EAL

DLM: Omega-3 Fatty Acids (2009-2010)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To assess the relationship between left ventricular systolic function and the risk of sudden death in post-MI patients with left ventricular systolic dysfunction in patients enrolled in the in the GISSI prevention trial.

Inclusion Criteria:

Participant in the GISSI-Prevenzione Trial
Echocardiograhic measurement of ejection fraction.

Exclusion Criteria:

Missing information regarding dyspnea status.

Description of Study Protocol:

Recruitment

Participants were enrolled in the GISSI-Prevenzione trial, which was a multicenter, open-label clinical trial to assess the efficacy of PUFA (one gram daily) and vitamin E (300mg daily). Subjects were followed for 3.5 years.

Design

Cohort.

Blinding Used

Validation of clinical events was assured by an ad hoc committee of cardiologists and neurologists blinded to patients' treatment assignment.

Intervention

PUFA (one gram daily) and vitamin E (300mg daily) for 3.5 years.

Statistical Analysis

Data analyses on the relationship between ejection fraction and outcome as well as on the effect of n-3 PUFA treatments were carried out by fitting various multivariable Cox regression models adjusted for the confounding effect of relevant prognostic indicators
- Efficacy of n-3 PUFA treatments was assessed according to intention to treat and adjusted for interaction between treatments to ensure the full assessment of the independent effects of PUFA
- Confounding variables
  - Non-modifiable risk factors
  - Complications after MI
  - Cardiovascular risk factors
  - Treatment-related variables
Computed X² tests for trend and heterogeneity as appropriate
Linearity of the effect of left ventricular systolic dysfunction (LSVD) on the outcome was assessed through fitting classes of LVSD as a continuous variable and the heterogeneity of the effect of n-3 PUFA by increasing levels of LVSD by adding n-3 PUFA by LVSD interactim term
Two-sided probability values.

Data Collection Summary:

Timing of Measurements

Not described.

Dependent Variables

Sudden death (defined as natural death, instantaneous within one hour of the onset of acute symptoms and unexpected as to the time and mode of death; unwitnessed deaths in patients with no known preceding illness other than coronary heart disease)
Total mortality.

Independent Variables

Supplementation with one gram PUFA and 300mg vitamin E (or placebo).

Description of Actual Data Sample:

Initial N: 9,630 (85% of initial cohort)
Attrition (final N): 9,630
Age: See table below
Other relevant demographics: See table below
Anthropometrics: See table below.

Characteristics of Patients With and Without Left Ventricular Systolic Dysfunction (EF Less Than 50%)

	No Systolic Dysfunction	Systolic Dysfunction	P
N	5,306	4,324
Age (means, SD)	57.8 (10.4)	60.5 (10.4)	<0.0001
Age, more than 70 years	669 (12.6)	804 (18.6)	<0.001
Ejection fraction (means, SD)	60.1 (16.7)	43.4 (6.3)	<0.001
Females (Number, percentage)	768 (14.5)	622 (14.5)	0.90
Hypertension	1,847 (34.8)	1,556 (36)	0.23
Diabetes mellitus	677 (12.8)	724 (16.7)	<0.0001
Smokers	2,457 (46.3)	1,743 (40.3)	<0.0001
Peripheral vascular disease	213 (4.0)	231 (5.3)	0.002
Previous MI	411 (7.8)	729 (16.9)	<0.0001
BMI (means, SD)	26.4 (3.4)	26.5 (3.9)	0.25
Previous sustained ventricular tachycardia	25 (0.7)	37 (1.2)	0.03
Days since diagnosis AMI (mean, SD)	24.5 (20.5)	24.7 (20.7)	0.59
Dyspnea on normal or mild exertion (NYHA II)	279 (5.3)	753 (17.5)	<0.0001
Ergometric test positive	1,104 (20.8)	761 (16.6)	<0.0001
Ergometric test contraindicated	239 (4.5)	487 (11.3)	<0.0001
Total cholesterol less than 200mg, percentage	3,142 (59.3)	2,431 (56.4)	0.004
HDL cholesterol less than or equal to 45mg, percentage	3,334 (68.1)	2,761 (69.9)	0.07
Triglycerides more than 150mg, percentage	2,549 (48.2)	1,925 (44.8)	0.0009
Anti-platelets*	4,417 (89.4)	3,418 (86.8)	0.0002
Beta blockers*	2,215 (44.8)	1,476 (37.5)	<0.0001
ACE inhibitors*	1,665 (33.7)	1,959 (49.7)	<0.0001
Statins*	1,093 (21.2)	856 (20.8)	0.62
Revascularization procedures	848 (16.0)	742 (17.2)	0.12
Outcome Measures
Total mortality	319 (6.01)	531 (12.28)	<0.0001
Sudden death	75 (1.41)	146 (3.38)	<0.0001

Some figures don't add up to 100% because of missing values.

*Treatment-related variables are depicted at six months.

Location

Italy.

Summary of Results:

Left ventricular systolic dysfunction was an independent predictor of total mortality.

Rates of Total Mortality and Sudden Death According to Left Ventricular Systolic Function

EF Percentage	Hazards Ratio	95% CI	P-Value
More than 50%, N=5,306 Total mortality, 6.2% Sudden death, 1.4%	1.0
46% to 50%, N=1,873 Total mortality, 8.4% Sudden death, 2.2%	1.32	1.09 to 1.61	0.005
41% to 45%, N=1,131 Total mortality, 10.1% Sudden death, 2.7%	1.43	1.15 to 1.78	0.002
36% to 40%; N=756 Total mortality, 14.4% Sudden death, 4.1%	2.06	1.64 to 2.57	<0.0001
Less than 36%, N=564 Total mortality, 26.6% Sudden death, 7.8%	3.40	2.75 to 4.20	<0.0001

Treatment with n-3 PUFA and Sudden Death

Effect of sudden death was asymmetrical, with greater effect in patients with LVSD [RR reduction 58% (-74% to -33%), P=0.003] as compared to patients with preserved systolic function [RR reduction 11% (-54% to +69%), P=0.71]
Effect of n-3 PUFA treatment was related to the degree of systolic dysfunction with the benefit on sudden death reduction in patients with EF less than or equal to 40% being four-fold higher than in those with EF more than 50%.

Author Conclusion:

Benefit of n-3 PUFA treatment on sudden death seems to increase in parallel with the worsening of left ventricular systolic function, suggesting an even greater benefit in patients with heart failure, a hypothesis that should be tested prospectively.

Funding Source:

Reviewer Comments:

No information provided relative to compliance with n-3 fatty acid supplementation
Effect of vitamin E, if any, was not discussed.

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?	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	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?	Yes
	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?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	N/A
	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%.)	N/A
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	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?	N/A
	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?	Yes
	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?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	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?	???
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	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?	Yes
	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?	Yes
	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)?	Yes
	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?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
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