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Health benefits and safety profile of omega-3 fatty acids in heart failure and CHD. Jodi N. Sparkman PharmD, BCPS, NCPS LCDR USPHS Clinical Pharmacist Claremore Indian Hospital, Inpatient Pharmacy Director May 26, 2010. Objectives. - PowerPoint PPT Presentation
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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.
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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
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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.
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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
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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.
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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.
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