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Health benefits and safety Health benefits and safety profile of omega-3 fatty acids in profile of omega-3 fatty acids in

heart failure and CHDheart failure and CHD

Jodi N. Sparkman PharmD, BCPS, NCPSJodi N. Sparkman PharmD, BCPS, NCPSLCDR USPHSLCDR USPHS

Clinical PharmacistClinical PharmacistClaremore Indian Hospital, Inpatient Pharmacy DirectorClaremore Indian Hospital, Inpatient Pharmacy Director

May 26, 2010May 26, 2010

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ObjectivesObjectives

Identify doses at which omega-3 fatty Identify doses at which omega-3 fatty acids provide cardiovascular benefitacids provide cardiovascular benefit

Describe the health benefits on omega-3 Describe the health benefits on omega-3 fatty acidsfatty acids

Describe the adverse effects related to Describe the adverse effects related to treatment with omega-3 fatty acidstreatment with omega-3 fatty acids

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What are Omega-3 Polyunsaturated What are Omega-3 Polyunsaturated Fatty Acids (PUFAs) and How Do They Fatty Acids (PUFAs) and How Do They differ from other Essential Fatty Acids?differ from other Essential Fatty Acids?

Essential fatty acids cannot be made in the body Essential fatty acids cannot be made in the body because the desaurase enzymes required for because the desaurase enzymes required for adding double bonds on the CHadding double bonds on the CH33 end of these end of these molecules are not present in mammalsmolecules are not present in mammals

For the most part, EPA and DHA must be For the most part, EPA and DHA must be ingested from external sources: arachidonic acid ingested from external sources: arachidonic acid is easily made from linoleic acidis easily made from linoleic acid

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COOH

C20:5 ω-3 Eicosapentaenoic(EPA)

H3C

Essential Fatty Acid FamiliesEssential Fatty Acid Families

C18:3 ω-3

ω-3 family

-Linolenic• Flaxseed Oil• Canola Oil• Soybean Oil

C22:6 ω-3 Docosahexaenoic(DHA)

COOHH3C

• Oily Fish• Fish Oil Capsules

H3CCOOH

ω-6 family

C20:4 ω-6

C18:2 ω-6 Linoleic

Arachidonic

H3CCOOH

More thrombotic More thrombotic and inflammatory and inflammatory metabolitesmetabolites

• Corn Oil• Safflower Oil• Sunflower Oil

Less thrombotic Less thrombotic and inflammatory and inflammatory metabolitesmetabolites

H3C COOH

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FishFish Amount (g) in Amount (g) in 3 oz serving3 oz serving

Serving amount Serving amount required to provide required to provide 1 g of EPA/DHA1 g of EPA/DHA

MackerelMackerel 0.34-1.570.34-1.57 2-8.52-8.5

HerringHerring 1.71-1.811.71-1.81 1.5-2.01.5-2.0

SalmonSalmon 0.68-1.830.68-1.83 1.5-4.51.5-4.5

TroutTrout 0.84-0.980.84-0.98 3.0-3.53.0-3.5

CatfishCatfish 0.1-2.00.1-2.0 15-2015-20

Flounder/SoleFlounder/Sole 0.420.42 77

CodCod 0.1-0.240.1-0.24 12.5-2312.5-23

Tuna, freshTuna, fresh 0.24-1.280.24-1.28 2.5-122.5-12

Sources of EPA and DHASources of EPA and DHA

Kris-Etherton, et al. Circulation. 2002;106:2747-2757.

66

Sources of EPA and DHASources of EPA and DHASupplementsSupplements Amount (g) in Amount (g) in

1 gram 1 gram capsulecapsule

Capsules required Capsules required to provide 1 g of to provide 1 g of EPA/DHAEPA/DHA

Cod Liver OilCod Liver Oil

0.190.19 5.05.0

Fish Body OilFish Body Oil0.300.30 3.03.0

Omega-3 Omega-3 concentrateconcentrate 0.50.5 2.02.0

Rx omega-3 Rx omega-3 FA FA concentrateconcentrate 0.850.85 11

Kris-Etherton, et al. Circulation. 2002;106:2747-2757.

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The Potential Cardiovascular The Potential Cardiovascular Benefits of EPA and DHABenefits of EPA and DHA

AntilipidAntilipid AntiarrhythmiaAntiarrhythmia AntiatherogenicAntiatherogenic AntithromboticAntithrombotic Anti-inflammatoryAnti-inflammatory AntihypertensiveAntihypertensive

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GISSI-HF omega-3 fatty acid study: GISSI-HF omega-3 fatty acid study: Primary and secondary outcomesPrimary and secondary outcomes

End pointEnd point Omega-3 fatty Omega-3 fatty acids, n=3494(%)acids, n=3494(%)

Placebo Placebo n=3481 (%)n=3481 (%)

Adjusted hazard Adjusted hazard ratio (95% CI)ratio (95% CI)

Primary end pointsPrimary end points

MortalityMortality 27.327.3 29.129.1 0.91 (0.833–0.998)0.91 (0.833–0.998)

All-cause mortality or All-cause mortality or hospitalization for hospitalization for cardiovascular causescardiovascular causes

56.756.7 59.059.0 0.92 (0.849–0.999)0.92 (0.849–0.999)

Secondary end pointsSecondary end points

Death from cardiovascular Death from cardiovascular causes causes 20.420.4 22.022.0 0.90 (0.81–0.99)0.90 (0.81–0.99)

Sudden cardiac death Sudden cardiac death 8.88.8 9.39.3 0.93 (0.79–1.08)0.93 (0.79–1.08)

Patients admitted for Patients admitted for cardiovascular causes cardiovascular causes 46.846.8 48.548.5 0.93 (0.87–0.99)0.93 (0.87–0.99)

Patients with fatal and Patients with fatal and nonfatal MI nonfatal MI 3.13.1 3.7 3.7 0.82 (0.63–1.06)0.82 (0.63–1.06)

Patients with fatal and Patients with fatal and nonfatal strokenonfatal stroke 3.53.5 3.0 3.0 1.16 (0.91–1.53)1.16 (0.91–1.53)

GISSI-HF investigators. Lancet 2008; available at: http://www.thelancet.com.

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GISSI-HF : More outcomesGISSI-HF : More outcomes

GISSI-HF investigators. Lancet 2008; available at: http://www.thelancet.com.

Number needed to treatNumber needed to treat– All cause mortality = 56All cause mortality = 56– All cause mortality or hospitalization for All cause mortality or hospitalization for

cardiovascular cause = 44cardiovascular cause = 44

When 1,000 patients were treated with When 1,000 patients were treated with omega-3 FA for ~4 years, 18 lives were omega-3 FA for ~4 years, 18 lives were saved and 17 cardiovascular saved and 17 cardiovascular hospitalizations were preventedhospitalizations were prevented

1010

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GISSI-Prevenzione Trial:GISSI-Prevenzione Trial:Endpoint ResultsEndpoint Results

EndpointEndpoint Control Control (%)(%)

Omega-Omega-3 FA (%)3 FA (%)

Risk Risk Reduction(%)Reduction(%)

P-valueP-value

All-cause All-cause mortalitymortality 10.410.4 8.38.3 2020 0.00640.0064

CV deathCV death 6.86.8 4.84.8 3030 <0.001<0.001

Cardiac Cardiac DeathDeath 5.35.3 3.53.5 3535 <0.01<0.01

Sudden Sudden DeathDeath 3.53.5 1.91.9 4545 0.00060.0006

Non-fatal Non-fatal CV eventsCV events 5.15.1 4.94.9 44 NSNS

GISSI Prevenzione Investigators. Lancet. 1999;354:447-455.

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Relative Risk of a Clinical Endpoint with Relative Risk of a Clinical Endpoint with Supplemental Omega-3 FA: Meta AnalysisSupplemental Omega-3 FA: Meta Analysis

9 studies, randomized, controlled, N= 13,1689 studies, randomized, controlled, N= 13,168 Dose range= EPA 0.3 to 6.0 g/day and DHA 0.6 Dose range= EPA 0.3 to 6.0 g/day and DHA 0.6

to 3.7 g/dayto 3.7 g/day Included pts with and without CHDIncluded pts with and without CHD Mean Duration 20 monthsMean Duration 20 months

Nonfatal MINonfatal MI Sudden DeathSudden Death Overall Overall MortalityMortality

0.8 (0.55 to 1.2)0.8 (0.55 to 1.2) 0.7 (0.6 to 0.9)0.7 (0.6 to 0.9) 0.8 (0.7 to 0.9)0.8 (0.7 to 0.9)

Bucher et al. Am J Med. 2002;112:298-304.

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Possible BenefitsPossible Benefits

Treatment with n-3 fatty acids may be Treatment with n-3 fatty acids may be associated with reductions in plasma levels associated with reductions in plasma levels of tumor necrosis factor-α and interleukin-of tumor necrosis factor-α and interleukin-1β in healthy subjects 1β in healthy subjects

Disadvantages with studiesDisadvantages with studiesLarge doses Large doses Small sample sizeSmall sample size

G.E. Caughey, E. Mantzioris, R.A. Gibson, L.G. Cleland and M.J. James, The effect on human tumor necrosis factor α and interleukin1 β production of diets enriched in n-3 fatty acids from vegetable oil or fish oil, Am J Clin Nutr . 1996; 63:116–122.

S. Endres, R. Ghorbani, V.E. Kelley, K. Georgilis, G. Lonnemann, J.W. van der Meer, J.G. Cannon, T.S. Rogers, M.S. Klempner, P.C. Weber, E.J. Schaefer, S.M. Wolff and C.A. Dinarello, The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells, N Engl J Med. 1989; 320:265–271.

Possible BenefitsPossible Benefits

Weight LossWeight LossObese people had blood levels of omega-3 fatty acids Obese people had blood levels of omega-3 fatty acids almost 1% less than those at a healthy weightalmost 1% less than those at a healthy weight

Higher plasma levels of total Higher plasma levels of total nn-3 PUFA are -3 PUFA are associated with a healthier BMI, waist associated with a healthier BMI, waist circumference and hip circumference.circumference and hip circumference.

1414M Micallef, I Munro, M Phang, M Garg. Plasma n-3 poluunsaturate fatty acids are negatively associated with obesity. Br Jof Nutr .2009; 102:1370-1374.

1515

1616

1717

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1919

Risk for Primary Cardiac Arrest and Risk for Primary Cardiac Arrest and Red Blood Cell EPA+DHA LevelRed Blood Cell EPA+DHA Level

Adapted from Siscovick DS et al. JAMA 1995;274:1363-1367.

Odds

Rati

o

3.3%

Mean RBC EPA+DHA by Quartile

4.3% 5.0% 6.5%

90%reductionin risk

*p<0.05 vs Q1

0.0

0.2

0.4

0.6

0.8

1.0

2020

Summary of AHA Summary of AHA Recommendations for Omega-3 FARecommendations for Omega-3 FA

Patients without CHD Patients without CHD

Patients with CHDPatients with CHD

Patients who need to Patients who need to lower triglycerideslower triglycerides

Eat a variety of fish at least Eat a variety of fish at least twice a weektwice a week

1 Gram of EPA/DHA per day, 1 Gram of EPA/DHA per day, preferably from fatty fish; preferably from fatty fish; supplements only under supplements only under physician’s carephysician’s care

2 to 4 grams of EPA/DHA per 2 to 4 grams of EPA/DHA per day under a physician’s day under a physician’s carecare

Kris-Etherton PM, et al. Circulation. 2002;106:2747-2757.

2121

Summary of NCEP ATP III Summary of NCEP ATP III Recommendations for Omega-3 FARecommendations for Omega-3 FA

Patients with elevated Patients with elevated triglyceridestriglycerides

Patients with CHDPatients with CHD

An alternative to fibrates An alternative to fibrates or niacin at doses of 3 to or niacin at doses of 3 to 12 g/day12 g/day

A therapeutic option in A therapeutic option in secondary prevention in secondary prevention in doses 1 to 2 g/day doses 1 to 2 g/day (moderate evidence)(moderate evidence)

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Circulation. 2004;110: 227-230.

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Research in ProgressResearch in Progress

VITAL StudyVITAL Study– Vitamin D and Omega-3 trialVitamin D and Omega-3 trial– 20,000 patients20,000 patients– Women >65 and men >60Women >65 and men >60– Follow-up 5 yearsFollow-up 5 years– At least 25% African AmericanAt least 25% African American– primary end point is a composite of nonfatal primary end point is a composite of nonfatal

MI, nonfatal stroke, or vascular deathMI, nonfatal stroke, or vascular death

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Implications for ResearchImplications for Research

Further trials with prespecified cardiovascular endpoints including sudden cardiac death, and blinding of participants and health providers are needed to test for any protective effect of omega 3 fats for those at increased cardiovascular risk, to run for long enough to assess long term events (ideally beyond four years), and to report any adverse effects associated with treatment (including cancer diagnosis, different types of stroke, and neurological status).

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Implications for ResearchImplications for Research

At present almost no RCT data exist on health outcomes in healthy populations, hopefully the VITAL study will provide answers in this population.

The association between exposure to fat soluble toxins from fish and risk of MI or CHD should also be examined.

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Implications for ResearchImplications for Research

Trials assessing higher doses of omega-3 Trials assessing higher doses of omega-3 fatty acids. Many studies use around 1 fatty acids. Many studies use around 1 gram/day. Trials with >3 grams daily are gram/day. Trials with >3 grams daily are warranted.warranted.