EAL

DLM: Elevated Triglycerides and Omega-3 Fatty Acids (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate the effects of simvastatin combined with omega-3 fatty acids on high sensitive C-reactive protein, lipidemia, and fibrinolysis in coronary heart disease (CHD) and CHD risk equivalent patients with mixed dyslipidemia.

Inclusion Criteria:

Coronary heart disease (CHD) and CHD risk equivalent dyslipidemia not regularly treated within recent 6 months
- Defined as serum triglyceride > 200 mg/dl and < 500 mg/dl; and LDL > 100 mg/dl after a 12 hour fast.
Seen at an outpatient clinic of the department of cardiovascular internal medicine at Beijing Chaoyang Hospital

Exclusion Criteria:

Acute MI, serious trauma, and surgery with general anesthesia within recent 6 months
Disease status unstable (for example, uncontrolled diabetes)
Life expectancy lower than 6 months
Hormones used due to disease, with dose regulation within recent 6 months
Serious disease of the digestive system
Hemorrhagic disease
Liver dysfunction (elevated transaminase > two times of normal superior limit
Primary hypothyroidism

Description of Study Protocol:

Recruitment not described

Design randomized, double-blind, placebo-controlled parallel group trial

Blinding used

A third party randomly numbered omega-3 fatty acids and placebos, and the numberings representing drugs were sealed until the end of the trial.
The subjects' random numberings were given out by computer.
Capsules were similar in appearance that physicians and subjects were unable to tell the difference.

Intervention

Run in period
- Physicians prescribed simvastatin (10 mg/day or 20 mg/day) for 6-12 weeks to patients who had serum triglycerides >200 mg/dl but <500 mg/dl and LDL-cholesterol >100 gm/dl after a 12 hour fast.
- Patients were invited to participate in the study if serum lipids (after a 12 hour fast) met the following criteria after receiving 6-12 weeks of simvastatin:
  - In the 20 mg/day group: triglyceride >200 mg/dl, LDL-cholesterol <130 mg/dl, non-HDL-cholesterol (total cholesterol-HDL-cholesterol) >130 mg/dl
  - In the 10 mg/day group: triglyceride >200 mg/dl, LDL-cholesterol <100 mg/dl, non-HDL-cholesterol (total cholesterol-HDL-chol) >130 mg/dl
Randomization
- Simvastatin + omega-3 fatty acids
  - Individual simvastatin doses maintained from run in period
  - Four capsules of omega-3 fatty acids were consumed three times daily. Each omega-3 fatty acid capsule contained 0.25 g omega-3 fatty acids.
- Simvastatin + placebo
  - Individual simvastatin doses maintained from run in period
  - Four placebo capsules were consumed three times daily. Each capsule contained 0.28 gm rapeseed oil.
- All subjects were told to improve lifestyle
- All subjects were told to maintain original doses of other cardiovascular and/or diabetes drugs

Statistical Analysis

Measurement data were expressed as mean±SD and analyzed using t tests.
Enumeration data were analyzed by X² tests.
Pearson correlation coefficients were used to estimate the degree of linear correlation.
Two-sided probability values of P<0.05 were considered statistically significant.

Data Collection Summary:

Timing of Measurements Not described

Dependent Variables

Serum lipids: measured in the morning after a 12 hour fast with an auto analyzer. (Quality control: intra-assay, CV <3%-5%; inter-assay, CV <6%-9%.)
- Total cholesterol (TC)
- HDL-cholesterol
- LDL-cholesterol
- Triglycerides
Lp(a): measured by ELISA (intra-assay CV <5%, inter-assay CV <8%)
ApoA1: measured by nephelometry (intra-assay CV <4%, inter-assay <6%)
ApoB: measured by nephelometry (intra-assay CV <4%, inter-assay <6%)
High sensitivity C-reactive protein (HsCRP): measured by ELISA (intra-assay CV <3%, inter-assay CV <4%)
Plasminogen activator inhibitor (PAI-1): measured by ELISA
Tissue plasminogen activator (tPA): measured by ELISA

Independent Variables

3.0 gm omega-3 fatty acids
3.36 gm rapeseed oil (placebo)

Control Variables

Description of Actual Data Sample:

Initial N: Appears to be 40

Attrition (final N): N=40

omega-3 fatty acids group: N=20
placebo group: N=20

Age: see table

Ethnicity: not described

Other relevant demographics: not described

Anthropometrics

	omega-3 Fatty acids	Placebo
	N=20	N=20
Sex (M/F) (%)	12/8 (60/40)	8/12 (40/60)
Age (yr)	61.4±7.9	59.6±8.2
BMI	27.5±4.8	26.4±2.5
Current smoker (%)	4 (20)	6 (30)
Diabetes (%)	4 (20)	7 (35)
Hypertensive disease (%)	16 (80)	15 (75)
CHD (%)	17 (85)	14 (70)
Stroke history (%)	4 (20)	6 (30)
Peripheral angiopathy history (%)	2 (10)	3 (15)
Drug therapy
Aspirin (%)	19 (95)	17 (80)
Insulin (%)	1 (5)	3 (15)
Diuretic (%)	6 (30)	2 (10)
Calcium antagonist (%)	9 (45)	7 (35)
ß blocker (%)	17 (85)	12 (60)
ACE inhibitor (%)	7 (35)	8 (40)

No significant differences between the groups at baseline.

Location: Heart Center, Beijing Chaoyang Hospital, Capital University of Medical Science, Beijing, China

Summary of Results:

	Omega-3 Fatty acids	N=20		Placebo	N=20
	Before	After	Change	Before	After	Change
HsCRP (mg/L)	3.97±3.04	1.81±1.04**	—2.16±2.77^§	2.92±3.51	2.82±4.29	—0.10±2.68
Total cholesterol [TC (mg/dl)]	195.2±28.4	181.9±27.2*	—13.3±22.3	193.1±22.3	187.1±24.5	—6.1±23.9
TG (mg/dl)	292.8±67.5	198.8±66.5***	—94.0±65.4^§	269.5±57.0	227.3±75.5**	—42.2±56.0
HDL-cholesterol (mg/dl)	36.9±8.3	40.5±9.0	3.6±9.9	37.7±10.0	39.5±12.4	1.8±13.7
LDL-cholesterol (mg/dl)	89.4±19.8	86.5±15.9	—3±20.8	89.6±23.9	91.2±23.6	1.6±16.8
TC/HDL-cholesterol	5.52±1.45	4.74±1.45*	—0.78±1.60	5.40±1.25	5.04±1.14	—0.37±1.70
Lp(a) (mg/dl)	11.64±10.87	11.55±9.22	—0.09±6.16	15.28±15.61	12.44±15.39	—2.84±7.08
ApoA1 (g/L)	1.99±0.44	1.83±0.63	—0.17±0.59	1.87±0.58	1.62±0.67	—0.25±0.67
ApoB (g/L)	1.41±0.57	1.49±0.56	0.07±0.63	1.40±0.58	1.30±0.32	—0.10±0.67
tPA (ng/ml)	6.12±4.41	7.06±7.98	0.94±4.57	8.83±6.62	7.76±8.59	—1.07±4.87
PAI-1 (ng/ml)	57.13±28.0	59.87±30.25	2.75±37.34	57.15±19.44	57.18±25.30	0.02±28.46
PAI-1/tPA	12.3±8.12	13.64±8.51	1.32±12.16	13.98±10.6	12.72±7.62	—1.26±9.09

HsCRP, lipids, and fibrinolysis changes before and after treatment

*P<0.05, **P<0.01, ***P<0.001 compared with "before treatment" within group; ^§P<0.05 compared with placebo

Significant reductions of HsCRP, TG, total cholesterol and total cholesterol/HDL-cholesterol which decreased by 2.16±2.77 mg/dl (38.5%), 94.0±65.4 mg/dl (31.1%), 13.3±22.3 mg/dl (6.3%) and 0.78±1.6, respectively, in the omega-3 fatty acids group (P<0.01, <0.001, <0.05, <0.05, respectively, compared to baseline).
HsCRP and triglyceride reduction were more significant in the omega-3 fatty acids group than in the placebo group (P=0.021 and 0.011 respectively).
There were no significant changes in LDL-cholesterol, HDL-cholesterol, Lp(a), ApoA1, ApoB, PAI-1, tPA and PAI-1/tPA between the two groups or compared to baseline.
In the omega-3 fatty acids group, the values and percentage of TG reduction had a significantly positive relation with that of the HsCRP reductions (r=0.51 and 0.45, P=0.021 and 0.047, respectively). In the placebo group, there were no similar reductions.

Other Findings

Author Conclusion:

In CHD and CHD risk equivalent patients with mixed dyslipidemia, dyslipidemias's therapeutic effect using simvastatin and omega-3 fatty acids may result from not only the combination of lipid adjustment, but also enhancement of their own nonlipid influences.

Funding Source:

Reviewer Comments:

There was a general lack of detail in this paper including the following:

No information provided on how many subjects entered the run in phase and how many were subsequently eligible for the trial and eventually randomized.
No information on the length of the trial although there is reference to the study being 2 months long in the discussion.
No information on how many measurements were taken during the trial: was it just at baseline and at conclusion of trial?
How did physicians determine how much simvastatin a patient should receive during the run in phase?
Why was the run in period (6-12 weeks) different? Was it of sufficient duration?
Simvastatin doses by group not described.
Fatty acid composition of the omega-3 fatty acids capsule not described.
No reference made to compliance with the omega-3 fatty acids or placebo.
No description of what "improve lifestyle" entailed. Did lifestyle, including diet, change during the course of the study?
Did body weight change during the study?
Unsure what CHD risk equivalent meant.

Not convinced that results are solely related to the use of omega-3 fatty acids. Could some of the effects seen be related to recent use of simvastatin? Study didn't appear to consider other factors that might affect results.

Beijing Beihui Biochemical Pharmaceutical Company provided the omega-3 fatty acids capsules (trade name, Meilekang).

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		No
	4.1.	Were follow-up methods described and the same for all groups?	No
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	No
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	???
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		No
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	No
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	No
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	No
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	???
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	N/A
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	No
9.	Are conclusions supported by results with biases and limitations taken into consideration?		???
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes