ALPHA OMEGA:
Effect of low doses of n-3 fatty acids on
cardiovascular diseases in post-MI patients
Daan Kromhout, MPH PhD
for the Alpha Omega Trial Group
Wageningen University, Division of Human Nutrition, The Netherlands
ESC, Stockholm, 29 August 2010
GRANTS
• Netherlands Heart Foundation, The Hague, The Netherlands
• National institutes of Health, Bethesda MD, U.S.A.
• Unilever, Vlaardingen, The Netherlands
• Presenter disclosure: no conflicts of interest
TRIAL CONDUCT
• Investigator-initiated study
• Study design, conduct and reporting are solely those of the Alpha Omega Trial Group
• Data-analysis by independent statistician
N-3 FATTY ACIDS
CH3
CH3
CH3
COOH
COOH
COOH
3
3
3
Alpha-linolenic acid (ALA, C18:3n-3)
Eicosapentaenoic acid (EPA, C20:5n-3)
Docosahexaenoic acid (DHA, C22:6n-3)
Limited conversion in humans (<10%)
HYPOTHESES
N-3 fatty acids reduce the risk of:
• major cardiovascular events
• fatal coronary heart disease
• ventricular arrhythmia-related events
PATIENT CHARACTERISTICS
EPA+DHA and ALA EPA+DHA ALA Placebon=1212 n=1192 n=1197 n=1236
Age, y 69 ± 6 69 ± 6 69 ± 6 69 ± 6Men, % 78 78 78 79Time since MI, y 4.2 ± 3.1 4.3 ± 3.2 4.4 ± 3.3 4.3 ± 3.3
Diabetes mellitus, % 20 22 22 20Cardiovascular medication, % Antithrombotic agents 96 98 98 98 BP lowering drugs 90 91 88 89 Lipid lowering drugs 87 85 86 85 Antiarrhythmic drugs 3 3 3 3Systolic blood pressure, mmHg 141 ± 22 142 ± 22 141 ± 21 142 ± 22Serum total cholesterol, mmol/l 4.7 ± 1.0 4.8 ± 1.0 4.7 ± 1.0 4.8 ± 1.0Body mass index, kg/m2 27.8 ± 4.0 27.7 ± 3.7 27.8 ± 3.8 27.8 ± 3.9Current smoker, % 15 17 17 18
DESIGN ALPHA OMEGA TRIAL
2009
Car
diov
ascu
lar e
vent
s
40 months)
TRIAL MARGARINES
Use of trial margarine on bread 20 grams per day 3-4 slices of bread
Daily doses of n-3 fatty acids in the 4 groups:
I: 400 mg EPA+DHA
II: 2 g ALA
III: 400 mg EPA+DHA and 2 g ALA
IV: 0 mg EPA+DHA, 0 mg ALA
PARTICIPATING CENTERSCenters are listed at www.alphaomegatrial.com
COMPLIANCE
Change in plasma n-3 fatty acids during the trial
Baseline 20 mo. 40 mo.
Alph
a lino
lenic
acid
(ALA
; mass
-%)
0.0
0.5
1.0
1.5
2.0
2.5EPA + DHA and ALAEPA + DHAALAPlacebo
Baseline 20 mo. 40 mo.
Eicos
apen
taeno
ic ac
id (EP
A; m
ass-%
)
0.0
0.5
1.0
1.5
2.0
2.5
Baseline 20 mo. 40 mo.
Doco
sahex
aeno
ic ac
id (D
HA; m
ass-%
)
0.0
0.5
1.0
1.5
2.0
2.5
* P < 0.001
n=887 n=795 n=804 n=887 n=795 n=804 n=887 n=795 n=804
* * * ** *
ENDPOINTSPrimary outcome
Major cardiovascular events: fatal and non-fatal cardiovascular events and cardiac interventions (PCI, CABG)
Secondary outcomes
Incidence of cardiovascular diseases
Fatal cardiovascular diseases
Fatal coronary heart disease
Ventricular arrhythmia-related events: sudden death, cardiac arrest and placement of implantable cardioverter-defibrillator
Death from any cause
EPA+DHA AND ENDPOINTS
Findings were similar in men and women
EPA+DHA better
Hazard ratio (95% CI)
Placebo betterMonths
0 12 24 36 40
Cumu
lative
Incid
ence
(%)
0
2
4
6
8
10
12
14
16
Placebo
EPA + DHA
Major Cardiovascular Events
HR: 1.01 (95% CI: 0.87-1.17)
P = 0.93
ALA AND ENDPOINTS
Findings differed between men and women
Hazard ratio (95% CI)
ALA better Placebo betterMonths
0 12 24 36 40
Cumu
lative
Incid
ence
(%)
0
2
4
6
8
10
12
14
16
PlaceboALA
Major Cardiovascular Events
HR: 0.91 (95% CI: 0.78-1.05)
P = 0.20
RESULTS IN WOMEN
Months0 12 24 36 40
Cumu
lative
Incid
ence
(%)
0
2
4
6
8
10
12
14
16
Placebo
ALA
Major Cardiovascular Events
HR: 0.73 (95% CI: 0.51-1.03)
P = 0.07
Post-hoc analysis
Patients with diabetes (n=1,014) had
30% higher risk of major cardiovascular
events than non-diabetics (n=3,823)
RESULTS IN DIABETIC PATIENTS
Hazard ratio (95% CI)
Hazard ratio (95% CI)
EPA+DHA better
Placebo better ALA better Placebo better
EPA+DHA ALA
VENTRICULAR ARRHYTHMIA-RELATED EVENTS IN DIABETIC PATIENTS
Ventricular arrhythmia-related events: defined as sudden death, cardiac arrest, and implantable cardioverter-defibrillator placement
Months0 12 24 36 40
Cumu
lative
Incid
ence
(%)
0
1
2
3
4
5
6
Placebo
EPA + DHA
Months0 12 24 36 40
Cumu
lative
Incid
ence
(%)
0
1
2
3
4
5
6
Placebo
ALA
HR: 0.39 (95% CI: 0.17-0.88)
P = 0.02
HR: 0.51(95% CI: 0.24-1.11)
P = 0.09
A EPA+DHA vs. placebo B ALA vs. placebo
CONCLUSIONS
• In the total patient population, low doses of n-3 fatty acids
were not related to major cardiovascular events
• In women, ALA reduced major cardiovascular
events borderline significantly
• In diabetic patients, n-3 fatty acids reduced ventricular
arrhythmia-related events (exploratory analysis)
IMPLICATIONS
• Major cardiovascular events cannot be prevented by low
doses of n-3 fatty acids in stable, well-treated post-MI patients
• ALA may prevent major cardiovascular events in
women, which needs confimation
• Whether n-3 fatty acids prevent ventricular arrhythmia-related
events in post-MI patients with comorbid diabetes warrants
further study
