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Study Title and Description

Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial.



Key Questions Addressed
1 RCTs and other Comparative studies
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Primary Publication Information
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TitleData
Title Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial.
Author Kastelein JJ., Maki KC., Susekov A., Ezhov M., Nordestgaard BG., Machielse BN., Kling D., Davidson MH.
Country Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Electronic address: j.j.kastelein@amc.uva.nl.
Year 2014
Numbers Pubmed ID: 24528690
16823 (internal)

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Comparative Studies
Arms
Number Title Description Comments
1 Placebo olive oil
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2 "Fish oil" (DHA+EPA) Omega-3 2 g/d; olive oil 2 g/d
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3 "Fish oil" (DHA+EPA) Omega-3 3 g/d, olive oil 1 g/d
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4 "Fish oil" (DHA+EPA) Omega-3 4 g/d
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Design Details
Question... Follow Up Answer Follow-up Answer
Study Design Trial: Randomized Parallel (Omega-3 vs. Control; Omega-3 + X vs. X)
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What is the name of this study? (e.g. DART, Physician's Health Study) EVOLVE
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Country in which study conducted (where subjects live) US
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Denmark
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Netherlands
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Other(s) [Separate countries with commas]: ... India, Hungary, Ukraine, Russia
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Funding source Industry funded
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Eligibility Criteria: Participants included men and women (nonpregnant, nonlactating) >=18 years of age with average serum TG concentrations >=500 mg/dL but <2000 mg/dL at screening (1 and 2 weeks before random assignment) who were either untreated for dyslipidemia or were using a stable (for at least 6 weeks before the first qualifying lipid measurement) dosage of a statin, CAI, or their combination. Subjects were also required to have a body mass index (calculated as weight divided by height squared; kg/m2) >=20 and be willing to maintain their customary activity level, follow the TLC diet with weight maintenance, and restrict their consumption of fish to no more than twice per week throughout the study. Persons with known lipoprotein lipase impairment or deficiency, apolipoprotein (Apo) CII deficiency, or familial dysbetalipoproteinemia were excluded from the study, as were persons with a history of pancreatitis, symptomatic gallstone disease (unless treated with cholecystectomy), uncontrolled diabetes (glycosylated hemoglobin $9%), or cancer in the past 2 years (basal cell carcinoma was not exclusionary). Persons with a recent history (past 6 months) of a cardiovascular event (ie, myocardial infarction, acute coronary syndrome, new onset angina, stroke, transient ischemic attack, or unstable congestive heart failure that required a change in treatment); revascularization procedure; aortic aneurysm; nephrotic syndrome; or pulmonary, hepatic, biliary, gastrointestinal, or immunologic disease were also excluded. Persons with uncontrolled hypothyroidism, thyroid-stimulating hormone >5 mIU/L, or poorly controlled hypertension (resting blood pressure >=160 mm Hg systolic or >=100 mm Hg diastolic) at 2 consecutive visits before random assignment were not enrolled, nor were persons with any of the following laboratory results: serum alanine aminotransferase or aspartate aminotransferase <3 times the upper limit of normal, fasting serum glucose <200 mg/dL, calculated glomerular filtration rate <30 mL/min, platelet counts <60 X 10^9/L, or hemoglobin <10.0 g/dL.
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Study Population Primary Prevention, Increased CVD Risk (ie, diabetes, metabolic syndrome*, hypertension, dyslipidemia, or chronic kidney disease)
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Duration of Intervention 12 weeks
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At baseline, did all subjects have (per eligibility criteria)...? ... Define: Dyslipidemia ... average serum TG concentrations 500-2000 mg/dL
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Obesity/Overweight ... body mass index >=20
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Conflict of interest ... Specify Conflict of interest stated ... The authors acknowledge that they have either received research grant funding from, or are employees of, or have ownership in Omthera Pharmaceuticals, Inc, the manufacturer of the product studied. The relationship of authors Dr Kastelein, Mr Machielse, Mr Kling, and Dr Davidson to Omthera are considered significant according to the definitions used by the Food and Drug Administration. The following authors further disclose that they have other modest relationships with industry that might pose a potential conflict of interest(s): Dr Kastelein (Amarin), Dr Maki (Abbott, Amarin, DSM, GSK, Pharmavite, Trygg Pharma), Dr Susekov (Abbott, Actavis, Amarin, Amgen, AstraZeneca, Gedeon-Richter, Genzyme, KRKA, Merck, Novartis, Pfizer, Promed, Sandoz, Sanofi-Aventis, Teva, Zentiva), Dr Ezhov (KRKA, Pfizer), and Dr Nordestgaard (AstraZeneca, Kara-Bio, Merck, Pfizer, Regeneron, Sanofi-Aventis).
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Does the study report a subgroup analysis for an outcome of interest? No
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Does the study report a regression analysis with interaction terms for an outcome of interest? No
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Does the study report an analysis of the association between n-3 biomarkers and an outcome of interest? No
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Study start date(s) 2011
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Baseline Characteristics
Question Placebo "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA) Total Comments
AnswerFollow-up AnswerFollow-up AnswerFollow-up AnswerFollow-up AnswerFollow-up
Baseline Diseases/Conditions 30.3 39 44.6 36.4
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64.6 69 68.3 67.7
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Baseline characteristics, continuous 50.8 51.1 51.2 52.9
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10.6 9.8 8.8 10.9
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130.4 130.1 129.2 129.6
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12.1 12.4 11.1 12.1
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80.5 80.9 81.1 80.7
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6.2 7.7 7.5 7.6
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nd nd nd nd
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mg/dL mg/dL mg/dL mg/dL
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246 241 244 254
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135, 409 131, 542 151, 641 119, 564
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mg/dL mg/dL mg/dL mg/dL
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78.2 77.3 81.0 90.3
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22.7, 161 19.7, 182 19.7, 213 11.7, 223
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mg/dL mg/dL mg/dL mg/dL
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28.7 27.3 28.0 28.7
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14, 60 13.3, 47.3 15.3, 58.7 12.7. 69.3
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mg/dL mg/dL mg/dL 655
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682 717 728 435, 2095
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418, 2007 415, 1578 439, 2158 31.0
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30.4 31.4 31.8 5.1
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4.3 4.8 4.1
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Male, percent 77.8 80.0 78.2 71.7
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Race 96.0 93.0 91.1 88.9
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0.0 0.0 1.0 2.0
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4.0 5.0 5.9 8.1
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6.1 8.0 4.0 7.1
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other or mixture: 0.0 other or mixture: 2.0 other or mixture: 2.0 other or mixture: 1.0
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Comments about baseline data No data entered.
Baseline diet description Subjects were instructed to follow the National Cholesterol Education Program Therapeutic Lifestyle Changes (TLC) diet and restrict their consumption of fish to no more than twice per week throughout the study. Subjects were instructed to follow the National Cholesterol Education Program Therapeutic Lifestyle Changes (TLC) diet and restrict their consumption of fish to no more than twice per week throughout the study. Subjects were instructed to follow the National Cholesterol Education Program Therapeutic Lifestyle Changes (TLC) diet and restrict their consumption of fish to no more than twice per week throughout the study. Subjects were instructed to follow the National Cholesterol Education Program Therapeutic Lifestyle Changes (TLC) diet and restrict their consumption of fish to no more than twice per week throughout the study.
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Baseline omega-3 intake No data entered.
Does this study report baseline omega-3 biomarker data? Yes
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Results & Comparisons


Results Data
Outcome: lipid      Population: 51861
Time Point Measure Placebo "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA)


0 weeks

N Analyzed 98 99 97 99
Median 682 717 728 655
Max 2007 1578 2158 2095
Min 418 415 439 435


12 weeks

N Analyzed 98 99 97 99
Median 642 554 544 513
Max 5655 1723 10317 2013
Min 190 73.5 141 138
Outcome: lipid      Population: 51862
Time Point Measure Placebo "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA)


0 weeks

N Analyzed 98 99 97 99
Median 78.2 77.3 81.0 90.3
Max 161 182 213 223
Min 22.7 19.7 19.7 11.7


12 weeks

N Analyzed 98 99 97 99
Median 86.3 93.3 95.0 110
Max 288 221 243 255
Min 7.5 28.5 18.0 4.0
Outcome: lipid      Population: 51863
Time Point Measure Placebo "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA)


0 weeks

N Analyzed 98 99 97 99
Median 28.7 27.3 28.0 28.7
Max 60.0 47.3 58.7 69.3
Min 14.0 13.3 15.3 12.7


12 weeks

N Analyzed 98 99 97 99
Median 30.0 29.0 28.5 29.0
Max 64.5 63.5 62.0 93.5
Min 12.0 15.0 14.0 14.0
Outcome: lipid      Population: 51864
Time Point Measure Placebo "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA) "Fish oil" (DHA+EPA)


0 weeks

N Analyzed 98 99 97 99
Median 8.8 8.8 8.9 9.0
Max 15.8 21.7 25.9 22.7
Min 4.3 4.3 3.4 4.0


12 weeks

N Analyzed 98 99 97 99
Median 8.3 8.1 7.9 8.3
Max 37.9 21.9 101 16.7
Min 3.5 2.9 2.6 3.1

Adverse Events
Arm or Total Title Description Events (n) At Risk (N) Follow-up time Comments
Placebo Gastrointestinal disorders includes upper abdominal pain, diarrhea, erutation, nausea, vomiting. Nine subjects withdrew because of gastrointestinal events among the OM3-FFA groups, and they were evenly distributed across the dosage groups: 3 (3%) in OM3-FFA 2 g/d, 3 (3%) in OM3-FFA 3 g/d, and 3 (3%) in OM3-FFA 4 g/d. 7 99 12 weeks
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"Fish oil" (DHA+EPA) 19 100 12 weeks
"Fish oil" (DHA+EPA) 21 101 12 weeks
"Fish oil" (DHA+EPA) 27 99 12 weeks
Placebo upper abdominal pain Of the 7 subjects who reported upper abdominal pain, 3 instances were mild (1 in the OO group and 2 in the OM3-FFA 2 g/d group) and 4 were moderate (2 in the OM3-FFA 2 g/d group, and 1 each in the OM3-FFA 3 and 4 g/d groups) 1 99 12 weeks
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"Fish oil" (DHA+EPA) 4 100 12 weeks
"Fish oil" (DHA+EPA) 1 101 12 weeks
"Fish oil" (DHA+EPA) 1 99 12 weeks
Placebo diarrhea Of the 28 subjects with reports of diarrhea, 19 were mild (2, 6, 5, and 6 in the OO group and the 2, 3, and 4 g/d OM3- FFA groups, respectively), 8 were moderate (0, 4, 1, and 3), and 1 was severe (OM3-FFA 4 g/d). 2 99 12 weeks
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"Fish oil" (DHA+EPA) 10 100 12 weeks
"Fish oil" (DHA+EPA) 6 101 12 weeks
"Fish oil" (DHA+EPA) 10 99 12 weeks
Placebo eructation Eructation was reported by 12 subjects; all except 1 moderate instance in the OM3-FFA 2 g/d group were considered mild. 1 99 12 weeks
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"Fish oil" (DHA+EPA) 3 100 12 weeks
"Fish oil" (DHA+EPA) 4 101 12 weeks
"Fish oil" (DHA+EPA) 4 99 12 weeks
Placebo nausea Of the 21 reports of nausea, 11 were considered mild (1, 2, 5, and 3) and the remainder were moderate (0, 4, 4, and 2). 1 99 12 weeks
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"Fish oil" (DHA+EPA) 6 100 12 weeks
"Fish oil" (DHA+EPA) 9 101 12 weeks
"Fish oil" (DHA+EPA) 5 99 12 weeks
Placebo vomiting Of the 7 subjects who had vomiting, 4 cases were mild (2 each in the OM3-FFA 2 and 3 g/d groups) and 3 were moderate (1 in the OO group and 2 in the OM3-FFA 3 g/d group). 1 99 12 weeks
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"Fish oil" (DHA+EPA) 2 100 12 weeks
"Fish oil" (DHA+EPA) 4 101 12 weeks
"Fish oil" (DHA+EPA) 0 99 12 weeks
Placebo general disorders not defined 1 99 12 weeks
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"Fish oil" (DHA+EPA) 5 100 12 weeks
"Fish oil" (DHA+EPA) 7 101 12 weeks
"Fish oil" (DHA+EPA) 1 99 12 weeks
Placebo infections and infestations 11 99 12 weeks
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"Fish oil" (DHA+EPA) 14 100 12 weeks
"Fish oil" (DHA+EPA) 7 101 12 weeks
"Fish oil" (DHA+EPA) 12 99 12 weeks
Placebo Nasopharyngitis 2 99 12 weeks
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"Fish oil" (DHA+EPA) 7 100 12 weeks
"Fish oil" (DHA+EPA) 3 101 12 weeks
"Fish oil" (DHA+EPA) 1 99 12 weeks
Placebo Investigations 4 99 12 weeks
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"Fish oil" (DHA+EPA) 5 100 12 weeks
"Fish oil" (DHA+EPA) 4 101 12 weeks
"Fish oil" (DHA+EPA) 9 99 12 weeks
Placebo Metabolism and nutrition disorders 2 99 12 weeks
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"Fish oil" (DHA+EPA) 0 100 12 weeks
"Fish oil" (DHA+EPA) 1 101 12 weeks
"Fish oil" (DHA+EPA) 4 99 12 weeks
Placebo Musculoskeletal and connective tissue disorders 6 99 12 weeks
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"Fish oil" (DHA+EPA) 5 100 12 weeks
"Fish oil" (DHA+EPA) 6 101 12 weeks
"Fish oil" (DHA+EPA) 3 99 12 weeks
Placebo Nervous system disorders primarily headache, dysgeusia 0 99 12 weeks
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"Fish oil" (DHA+EPA) 6 100 12 weeks
"Fish oil" (DHA+EPA) 5 101 12 weeks
"Fish oil" (DHA+EPA) 4 99 12 weeks
Placebo Skin and subcutaneous tissue disorders 0 99 12 weeks
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"Fish oil" (DHA+EPA) 4 100 12 weeks
"Fish oil" (DHA+EPA) 1 101 12 weeks
"Fish oil" (DHA+EPA) 2 99 12 weeks

Quality Dimensions
Dimension Value Notes Comments
Was the allocation sequence (RANDOMIZATION METHOD) adequately generated? UNCLEAR
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Was ALLOCATION adequately concealed (prior to assignment)? UNCLEAR
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Were PARTICIPANTS adequately BLINDED? LOW
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Were OUTCOME ASSESSORS adequately BLINDED? UNCLEAR
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Incomplete outcome data (ATTRITION BIAS) due to amount, nature or handling of incomplete outcome data low
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Is there evidence of SELECTIVE OUTCOME REPORTING bias (Yes/No)? No
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INTENTION-TO-TREAT analysis? (Yes/No) Yes
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Group SIMILARITY AT BASELINE (**GENERAL**) LOW
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Was there incomplete COMPLIANCE with interventions across groups? No
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Group SIMILARITY AT BASELINE (**OMEGA-3**) LOW
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Additional Bias: Bias due to problems not covered elsewhere in the table.
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If outcome assessor blinding risk of bias is different for different outcomes (eg, lipids vs. MI), choose HIGH risk of bias and describe in Notes
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If attrition risk of bias is different for different outcomes (eg, lipids vs. MI) or different time points (eg, 1 year vs. 5 years), choose HIGH risk of bias and describe in Notes
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Quality Rating
No quality rating data was found.