Definition of Oily FishDefinition of Oily FishNHFA Position StatementNHFA Position Statement

LeanLean < < 1% Fat (body weight)1% Fat (body weight)

e.g. Cod, troute.g. Cod, trout

IntermediateIntermediate 1 - 10% Fat1 - 10% Fat

e.g. Trout, sea bass, breame.g. Trout, sea bass, bream

OilyOily >> 10% Fat10% Fat

e.g. Atlantic salmon, herring, swordfishe.g. Atlantic salmon, herring, swordfish

www.heartfoundation.org.auwww.heartfoundation.org.au

www.heartfoundation.org.au

Marine n-3 PUFA Content in fish with recommended Marine n-3 PUFA Content in fish with recommended intake intake

USA Comparison of mercury and marine n-3 PUFA content in USA Comparison of mercury and marine n-3 PUFA content in fishfish

NHFA Update 2010NHFA Update 2010New Clinical Outcome TrialsNew Clinical Outcome Trials

Trial Result Comment

OMEGA Trial

ALPHA OMEGA Trial(post AMI)

GISSI-HF Trial(Heart failure)

Nil benefit

Nil benefit

Improved survival

Underpowered (50% power only)

Dose 400mg inadequate(in margarine)

Benefit on top of standard therapy

OMEGA-3OMEGA-3 TRIALTRIAL

Chief author/investigator Dr Jochen Serges

“The study was underpowered to show an effect because of the low rate of sudden cardiac death” Serges explained.“It would be incorrect to say that omega-3 fatty acids are not effective”

Ref: ACC Scientific Sessions March 2009www.theheart.org/article April 3, 2009

GISSI-HF TRIALGISSI-HF TRIAL(Gruppo Italiano per Lo Studio della Sopravvivenza (Gruppo Italiano per Lo Studio della Sopravvivenza

nell’Infarcto Miocardio Prevenenzione Trial)nell’Infarcto Miocardio Prevenenzione Trial)

6,975 patients from 357 Italian centres with CHF NHA Class II-IV irrespective of EF

2X2 Factorial design Omega-3 (EPA & DHA 850-882 mg) vs placebo Rousvastatin 10mg vs placebo)

Follow-up median 3.9 years

Ref: GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (The GISSI-HF Trial): a randomised, double blind, placebo controlled trial. Lancet 2008 372;9645:1223-1230

GISSI-HF TRIALGISSI-HF TRIAL

Background TRMean Age 67, women 22%

Omega-3(3,494 patients) %

Placebo(3,481 patients) %

ACE I 77 77.9

ARB 19 18

β-blocker 65 65

Spironolactone 39 40

Digitalis 37 37

Amiodarone 19 20

Diuretics 90 90

Anti-Coagulant 29 28

Aspirin 10 11

Statin 22 23

EF (mean) 33% 33%

EF > 40% 10% 9%

GISSI-HF TRIALGISSI-HF TRIAL

PRIMARY END-POINT OVER 3.9 YEARSPRIMARY END-POINT OVER 3.9 YEARSOmega-3 Omega-3 PlaceboPlacebo Hazard RatioHazard Ratio

End-PointEnd-Point nn %% nn %%DeathDeath 955955 27%27% 10141014 29%29% 0.91 P=0.040.91 P=0.04

(CI 0.83 – 0.99)(CI 0.83 – 0.99)Death or CVDeath or CV 19811981 57%57% 20532053 59%59% 0.92 P=0.0090.92 P=0.009admissionadmission (0.84 – 0.99)(0.84 – 0.99)

56 Patients NNT median 3.9 years to avoid death56 Patients NNT median 3.9 years to avoid death44 Patients NNT to prevent death or CV admission44 Patients NNT to prevent death or CV admission

GI side effects 96 (3%) in Omega 3 vs 92 (3%) in placeboGI side effects 96 (3%) in Omega 3 vs 92 (3%) in placeboDiscontinued therapy 1004 (28.7% in Omega 3 vs 1029 (29.6%)Discontinued therapy 1004 (28.7% in Omega 3 vs 1029 (29.6%)

GISSI-HF Investigators Lancet Online Aug 31,2008:1-8GISSI-HF Investigators Lancet Online Aug 31,2008:1-8

NHFA Update 2010NHFA Update 2010

Awareness of poor implementation of Position Awareness of poor implementation of Position StatementStatement

Different kinetics of fish oil triglycerides and Different kinetics of fish oil triglycerides and ethyl ester derivatives ethyl ester derivatives

(may modify recommendations similar to (may modify recommendations similar to NICE.)NICE.)

Physiology of Triglycerides and Physiology of Triglycerides and Omega-3 ethyl estersOmega-3 ethyl esters

The ESTER bond influences absorption kinetics of EPA and The ESTER bond influences absorption kinetics of EPA and DHA in duodenum.DHA in duodenum.

All forms are not fully absorbedAll forms are not fully absorbed Triglycerides rapidly digested by (Pancreatic lipase), less Triglycerides rapidly digested by (Pancreatic lipase), less

active if they contain EPA/DHA (due to double bond position) active if they contain EPA/DHA (due to double bond position) PUFA by <Carboxyl ester hydrolase>PUFA by <Carboxyl ester hydrolase>

Compared to triglycerides ethyl esters of EPA/DHA are more Compared to triglycerides ethyl esters of EPA/DHA are more slowly absorbed from duodenum into lymph and via thoracic slowly absorbed from duodenum into lymph and via thoracic duct into the bloodstream.duct into the bloodstream.

Ikeda I et al. Life Sciences 1993;52:1371-9Ikeda I et al. Life Sciences 1993;52:1371-9

Lawson L et al. Biochem and Biophysical Res Comm 1988;152:328-335Lawson L et al. Biochem and Biophysical Res Comm 1988;152:328-335

Clinical implications of ethyl ester Clinical implications of ethyl ester EPA/DHA therapy VS Fish Oil EPA/DHA therapy VS Fish Oil

TriglyceridesTriglycerides Less saturated fatty acids Less saturated fatty acids Less LDL-raising effectLess LDL-raising effect Less contaminants (e.g. mercury)Less contaminants (e.g. mercury) Greater compliance as one-third as many capsulesGreater compliance as one-third as many capsules Greater protection at vulnerable SCD time in AM Greater protection at vulnerable SCD time in AM

(due to kinetics)(due to kinetics) Use of proven form of EPA/DHA in clinical outcome Use of proven form of EPA/DHA in clinical outcome

trialstrials

NICE Recommendations for NICE Recommendations for Secondary Prevention Secondary Prevention

““Consume at least 7 g of omega-3 fatty acids per Consume at least 7 g of omega-3 fatty acids per week from 2-4 portions of oily fish per week. If week from 2-4 portions of oily fish per week. If within 3 months of a myocardial infarction and they within 3 months of a myocardial infarction and they are not achieving this, consider providing are not achieving this, consider providing at least 1 g at least 1 g daily of omega-3 acid ethyl esters treatment licensed daily of omega-3 acid ethyl esters treatment licensed for secondary prevention after myocardial infarction for secondary prevention after myocardial infarction for up to 4 years.for up to 4 years. Initiation of omega-3 acid ethyl Initiation of omega-3 acid ethyl esters supplement treatment is not routinely esters supplement treatment is not routinely recommended in patients that have had a myocardial recommended in patients that have had a myocardial infarction more than 3 months earlier infarction more than 3 months earlier (no evidence of benefit)(no evidence of benefit)” ” JS Skinner et al. HEART 2007;93(7) 862-64JS Skinner et al. HEART 2007;93(7) 862-64

NHFA Update 2010NHFA Update 2010

MechanismsMechanisms::

EPA/DHAEPA/DHA lowers Non-LDL cholesterollowers Non-LDL cholesterol restores anti-platelet effect of aspirin and restores anti-platelet effect of aspirin and

Clopidogrel in resistant patientsClopidogrel in resistant patients with aspirin, formation of anti-inflammatory with aspirin, formation of anti-inflammatory

resolvins and protectinsresolvins and protectins may improve depressionmay improve depression

Aspirin Resistance in CHD patients Aspirin Resistance in CHD patients improved by omega-3 or dose increaseimproved by omega-3 or dose increase

30 pts (6.2%) were ASA-R30 pts (6.2%) were ASA-R

Randomized to 75-162mg ASA & Omega 3 Randomized to 75-162mg ASA & Omega 3

or ASA 325mg / dayor ASA 325mg / dayOmega 3 : EPA 360 & DHA 240 x 4 / day Omega 3 : EPA 360 & DHA 240 x 4 / day (OmegaMax 3)(OmegaMax 3)

Exclusion:Exclusion: - PCI within 1 month - PCI within 1 month

- Concomitant treatment with - Concomitant treatment with

omega-3, NSAID or warfarinomega-3, NSAID or warfarin

Lev EI, Solodky A, et al. JACC 2010 Vol 55 (2):114-21Lev EI, Solodky A, et al. JACC 2010 Vol 55 (2):114-21

Aspirin resistance in CHD patients Aspirin resistance in CHD patients improved by omega-3 or dose improved by omega-3 or dose

increaseincrease30 pts with ASA resistance (ASA-R) had repeat platelet 30 pts with ASA resistance (ASA-R) had repeat platelet

testing at 30 days and one yeartesting at 30 days and one year

20 control – no change in platelet function tests20 control – no change in platelet function tests

Aspirin resistance was largely abolished with increased Aspirin resistance was largely abolished with increased ASA dose or addition of Omega-3ASA dose or addition of Omega-3

Lev EI, et al. Treatment of ASA-R. J Am Cardiol 2010;55:114-21Lev EI, et al. Treatment of ASA-R. J Am Cardiol 2010;55:114-21

Result Plasma thromboxane B2

No longer ASA-R

At 30 daysOmega-3 Group

56.8%↓ 80% (n=12)

ASA 325mg 39.6%↓ 73% (n=11)

NHFA Update 2010NHFA Update 2010

COMPLIANCECOMPLIANCE:: Compliance is a critical issue for primary and Compliance is a critical issue for primary and

secondary preventionsecondary prevention.. Minimizing number of pills is a factor.Minimizing number of pills is a factor. Ideal source of EPA/DHA is most concentrated Ideal source of EPA/DHA is most concentrated

and devoid of potential contaminants.and devoid of potential contaminants.

NHFA Update 2010NHFA Update 2010SUSTAINABILITYSUSTAINABILITY:: Fish stocks long term are fragile.Fish stocks long term are fragile. Awareness that fish do not synthesize Awareness that fish do not synthesize

EPA/DHA.EPA/DHA. Phytoplankton (algae, cyanobacteria) make Phytoplankton (algae, cyanobacteria) make

EPA/DHA found in fish.EPA/DHA found in fish. Algal bioreactors (farms) are a direct source Algal bioreactors (farms) are a direct source

for sustainable EP/DHA for health and energy for sustainable EP/DHA for health and energy to to power industry.power industry.

Access Economics Report on cost Effectiveness of Access Economics Report on cost Effectiveness of Complementary MedicinesComplementary Medicines

Cost effective therapy for CHDCost effective therapy for CHD Access Economics 2010 Report commissioned by National Institute of Access Economics 2010 Report commissioned by National Institute of

Complementary Medicine (NICM) released in September 2010Complementary Medicine (NICM) released in September 2010

Access Economics report on Cost Access Economics report on Cost Effectiveness of Complementary Medicines Effectiveness of Complementary Medicines

““Fish oils were found to be highly cost effective – consistent Fish oils were found to be highly cost effective – consistent with other international cost effectiveness studies. The with other international cost effectiveness studies. The incremental cost per person was $128 per annum and the incremental cost per person was $128 per annum and the incremental effectiveness 0.06 DALYs. The cost per DALY incremental effectiveness 0.06 DALYs. The cost per DALY avoided was $2.041. Sensitivity analysis was conducted avoided was $2.041. Sensitivity analysis was conducted around treatment effect variables (MI, stoke, around treatment effect variables (MI, stoke, revascularisation, CHD mortality and other mortality). The revascularisation, CHD mortality and other mortality). The results remained highly cost effective under all of the results remained highly cost effective under all of the sensitivity scenarios, evaluated against all the cost sensitivity scenarios, evaluated against all the cost effectiveness thresholds. Where dietary changes cannot be effectiveness thresholds. Where dietary changes cannot be made (or sustained) there is a clear role for the use of dietary made (or sustained) there is a clear role for the use of dietary supplements to provide the necessary dietary intake of EPA supplements to provide the necessary dietary intake of EPA and DHA”.and DHA”.

Number Needed to Treat to Prevent CHD Event over 5 years

Summary of NHFA Position on fish, fish oils Summary of NHFA Position on fish, fish oils and omega-3 fatty acids 2010and omega-3 fatty acids 2010

Position Statement 2008 confirmed.Position Statement 2008 confirmed. New data refines certainty about recommendations New data refines certainty about recommendations

(GISSI-HF).(GISSI-HF). Aspirin/Clopidogrel resistance is improved Aspirin/Clopidogrel resistance is improved

(OMEGA-PCI).(OMEGA-PCI). Need to publicize recommendations.Need to publicize recommendations. TGA approval and PBS listing ought to make TGA approval and PBS listing ought to make

EPA/DHA more affordable, and aid compliance of EPA/DHA more affordable, and aid compliance of patients and doctors to “get with the guidelines”.patients and doctors to “get with the guidelines”.

May specifically recommend like NICE: omega-3-May specifically recommend like NICE: omega-3-acid ethyl esters rather than any source of EPA/DHA acid ethyl esters rather than any source of EPA/DHA (triglycerides or phospholipids).(triglycerides or phospholipids).

ContactContact

““Nothing will benefit human health and Nothing will benefit human health and increase the chances for survival of life on increase the chances for survival of life on

Earth as much as the evolution of a Earth as much as the evolution of a vegetarian diet ” vegetarian diet ” & the addition of fatty fish weekly & the addition of fatty fish weekly for healthy adults and ethyl ester EPA/DHA 1000mg per day for healthy adults and ethyl ester EPA/DHA 1000mg per day

for those with CHD (for those with CHD (The Quotable Colquhoun!The Quotable Colquhoun!))The Quotable EinsteinThe Quotable Einstein

New Jersey 1996New Jersey 1996