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To examine the triglyeride lowering effectiveness, safety, and tolerability of Omacor over one year in patients with established coronary heart disease receiving simvastatin.

• Established coronary heart disease
  • Defined as in Scandinavian simvastatin survival study (4S)
  • MI at least six month previously with definite ECG changes and enzyme changes or as angina with a positive exercise ECG
• Triglycerides exceeding 2.3 mmol/l (204 mg/dL)
• Attending lipid clinics at the Manchester Royal Infirmary and the Royal Oldham Hospital
• Currently receiving simvastatin (10-40 mg daily) at a stable dose for at least three months with the aim of lowering serum cholesterol to < 5.5 mmol/l
• Could not receive probucol or any other lipid lowering drug except simvastatin with six weeks of commencement
• Dietary instruction on the American Heart Association step 1 diet at least 6 months previously

• Suffering a MI within the previous six months

Recruitment Not described

 

Design Randomized, double-blind, placebo-controlled trial followed by an open label phase

 

Blinding used (if applicable)

• Double blind
  • Subjects and investigators remained blinded to previous treatment group in the open label phase as well as to laboratory results except kinase, liver function tests and blood counts until the last subject had completed the full evaluation period of 48 weeks.
• Omacor and placebo were provided in identical capsules

 

Intervention (if applicable)

• Randomized to receive either Omacor (2 gm twice daily) or placebo (corn oil) for 24 weeks
• Open label phase in which subjects from both groups were invited to receive Omacor for 24 weeks
• Encouraged to maintain usual diet throughout study

 

Statistical Analysis

• Differences between placebo and control at 12, 24, and 48 weeks were sought by analysis of covariance with the baseline as covariate.
• Primary endpoints for which the study was powered were serum triglycerides and VLDL cholesterol
• Baseline parameters were also compared with results obtained as 12, 24, and 48 weeks using the Wilcoxon signed rank test for serum triglycerides and VLDL cholesterol, and Student's paired t test for other variables.
  • Because this involved multiple statistical testing the level of probability considered significant was 0.025.

 

Timing of Measurements Not described

 

Dependent Variables

• Serum triglycerides: measured after an overnight fast using the GPO-PAP method with a coefficient of variation of 2.1%
• Cholesterol: measured after an overnight fast using the CHOD-PAP method with a coefficient of variation of 1.3%
• Serum phospholipid fatty acids were measured by gas chromatography
• Lipoproteins: isolated from plasma
  • VLDL isolated by ultracentrifugation and upper layer analyzed for cholesterol
  • LDL was precipitated with heparin/Mn²⁺ from remaining (lower) layer
    • LDL cholesterol concentration was calculated as the difference in cholesterol in the post-VLDL infranatant minus HDL cholesterol
  • HDL determined from supernatant
  • Serum Lp(a) lipoprotein concentration was determined using an IRMA with a coefficient of variation of 6%. Standards and controls supplied by the manufacturer.
  • ApoA1 and ApoB were determined by rate nephelometry with a coefficient of variation of 6%. Standards and controls supplied by the manufacturer.
• Plasma fibrinogen was measured on an automated coagulation laboratory analyzer by a thromboplastin initiated clotting technique.
• Glycosylated hemoglobin (HbA_1c) was measured by high performance liquid chromatography using the variant analyzer
• Blood pressure: measured within 2 mm Hg, with the subject semi-recumbent after resting for five minutes, using a mercury sphygmomanometer.
• Compliance: assessed by counting returned capsules
• Adverse events

Independent Variables

• Omacor or placebo

 

Control Variables

 

 

Initial N:

• Overall
  • Baseline: N=59
  • 12 weeks: N=57
  • 24 weeks: N=55
  • 24-48 weeks: N=46
• Randomized, double blind trial for first 24 weeks
  • Omacor
    • N=30 (23 males, 7 females)
  • Placebo
    • N=29 (20 males, 9 females)
• Open label phase
  • N=46
  • Omacor: N=25
  • Placebo: N=21
  • All declined to continue because of the inconvenience of frequent hospital visits

Attrition (final N):

• Omacor: N=29
  • One withdrew because of loose motions
• Placebo: N=26
  • One died from acute MI
  • One withdrew for severe heartburn
  • One withdrew because visits were inconvenient

Age: Mean±SD

• Omacor: 55.2±7.0 yr
• Placebo: 54.8±10.2 yr

Ethnicity: not described

Other relevant demographics: not described

Anthropometrics

• Diabetes mellitus
  • Omacor: N=8
  • Placebo: N=7
• 40 mg simvastatin
  • Omacor: N=10
  • Placebo: N=10
• 20 mg simvastatin
  • Omacor: N=20
  • Placebo: N=17
• 10 mg simvastatin
  • Omacor: N=0
  • Placebo: N=2
• BMI (mean±SD)
  • Omacor: 28.8±2.8
  • Placebo: 28.4±4.2
• Fasting glucose (all patients) (mmol/l) (mean±SD)
  • Omacor: 6.67±2.5
  • Placebo: 6.7±2.7
• Fasting glucose (diabetic patients) (mmol/l) (mean±SD)
  • Omacor: 9.8±2.6
  • Placebo: 10.8±2.4
• HbA_1c (all patients) (%) (mean±SD)
  • Omacor: 5.9±1.4
  • Placebo: 5.4±1.5
• HbA_1c (diabetic patients (%)
  • Omacor: 6.7±1.9
  • Placebo: 7.6±1.3
• Plasma fibrinogen (g/l) (mean±SD)
  • Omacor: 3.5±1.2
  • Placebo: 3.4±1.4
• Serum phospholipid EPA (mg/l) (mean±SD)
  • Omacor: 21.6±14.9
  • Placebo: 21.0±12.7
• Serum phospholipid DHA (mg/l)
  • Omacor: 72.9±24.5
  • Placebo: 75.4±25.6
• Average dose of simvastatin
  • Omacor: 33.3 mg daily
  • Placebo: 31.0 mg daily
  • Simvastatin dose remained constant throughout trial
• Use of ß blockers, angiotensin converting enzyme inhibitors, calcium channel antagonists, and oral hypoglycemic agents was similar in the Omacor and placebo groups.

Location: Lipid clincs at the Manchester Royal Infirmary and the Royal Oldham Hospital, Manchester, UK

 

• The results presented are for all evaluable patients at 0, 12, 24, and 48 weeks.
• Exclusion of all patients other than the 46 present at each of these time points does not alter the conclusions.
• Subjects were included in the statistical analysis regardless of compliance (intention to treat).

Primary Endpoints

• Change in serum triglycerides and VLDL cholesterol concentrations as a percentage of baseline values
  • At randomization the mean (SD) serum triglyceride in the Omacor group was 4.6 (2.2) mmol/l (407.6 mg/dL) and in the placebo group was 3.8 (2.2) mmol/l (336.7 mg/dL).
  • Significant decrease in serum triglyerides by 20-30% (p<0.005) and in VLDL cholesterol by 30-40% (p<0.005) in subjects receiving Omacor at three, six, and 12 months compared either to baseline or placebo.

Secondary endpoints [mean (SD); median (range) for Lp(a) lipoprotein]

	None	Omacor	Omacor	Omacor	None	Placebo	Placebo	Omacor
Weeks	0	12	24	48	0	12	24	48
N	30	30	29	25	29	27	26	21
Serum TG (mmol/l)	4.6 (2.2)	3.3 (1.4)***	3.5 (1.8)***	3.0 (1.7)***	3.8 (2.2)	3.9 (2.0)	3.9 (2.5)	2.9 (1.9)***
Serum cholesterol (mmol/l)	5.6 (1.5)	4.9 (1.2)*	5.0 (1.2)*	4.9 (0.9)**	6.2 (1.4)	6.3 (1.5)	6.4 (1.5)	6.0 (1.4)
VLDL cholesterol (mmol/l)	1.0 (0.5)	0.6 (0.5)**	0.6 (0.4)**	0.7 (0.5)**	0.9 (0.6)	0.8 (0.6)	0.8 (0.6)	0.6 (0.6)*
LDL cholesterol (mmol/l)	3.5 (1.4)	3.1 (1.1)	3.3 (1.2)	2.8 (1.0)*	4.2 (1.6)	4.2 (1.7)	4.4 (1.7)	3.7 (1.8)
HDL cholesterol (mmol/l)	1.1 (0.4)	1.2 (0.4)	1.0 (0.3)	1.2 (0.4)	1.1 (0.4)	1.2 (0.5)	1.3 (0.4)	1.3 (0.5)
ApoAI (mg/dl)	90 (14)	not done	84 (13)	96 (20)	89 (15)	not done	89 (13)	95 (18)
ApoB (mg/dl)	96 (31)	not done	95 (26)	93 (24)	110 (31)	not done	114 (33)	108 (34)
Lp(a) lipoprotein (mg/dl)	10.5 (2.1-152.1)	not done	16.2 (1.9-99.1)	15.5 (2.1-105.4)	26 (6.7-178)	not done	38.5 (6.7-176)	26.6 (5.9-176.4)
Systolic BP	129 (15)	not done	130 (22)	127 (15)	131 (20)	not done	130 (19)	131 (20)
Diastolic BP	79 (8)	not done	78 (11)	79 (8)	79 (11)	not done	79 (10)	81 (11)

Significantly different from their baseline values on paired testing: *p<0.025; **p<0.005; ***p<0.0005.

• Serum triglyeride and VLDL concentrations decreased significantly compared to baseline on Omacor (p<0.0005 and p<0.005, respectively)
• At no stage was there any tendency for LDL cholesterol to rise or for HDL cholesterol to decrease.
• Changes in lipoprotein concentrations were unrelated to the dose of simvastatin.
  • 10-20 mg/day: mean decrease of 25%
  • 40 mg/day: mean decrease of 27%
• The triglyeride, VLDL cholesterol and the serum cholesterol responses of diabetic subjects to Omacor were not significantly different from non-diabetics.
  • Numerically they were greater, for example, the decrease in triglycerides being 35% in the diabetic subjects at the end of the double blind phase and 44% at the end of the trial.
• No significant change in fasting blood glucose or HbA_1c occurred in either the diabetic or non-diabetic subjects receiving Omacor for 48 weeks.
  • This was also true when the combined groups and the 15 diabetic subjects receiving Omacor for 24 weeks was analyzed.
• There were no apparent differences between placebo and Omacor in the frequency of laboratory values outside the reference range.
• No significant effects were observed on ApoAI or B, Lp(a) lipoprotein, fibrinogen, or blood pressure.

 

Compliance: >80% in all but three subjects

Adverse Events:

• Reported by 22 subjects in the Omacor group and 17 receiving placebo
• Classified as minor except for: 1 death from acute MI, 1 with severe heartburn, 1 for loose motions

Serum Phospholipids:

• EPA concentrations
  • Omacor
    • At 6 months rose by a mean of 260% (95% CI 192% to 327%)
    • At 12 months rose by a mean of 361% (95% CI 276% to 447%)
  • Placebo
    • No significant changes at 6 months [12% (95% CI —33% to 57%)]
• DHA concentrations
  • Omacor
    • At 6 months rose by a mean of 54% (95% CI 38% to 70%)
    • At 12 months rose by a mean of 52% (95% CI 35% to 69%)
  • Placebo
    • No significant changes at 6 months [—6.1% (95% CI —13% to 1%]

 

Other Findings

 

Omacor was found to be a safe and effective means of lowering serum triglyerides in subjects with CHD and combined hyperlipidemia with elevated triglycerides despite simvastatin treatment over one year.

Frequency of measurements not outlined clearly. The paper gives the impression that measurements were collected every 12 weeks after randomization for the first 24 weeks and then at the end of the open label phase.

No listing of the minor adverse events provided.

Study was supported by Pronova.