1354 ET davidson 7/31/07 1:48 PM Page 1354 Clinical Therapeutics/Volume 29, Number 7, 2007 Efficacy and Tolerability of Adding Prescription Omega-3 Fatty Acids 4 g/d to Simvastatin 40 mg/d in Hypertriglyceridemic Patients: An 8-Week, Randomized, Double-Blind, Placebo-Controlled Study Michael H. Davidson, MD1; Evan A. Stein, MD, PhD2; Harold E. Bays, MD3; Kevin C. Maki, PhD4; Ralph T. DoyleS; Robert A. Shalwitz, MDS; Christie M. Ballantyne, MD6; and Henry N. Ginsberg, MD7; for the COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators 1Radiant Research, Chicago, Illinois; 2Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio; 3Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky; 4Provident Clinical Research ~ Consulting~ Inc., Bloomington, Indiana; SReliant Pharmaceuticals, Inc., Liberty Corner, New Jersey; 6Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Baylor College of Medicine, Houston, Texas; and 7Irving Center for Clinical Research, College of Physicians and Surgeons of Columbia University , New York, New York + ABSTRACT Background: Patients with elevated serum triglyc- eride (TG) levels often have elevations in non-high- density lipoprotein cholesterol (non-HDL-C) levels as well. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) has identi- fied non-HDL-C as a secondary therapeutic target in these patients, but treatment goals may not be reached with statin monotherapy alone. Objective: This study evaluated the effects on non- HDL-C and other variables of adding prescription omega-3-acid ethyl esters (P-OM3; Lovaza TM, former- ly Omacor ® ]Reliant Pharmaceuticals, Inc., Liberty Corner, New Jersey]) to stable statin therapy in pa- tients with persistent hypertriglyceridemia. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in adults who had received >8 weeks of stable statin therapy and had mean fasting TG levels >200 and <500 mg/dL and mean low-density lipoprotein choles- terol levels <10% above their NCEP ATP III goal. The study regimen consisted of an initial 8 weeks of open- label simvastatin 40 mg/d and dietary counseling, followed by 8 weeks of randomized treatment with double-blind P-OM3 4 g/d plus simvastatin 40 mg/d or placebo plus simvastatin 40 mg/d. The main out- come measure was the percent change in non-HDL-C from baseline to the end of treatment. Results: The evaluable population included 254 pa- tients, of whom 57.5% (146) were male and 95.7% (243) were white. The mean (SD) age of the popula- tion was 59.8 (10.4) years, and the mean weight was 92.0 (19.6) kg. At the end of treatment, the median per- cent change in non-HDL-C was significantly greater with P-OM3 plus simvastatin compared with placebo plus simvastatin (-9.0% vs -2.2%, respectively; P < 0.001). P-OM3 plus simvastatin was associated with significant reductions in TG (29.5% vs 6.3%) and very- low-density lipoprotein cholesterol (27.5% vs 7.2%), a significant increase in high-density lipoprotein choles- terol (HDL-C) (3.4% vs -1.2%), and a significant re- duction in the total cholesterol:HDL-C ratio (9.6% vs 0.7%) (all, P < 0.001 vs placebo). Adverse events (AEs) reported by >1% of patients in the P-OM3 group that occurred with a higher frequency than in the group that received simvastatin alone were nasopharyngitis (4 [3.3%]), upper respiratory tract infection (4 [3.3%]), The COMBOS study centers and investigators are listed in the Acknowledgments. Accepted for publication June 26, 200Z Express Track online publication July 26, 2007. doi:l 0.1016/].clinthera.2007.07.018 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2007 Excerpta Medica, Inc. 1354 Volume 29 Number 7
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`1354 ET davidson 7/31/07 1:48 PM Page 1355 M.H. Davidson et al. + diarrhea (3 [2.5%]), and dyspepsia (3 [2.5%]). There was no significant difference in the frequency of AEs between groups. No serious AEs were considered treat- ment related. Conclusion: In these adult, mainly white patients with persistent hypertriglyceridemia, P-OM3 plus sim- vastatin and dietary counseling improved non-HDL-C and other lipid and lipoprotein parameters to a greater extent than simvastatin alone. (Clin Ther. 2007;29: 1354-1367) Copyright © 2007 Excerpta Medica, Inc. Key words: omega-3 fatty acids, hypertriglyc- eridemia, dyslipidemia, statins, lipoproteins, combina- tion therapy, non-HDL-C. INTRODUCTION In persons with high triglyceride (TG) levels, levels of low-density lipoprotein cholesterol (LDL-C) alone do not adequately represent the risk associated with atherogenic lipoproteins. 1 Thus, in addition to the pri- mary goal of LDL-C reduction, the National Choles- terol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines have identified non-high- density lipoprotein cholesterol (non-HDL-C) as a sec- ondary target of therapy in persons with serum TG levels _>200 mg/dL. 1 In the NEPTUNE (NCEP Evaluation Project Utilizing Novel E-Technology) II survey, 2 hypertriglyceridemia was present in 25% of patients undergoing treatment for dyslipidemia. Only 27% of patients with hypertriglyceridemia plus coro- nary heart disease (CHD) or NCEP ATP III-defined CHD risk equivalents had achieved their non-HDL-C treatment goal. This suggests a clinical need for effec- tive treatment options to lower elevated levels of TG and non-HDL-C. Non-HDL-C is calculated as the difference between total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C). 1 As a predictor of cardiovascular risk, it is as good as or better than LDL-C. 3'4 For ex- ample, in the Bypass Angioplasty Revascularization Investigation, 4 every 10-mg/dL increment in mean non- HDL-C increased the risk of nonfatal myocardial in- farction by 5% and the odds of angina pectoris by 10%; however, LDL-C was not correlated with either outcome. Non-HDL-C includes the cholesterol con- tained in all the potentially atherogenic apolipopro- tein (apo) B-containing lipoproteins, including TG-rich lipoproteins such as very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein, and chylomicron remnants, as well as LDL and lipopro- tein (a). 1,3 Elevated fasting TG levels are associated with an increase in plasma concentrations of VLDL particles. 1 Under such hypertriglyceridemic condi- tions, VLDL-C becomes an important component of non-HDL-C. 1 A statin is recommended as initial pharmacothera- py for lowering LDL-C and non-HDL-C in patients with hypertriglyceridemia, 1 but statin treatment alone may be insufficient to achieve non-HDL-C targets. As defined by the NCEP ATP lll, the non-HDL-C target is 30 mg/dL higher than the corresponding LDL-C tar- gets of <100 mg/dL for those with CHD or CHD risk equivalents, <130 mg/dL for those with >2 risk fac- tors, and <160 mg/dL for those with <1 risk factor. 2,5 Statin-treated patients may remain at risk because of persistent hypertriglyceridemia and elevated non- HDL-C, despite achieving their NCEP ATP lll goal for LDL-C. In patients with persistent hypertriglyceridemia while receiving statin therapy, the addition of a TG- lowering agent is recommended as a therapeutic op- tion to reduce levels of non-HDL-C. 1 In such patients, one approach is to combine prescription omega-3-acid ethyl esters* (P-OM3) with the statin. P-OM3 is ap- proved by the US Food and Drug Administration for use as an adjunct to diet in adults with very high TG levels (>500 mg/dL). 6 Each 1-g capsule of P-OM3 contains highly concentrated ethyl esters of omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) 465 mg and docosahexaenoic acid (DHA) 375 mg. 6 The find- ings of 3 previous trials in patients with hypertriglyc- eridemia suggested that coadministration of P-OM3 with a statin was associated with greater improve- ments in the lipid profile than treatment with a statin alone: Nordoy et al r reported significant changes in TG (P < 0.007) and apo E (P < 0.035); Durrington et al 8 reported significant changes in TG (P < 0.001), VLDL-C (P < 0.005), TC (P < 0.025), and LDL-C (P < 0.025); and Chan et al 9 reported significant changes in TG (P = 0.002) and HDL-C (P = 0.041). *Trademark: Lovaza TM, formerly Omacor ® (Reliant Pharma- ceuticals, Inc., Libere/ Corner, New Jersey). The name has been changed as of August 2007 at the request of the US Food and DrugAdministration in response to a limited num- ber of reports of prescribing and dispensing errors (data on file, Reliant Pharmaceuticals) resulting from the similarie/in the names of Omacor and Amicar ® (aminocaproic acid; Xanodyne Pharmaceuticals, Inc., Newport, Kentucky). July 2007 1355
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`1354 ET davidson 7/31/07 1:48 PM Page 1356 Clinical Therapeutics + However, these studies were small (<60 patients each) and were not powered to provide a full evaluation of the addition of P-OM3 to a statin. The present study (clinicaltrials.gov identifier: NCT 00246701) assessed the efficacy and tolerability of P-OM3 in combination with simvastatin and dietary counseling for lowering non-HDL-C levels in patients with persistent hypertriglyceridemia despite statin thera- py. It was designed to determine whether the addition of P-OM3 to simvastatin would achieve a robust de- crease in non-HDL-C in these patients, primarily through reduction of TG, without attenuating the LDL-C-lowering effect of the statin. This was the first study powered to evaluate both the non-HDL-C and LDL-C end points. PATIENTS AND METHODS Patients Eligible patients were men or women between the ages of 18 and 79 years who had been receiving a stable dose of a statin for the control of LDL-C levels for _>8 weeks before screening and were judged to be in good health on the basis of a medical history, physical examination, electrocardiogram, and laboratory tests, including serum chemistry, hematology, and urinaly- sis. Major inclusion criteria included a mean fasting TG level _>200 and <500 mg/dL, and a mean LDL-C level below or within 10% of the patient's NCEP ATP III goal. Major exclusion criteria included poorly controlled diabetes mellitus (glycosylated hemoglobin [HbAlc ] >8.0% at screening); history of a cardiovascular event, a revascularization procedure, or an aortic aneurysm or resection within 6 months of screening; history of pancreatitis; sensitivity to statins or omega-3 fatty acids; poorly controlled hypertension (resting blood pressure _>160 mm Hg systolic and/or _>100 mm Hg diastolic at 2 consecutive visits); serum creatinine level _>2.0 mg/dL; serum transaminase (aspartate amino- transferase lAST] or alanine aminotransferase [ALT]) >1.5 times the upper limit of normal (ULN) (45 U/L for ALT, 31 U/L for AST); or creatine kinase (CK) level >2 times the ULN. Study Design and Procedures This randomized, double-blind, placebo-controlled, parallel-group study was conducted at 41 clinical sites throughout the United States. The study consisted of 7 clinic visits: 1 screening visit, 3 visits during the lead-in/baseline period, and 3 visits during double- blind treatment. Written informed consent was ob- tained from all patients. The protocol and consent form were reviewed and approved by the appropriate institu- tional review board for each site. The study was con- ducted in accordance with the Good Clinical Practice Guidelines, 1° the Declaration of Helsinki (2000), u and Title 21 of the US Code of Federal Regulations. 12 At screening (week -8), patients meeting the initial eligibility criteria received open-label treatment with simvastatin* 40 mg/d, which was continued for the re- mainder of the study. Simvastatin replaced any previ- ous statin. Patients discontinued all lipid-altering drugs (other than simvastatin 40 mg/d), omega-3 fatty acid supplements, and supplements known to alter lipid metabolism. In addition, they received dietary counsel- ing on the NCEP Therapeutic Lifestyle Changes diet. 1 Dietary instructions were reinforced at each subse- quent clinic visit. During the 8-week lead-in phase, pa- tients attended clinic visits at weeks -2, -1, and 0. After the lead-in phase, patients whose compliance (measured by the number of capsules consumed relative to the number expected to be consumed) with simva- statin therapy was 280% and who had mean TG levels (mean of weeks -2 and -1) _>200 and <500 mg/dL and LDL-C levels <10% above their NCEP ATP III goal were randomized to receive 8 weeks of double-blind P-OM3 4 g/d (four 1-g capsules, the approved dosage) or placebo (4 matching vegetable oil capsules). Patients were allocated to double-blind treatment according to a randomization schedule with a block size of 4; se- quentially numbered drug-supply kits were provided to sites in balanced blocks of 4, and patients were assigned sequential kit numbers at enrollment. All participants continued to receive simvastatin 40 mg/d. During the 8-week, double-blind treatment phase, patients attended clinic visits at weeks 4, 6, and 8. Outcome Variables The prespecified primary outcome variable was the percent change in non-HDL-C from baseline (mean of weeks -2, -1, and 0) to the end of treatment (mean of weeks 6 and 8), as computed for each patient. Addi- tional outcome variables included the percent changes from baseline to the end of treatment in levels of TG, VLDL-C, LDL-C, HDL-C, TC, and apo B. *Trademark: Zocor ® (Merck & Co., Inc., West Point, Pennsylvania). 1356 Volume 29 Number 7
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`1354 ET davidson 7/31/07 1:48 PM Page 1357 M.H. Davidson et al. + Mayo Central Laboratory for Clinical Trials (Rochester, Minnesota) performed all clinical labora- tory testing. Serum lipids (non-HDL-C, TG, LDL-C, HDL-C, and TC) were analyzed according to the Standardization Program of the Centers for Disease Control and Prevention and the National Heart, Lung, and Blood Institute. Laboratory assessments in- cluded hematology (Coulter LH 750 Hematology Analyzer, Beckman Coulter, Inc., Fullerton, Califor- nia); chemistry; urinalysis (reagent strip chemistry with microscopic analysis); pregnancy testing for women of childbearing potential (chemiluminometric immunoas- say); HbAlc (turbidimetric inhibition immunoassay); lipid panel (selective precipitation/enzymatic colorime- try or Friedewald equation); apo A-I, B, and C-III (automated turbidimetric immunoassay); remnant lipoprotein cholesterol (immunoaffinity isolation of remnant lipoprotein, followed by enzymatic choles- terol determination); and LDL (direct measurement by ultracentrifugation/selective precipitation/enzymatic col- orimetry). For each test, accuracy and performance were verified when control pools in a matrix behaved in the same way as patient samples. Precision data and acceptable limits were established for each analyte and each level of control, and performance was evaluated before disclosure of the results. Safety Assessments The safety profile was assessed by monitoring of adverse events (AEs) and measurement of vital signs at each clinic visit, as well as by serum chemistry, hema- tology, and urinalysis at visits 1, 4, and 7. AEs were categorized as not related, unlikely, possibly, proba- bly, or definitely related to study drug. A post hoc analysis of fructosamine concentrations was performed for further evaluation of increases in blood glucose levels. EDTA-treated plasma samples were assayed for fructosamine concentrations using a validated colorimetric rate reaction method. The fruc- tosamine assay is a colorimetric test based on the abili- ty of ketoamines to reduce nitroblue tetrazolium to formazan in an alkaline medium. The rate of forma- tion of formazan is directly proportional to the con- centration of fructosamine and is measured photo- metrically at 546 nm. 13 Statistical Methods An evaluable sample of >200 patients (100 per treat- ment group) was expected to provide >99% power (2-sided 0~ = 0.05) to detect an 8% difference in the mean percent change in non-HDL-C levels between the 2 treatment groups (assumed pooled SD, 13%). This sample size was also expected to provide 80% power (2-sided 0~ = 0.05) to detect a 6% between-group dif- ference in the mean percent change in LDL-C (as- sumed pooled SD, 15%) to rule out a possible marked attenuation of the LDL-C-lowering effect of the statin. The intent-to-treat (ITT) population included all randomized patients. Efficacy analyses involved all patients in the ITT population who received at least 1 dose of study medication and provided at least 1 post- randomization blood sample. The last-observation- carried-forward (LOCF) method was used to impute missing nonbaseline data for patients who did not complete the treatment period. Percent changes from baseline were evaluated by analysis of variance (ANOVA) 14 with treatment as a factor. In the case of variables for which baseline values differed between groups, the baseline value was included as a covariate in the model. The statistical analysis plan included use of the Shapiro-Wilk test 15 to evaluate assump- tions for the use of parametric tests. In cases in which these assumptions were rejected, rank transforma- tions were performed before running the ANOVA. Because the percent-change-from-baseline data were not normally distributed for the primary or second- ary efficacy end points, medians rather than means are reported here as the most appropriate descriptor of central tendency. There were no planned statistical corrections for multiple comparisons of secondary outcomes. All patients who received at least 1 dose of double- blind study drug and returned to the clinic for at least 1 safety assessment after randomization were includ- ed in the safety population. The Fisher exact test (2-tailed) 16 was used to compare the incidence of AEs between treatment groups. RES U LTS Population Of 690 patients screened, 256 qualified for entry and were randomized to treatment, 123 to P-OM3 plus simvastatin and 133 to placebo plus simvastatin. The unequal number of patients in the 2 treatment groups resulted from 41 of the participating sites en- rolling patients who were not in multiples of 4 at all sites. The efficacy-evaluable and safety populations included 122 patients in the P-OM3 group and 132 in July 2007 1357
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`1354 ET davidson 7/31/07 1:48 PM Page 1358 Clinical Therapeutics the placebo group who returned for at least 1 evalua- tion after randomization. Patient disposition is sum- marized in Figure 1. The number of patients completing the study was comparable in the P-OM3 (116/123 [94.3%]) and placebo (127/133 [95.5%]) groups. There were 7 non- completers in the P-OM3 group: 3 patients discontin- ued due to AEs, 1 was lost to follow-up, 1 was with- drawn for a laboratory abnormality (TG >500 mg/dL), 1 discontinued due to difficulty swallowing study medi- cation, and I was discontinued after being found to be receiving an exclusionary medication (warfarin). There + c c C~ L C~ Visit 1 (Week -8) Visit 4 - (Week 0) Visit 7 (Week 8) Allocated to simvastatin 40 mg + P-OM3 (n = 1 23) Received allocated intervention (122) Did not receive allocated intervention (1) Discontinued treatment (n = 7) Adverse events (3) Lost to Follow-up (1) Withdrew consent (0) Protocol noncompliance (0) Laboratory abnormality (1) Other (2) Assessed For eligibility (N = 690) Enrollment Simvastatin 40 mg Randomized (n = 256) Allocation Follow-up Excluded (n = 434) Did not meet inclusion criteria (379) Withdrew consent (24) Lost to Follow-up (3) Adverse events (14) Other reasons (14) Allocated to simvastatin 40 mg + placebo (n = 133) Received allocated intervention (132) Did not receive allocated intervention (1) Discontinued treatment (n = 6) Adverse events (3) Lost to Follow-up (0) Withdrew consent (2) Protocol noncompliance (1) Laboratory abnormality (0) Other (0) Analyzed (n = 122) Excluded From analysis (n = 1 ) Analysis Analyzed (n = 132) Excluded From analysis (n = I) Figure I. Patient disposition throughout the study. P-OM3 = prescription omega-3-acid ethyl esters. 1358 Volume 29 Number 7
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`1354 ET davidson 7/31/07 1:48 PM Page 1359 M.H. Davidson et al. + were 6 noncompleters in the placebo group: 3 patients discontinued due to AEs, 2 withdrew consent, and 1 was withdrawn for noncompliance with the proto- col. For the 13 patients who withdrew during the double-blind treatment period after providing at least 1 postrandomization blood sample for lipid analysis, the LOCF method was used to impute values for the missing data points. With the exception of 2 patients (1 lost to follow-up in the P-OM3 group, 1 who withdrew consent in the placebo group), neither of whom provided any postrandomization data, all non- completers were included in the efficacy and safety populations. The efficacy-evaluable and safety populations had a mean age of 59.8 years and were 57.5% (146/254) male and 95.7% white (243/254) (Table I). The 2 groups were comparable in age, sex, race, weight, height, body mass index, and waist circumference. With the exception of the TC:HDL-C ratio, which was significantly lower in the P-OM3 group com- pared with the placebo group (P = 0.012), there were no significant differences in any lipid/lipoprotein level between treatment groups at baseline in the efficacy- evaluable population. Efficacy Analyses Table II summarizes the results for the lipid and lipoprotein outcome variables. The percent change from baseline in non-HDL-C, the primary outcome variable, was significantly better with P-OM3 plus simvastatin compared with placebo plus simvastatin (-9.0% vs -2.2%, respectively; P < 0.001) (Figure 2). In the P-OM3 group, 91/122 (74.6%) patients were at their non-HDL-C treatment goal at baseline, and 102/122 (83.6%) were at their goal at the end of treatment. In the placebo group, the corresponding values at baseline and the end of treatment were 90/132 (68.2%) and 92/132 (69.7%). In the subset of patients who were not at their non-HDL-C goal at baseline, 16/31 (51.6%) patients in the P-OM3 group had attained their non-HDL-C goal by the end of treatment, compared with 10/42 (23.8%) in the place- bo group (Figure 3). The median percent change in TG levels was -29.5% in the P-OM3 group, compared with -6.3% in the placebo group (P < 0.001) (Table II). The medi- an change in VLDL-C was -27.5% in the P-OM3 group and -7.2% in the placebo group (P < 0.001). LDL-C changed by a median of +0.7% in the P-OM3 Table I. Baseline characteristics of" patients in the efficacy-evaluable population. Data are mean (SD), unless oth- erwise specified. Simvastatin + P-OH3 Simvastatin + Placebo Total P Characteristic (n = 122) (n = 132) (N = 254) Between Groups Age, y 60.3 (10.1) 59.3 (10.8) 59.8 (10.4) 0.44 Sex, no. (%) Male 66 (54.1) 80 (60.6) 146 (57.5) 0.31 Female 56 (45.9) 52 (39.4) 108 (42.5) Race, no. (%)~ White 116 (95.1) 127 (96.2) 243 (95.7) 0.76 Black 2 (1.6) 3 (2.3) S (2.0) Hispanic 1 (0.8) 3 (2.3) 4 (1.6) Asian 3 (2.5) 0 3 (1.2) Weight, kg 91.0 (19.3) 92.9 (20.0) 92.0 (19.6) 0.45 Height, cm 170.9 (10.2) 1 71.4 (9.6) 171.2 (9.9) 0.71 Body mass index, kg/m 2 31.0 (5.4) 31 .S (5.5) 31.2 (5.4) 0.49 Waist circumference, cm 103.5 (13.5) 104.4 (14.5) 104.0 (14.0) 0.61 P-OH3 = prescription omega-3-acid ethyl esters. *One patient receiving simvastatin and placebo was self-described as both white and Hispanic. July 2007 13.59
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`1354 ET davidson 7/31/07 1:48 PM Page 1361 M.H. Davidson et al. • P-OM3 + simvastatin [] Placebo + simvastatin + Figure 2. Non-HDL-C 5- • ~ -5 - ,..,q E -10- 0 -15 - c t.-. L) -20 - -25 - -30 -9.0* TG VLDL-C LDL-C 0.7 I I -2.8 -27.5* -29.5* Median percent change in non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides (TG), cal- culated ve~-low-density lipoprotein cholesterol (VLDL-C), and low-density lipoprotein cholesterol (LDL-C) from baseline to the end of treatment. The analysis was completed after rank transformation due to non- normality in the distribution of responses. P-OM3 = prescription omega-3-acid ethyl esters. *P < 0.001. group, compared with a median change of-2.8% in the placebo group (P = NS). The proportion of patients in the P-OM3 group at their LDL-C treatment goal remained constant from baseline to the end of treatment (92.6% [113/122]). P-OM3 plus simvastatin was associated with a median percent change in HDL-C of +3.4%, compared with -1.2% in the group receiving simvastatin plus placebo (P < 0.001). The change in the TC:HDL-C ratio was significantly greater in the P-OM3 group than in the placebo group (-9.6% vs -0.7%, respectively; P < 0.001). In addition, the change in apo B was signifi- cantly greater in the P-OM3 group compared with the placebo group (-4.2% vs -1.9%; P = 0.023). Safety Analyses There was no significant difference between groups in the proportion of patients experiencing AEs (Table III). Serious AEs (SAEs) occurred in 4/122 (3.3%) pa- tients in the P-OM3 group and 1/132 (0.8%) patients in the placebo group. The 4 SAEs in the P-OM3 group were hospitalization for an exacerbation of congestive heart failure in a 68-year-old woman; hospitalization for supraventricular tachycardia in a 41-year-old man with a history of hypertension and supraventricular tachycardia; hospitalization for pneumonia in a 71-year- old woman with a history of chronic obstructive pul- monary disease; and elevated ALT and AST (98 and 68 U/L, respectively) in a 54-year-old woman. None of these SAEs were considered by the investigators to be related to study treatment. AEs reported by >1% of patients in the P-OM3 group that occurred with a higher frequency than in the group that received simvastatin alone were naso- pharyngitis (4 [3.3%]), upper respiratory tract infec- tion (4 [3.3%]), diarrhea (3 [2.5%]), and dyspepsia (3 [2.5%]). There were no significant differences be- tween groups in either the incidence of AEs in any sys- tem organ class or the incidence of any individual AE (Table III). No AEs involved myopathy (CK >10 × ULN) or rhabdomyolysis. The combination of P-OM3 and simvastatin had no significant effects on creati- July 2007 1361
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`1354 ET davidson 7/31/07 1:48 PM Page 1362 Clinical Therapeutics + 60 O o u 50 c3 T i 40 c O z .~ 30 > (D ¢- ~o < 20 c ",~ ~ lO 0 • P-OM3 + simvastatin [] Placebo + simvastatin 51.6 Figure 3. Proportions of patients who were not at their non-high-density lipoprotein choles- terol (non-HDL-C) goal at baseline but had achieved the goal by the end of treatment (P = NS). P-OM3 = prescription omega-3- acid ethyl esters. Table III. Incidence of adverse events (no. [%] of patients). Variable Any adverse event Simvastatin + Simvastatin + P-OM3 Placebo (n= 122) (n= 132) 51 (41.8) 63 (47.7) Serious adverse events 4 (3.3) 1 (0.8) Specific adverse events ~ Nasopharyngitis 4 (3.3) 3 (2.3) Upper respiratory tract infection 4 (3.3) 1 (0.8) Diarrhea 3 (2.5) 3 (2.3) Dyspepsia 3 (2.5) 3 (2.3) Bronchitis 2 (1.6) 2 (1.5) Cystitis 2 (1.6) 1 (0.8) Alanine aminotransferase elevation 2 (1.6) 1 (0.8) Gastroenteritis 2 (1.6) 0 P-OM3 = prescription omega-3-acid ethyl esters. *Events reported by _>1% of patients receiving simvastatin + P-OM3 that occurred with a higher frequency than in those receiving simvastatin + placebo. nine, creatine phosphokinase, or homocysteine levels during the course of the trial. There were no cases of clinically significant increas- es in hepatic transaminase levels (>3.0 x ULN) in ei- ther group. There was a numerically higher incidence of mildly elevated ALT in the group that received P-OM3 plus simvastatin compared with the group that received simvastatin only (1.6% [2/122] vs 0.8% [1/132], respectively; P = NS). The group mean changes from baseline in ALT were +5.7 and -0.7 U/L, respectively (P < 0.001). The corresponding changes in AST were +1.9 U/L and +0.2 U/L (P < 0.032). The group mean changes in fasting blood glucose were +5.5 and -0.1 mg/dL (P = 0.002). There was no sig- nificant difference between groups in the mean per- cent change in fructosamine levels (1.0% and 0.3%). DISCUSSION The Third National Health and Nutrition Exami- nation Survey reported that 30.0% of 8814 men and women evaluated had serum TG levels >150 mg/dL. 17 Among persons aged >50 years, the proportion with serum TG levels >150 mg/dL was 42.8%. is The Pro- spective Cardiovascular Munster Study reported the importance of lowering serum TG independent of other lipid variables. 19 Given the aging of the US popu- lation, hypertriglyceridemia is likely to remain a com- mon problem in clinical practice. The most recent NCEP ATP III guidelines identify non-HDL-C as a secondary treatment target for CHD risk reduction in individuals with significant eleva- tions in plasma TG levels (>200 mg/dL). 1 However, in patients with hypertriglyceridemia, non-HDL-C levels may not be adequately controlled with statin mono- therapy. The results of the NEPTUNE II survey in- dicated that inadequate treatment of hypertriglyc- eridemia is common; only 27% of patients with TG levels >200 mg/dL and CHD or CHD risk equivalents treated with diet and/or drug therapy (69.9% receiv- ing statin monotherapy) achieved combined LDL-C and non-HDL-C goals. 2 The present study was de- signed to investigate the efficacy and tolerability of 1362 Volume 29 Number 7
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`1354 ET davidson 7/31/07 1:48 PM Page 1363 M.H. Davidson et al. + coadministration of P-OM3 with simvastatin for low- ering non-HDL-C in patients with persistent hyper- triglyceridemia despite statin therapy. In a previous placebo-controlled trial in patients with established CHD and hypertriglyceridemia (TG >200 mg/dL) who were receiving stable doses of simva- statin therapy (10-40 mg/d), s the addition of P-OM3 (4 g/d) to simvastatin for 24 weeks resulted in further reductions compared with placebo in TG (28.9%; P < 0.005), VLDL-C (21.1%; P < 0.005), and apo B (3.4%; P = NS). Non-HDL-C was also reduced by 8.2% (not reported, but calculated from the data presented). In the present study, coadministration of P-OM3 with simvastatin in patients with hypertriglyceridemia despite statin therapy was associated with a signifi- cantly greater reduction in non-HDL-C compared with simvastatin alone (P < 0.001). The addition of P-OM3 to simvastatin also increased the proportion of patients attaining their NCEP ATP III non-HDL-C treatment goal to an extent similar to that associated with doubling the statin dose. 20,21 In one study of 4 statins given at 10, 20, 40, and 80 mg/d, 2° the largest increases in the proportion of patients achieving non-HDL-C treatment goals upon doubling the dose were from 60% to 84% with atorvastatin 20 mg/d doubled to 40 mg/d and from 30% to 54% with sim- vastatin 10 mg/d doubled to 20 mg/d. The effect of treatment on LDL-C levels, which were already at or near the NCEP ATP III goal at the start of treatment, did not differ significantly between groups. The proportion of patients at their LDL-C goal re- mained constant (92.6% [113/122]) from baseline to the end of treatment in the P-OM3 group. Therefore, the addition of P-OM3 did not affect maintenance of NCEP ATP III treatment goals for LDL-C with statin therapy. Although compared with the placebo group, the P-OM3 group had a numerically greater increase from baseline in LDL-C (0.7%; P = NS), the median LDL-C level in the P-O