, DO, Berlin, NJ; Srini Hejeebu, DO, Toledo, OH; Richard Heuser, MD, Phoenix, AZ; Walter E. Hood, MD, Atlanta, GA; Harvey L. Katzeff, MD, New Hyde Park, NY; Robert H. Knopp, MD, Seattle, WA; Wayne Larson, MD, Lakewood, WA; James R. LaSalle, DO, FAAFP, Excelsior Springs, MO; Judy D. Laviolette, MD, Shreveport, LA; Robert S. Lipetz, DO, Spring Valley, CA; Dennis C. McCluskey, MD, Mogadore, CA; Jeffrey R. Medoff, MD, Greensboro, NC; Avishai Mendelson, MD, West Palm Beach, FL; Dennis Mikolich, MD, Cranston, RI; Michael Miller, MD, Baltimore, MD; Richard Mills, MD, Mount Pleasant, SC; Jane E. Mossberg, MD, Eugene, OR; Michael J. Noss, MD, Cincinnati, OH; Barry Packman, MD, Philadelphia, PA; Hitesh D. Patel, MD, Tustin, CA; Robert W. Reindollar, MD, Charlotte, NC; Deborah L. Richmond, DO, Lansing, MI; Dennis S. Riff, MD, Anaheim, CA; Sid Rosenblatt, Downloaded from by guest on October 15, 2014 The safety results showed that coadministration of ezetimibe plus pravastatin was well tolerated, with an overall safety profile similar to pravastatin alone and placebo. Generally, the adverse event profiles were similar across treatment groups. There was no evidence to suggest that the addition of ezetimibe to any dose of pravastatin increased the risk of developing a non-laboratory adverse event. Furthermore, there was no evidence to suggest a dose–response relationship in adverse events across the pravastatin treatment groups (10, 20, or 40 mg), either administered alone or in combination with ezetimibe. Asymptomatic, dose-dependent increases in transaminases are a well-recognized possible side effect of statin therapy, and most other lipidlowering therapies.18,19 Overall, very few patients in this study experienced clinically important elevations in liver function tests. All transaminase elevations were asymptomatic, and no cases of hepatitis, jaundice, or signs of liver dysfunction were reported. Of note was the finding that coadministration of ezetimibe with low doses of pravastatin (10, 20 mg) produced larger LDL-C reductions compared to the highest dose of pravastatin monotherapy (40 mg). Thus, the combination of ezetimibe with low-dose pravastatin therapy provided greater LDL-C-lowering efficacy than the highest recommended dose of pravastatin monotherapy with no increased risk of clinically important elevations in liver function tests. Statin therapy also is known to cause increases in CPK activity, mostly during the initial stages of treatment and upward dose titration. While CPK activity has been shown to fluctuate within a given individual over time (often related to physical exertion or muscular trauma), elevations of greater than or equal to 10× ULN are generally considered clinically relevant, requiring close monitoring for signs and symptoms of muscle damage and possible discontinuation of treatment. No cases of rhabdomyolysis were reported in this study. Overall, the lack of clinically relevant elevations in CPK activity in this study suggested no increased risk of myopathy with the coadministration of ezetimibe and any dose of pravastatin compared to pravastatin alone. 727 728 MD, FACP, Irvine, CA; Paul G. Sandall, MD, Albuquerque, NM; Shobha Sekhon, MD, Fresno, CA; Philip G. Smaldone, MD, Denver, CO; William Spisak, MD, Portland, OR; Daniel VanHamersveld, MD, Sacramento, CA; Robert Vogel, MD, Baltimore, MD; Robert J. Weiss, MD, FACC, FAC, Auburn, ME; Douglas G. Young, MD, Fair Oaks, CA; James H. Zavoral, MD, Edina, MN; Edward T. 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