ACE-Inhibitor Use in Cardiovascular Risk Reduction

Byron Hoogwerf, M.D., FACP, FACE, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.


Therapy with angiotensin converting enzyme inhibitors (ACE-I) has a well-established role in the treatment of diabetic nephropathy and in the treatment of patients with heart failure. Information from the heart failure studies suggested that there was a reduction in the risk for cardiovascular events (fatal or non-fatal MI) that was independent of any benefit on heart failure. In addition, this benefit appeared to be independent of any blood pressure reduction effect.

Heart Outcomes Prevention (HOPE) Study

The Heart Outcomes Prevention Study (HOPE) was double blind placebo controlled trial designed to assess whether ramipril 10 mg (vs. placebo) would reduce the risk for cardiovascular events in subjects at high risk for coronary disease events. The participants included a population of patients who had evidence of atherosclerotic vascular disease or diabetes with atherosclerotic vascular disease or (in the absence of clinical evidence of cardiovascular disease) one other cardiovascular risk factor. The diabetic population was a subset of patients specified for analyses at the beginning of the trial. The use of ramipril was associated with a significant reduction in the combined endpoint (non-fatal MI, stroke, cardiovascular death) as well as for each of these end-points individually. This was true for all participants in the study as well as for the diabetic patients (see slide sets for event rates/Kaplan Meier curves). Event rates were comparable in the diabetic patients and non-diabetic patients.

Whereas there were slightly lower mean blood pressure levels , most of the beneficial effect on MI and stroke reduction associated with ramipril use was independent of the blood pressure effect.

Event rates were slightly lower in patients without prior coronary heart disease (CHD, all with diabetes) vs. those with prior CHD. The incremental reduction in events with ramipril was comparable in patients both with and without CHD. In subsequent analyses, albuminuria was a continuous and graded risk factor for CHD events in both diabetic and non-diabetic participants. Patients with diabetes and elevated serum creatinine (>1.4 mg/dl) on placebo had higher event rates than those with serum creatinine levels (<1.4 mg/dl). Ramipril use had a greater incremental benefit in patients with creatinine >1.4 than in patients with values <1.4, although the absolute risk with ramipril treatment was higher in the elevated creatinine group.

Finally, the effects of ACE-I are in addition to other strategies associated with a reduction in risk for CHD (e.g. lipid lowering, aspirin use, or beta blocker use).

Perindopril Protection against Recurrent Stroke Study (PROGRESS)

The PROGRESS trial was a secondary prevention trial designed to assess whether perindopril 4.0 mg (vs. placebo) + indapamide would reduce the risk for stroke in subjects with a prior stroke or transient ischemic attack. There was a 28% reduction in the risk for recurrent stroke with perindopril use. The greatest effect was perindopril use in combination with indapamide (43% reduction) vs. perindopril alone (5% reduction (P=NS). Most of the beneficial effect on stroke reduction appears to be related to blood pressure reduction.

United Kingdom Prospective Diabetes Study (UKPDS)

The blood pressure treatment arm of the UKPDS used the ACE-I, captopril, and the beta blocker, atenolol, in the intensive treatment blood pressure arm. The intensive blood pressure treatment was associated with a reduction in the risk for microvascular and macrovascular diabetes endpoints. However, for comparable blood pressure reduction, there were no differences in clinical endpoints between captopril and atenolol treatment strategies based on intent to treat analyses. When outcomes in this trial were analyzed by in trial blood pressure levels, for every 10 mmHg reduction in blood pressure, there was a 12% reduction in fatal/non-fatal MI. It is not clear whether there was a beneficial effect of either the ACE-I or beta blocker beyond the reduction in blood pressure.

Other trials

There are several other trials that included ACE-I and diabetic patients as a part of the treatment strategy. In general, there is a beneficial effect on cardiovascular endpoints in these studies.

Implications of the ACE-I trials for a prevention trial with omega-3 fatty acids

The ACE-inhibitor trials provide strong evidence that patients with established CHD and cerebrovascular disease benefit from the use of ACE-inhibitors. Furthermore, the HOPE study data indicate that patients with diabetes and other CHD risk factors benefit from ACE-I therapy. Therefore, it is likely that diabetic patients eligible for a primary prevention trial will likely all be candidates for ACE-I therapy based on current clinical trial data and current guidelines. This will have an effect on the event rate calculations for such patients, as the projected event rates will be more than 20% lower than may be derived from other populations of diabetic patients.

There is clearly some benefit of blood pressure reduction with ACE-I on reduction in atherosclerotic disease events. It is not yet clear whether the beneficial effects of ACE-I reported for ramipril in the HOPE study are applicable to all ACE-inhibitors (class effect). Clinical trials currently in progress may help to address this question. Until these clinical trial data are available, any trial design needs to address the blood pressure effects of ACE-I use, as well as the pleiotrophic effects. Until more is known about whether this is class-effect specific, ACE-I type and dose should be carefully recorded for trial participants.

Selected References

The HOPE Study Investigators. Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Death from Cardiovascular Causes, Myocardial Infarction and Stroke in High Risk Patients. New Engl J. Med. 2000;342:145-153

The HOPE Study Investigators. Effects of Ramipril on Cardiovascular and Microvascular Outcomes in People with Diabetes Mellitus: Results of the HOPE and MICRO-HOPE Study. Lancet 2000;355;253-259

Mann JFE, Gerstein HC, Pogue J, Bosch J, Yusuf S for the HOPE Investigators. Renal Insufficiency as a Predictor of Cardiovascular Outcomes and the Impact of Ramipril: The HOPE Randomized Trial. Ann Intern Med 2001;134:629-636

Gerstein HC. Mann JF. Yi Q. Zinman B. Dinneen SF. Hoogwerf B. Halle JP. Young J. Rashkow A. Joyce C. Nawaz S. Yusuf S. HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286:421-6

PROGRESS COLLABORATIVE GROUP. Randomised trial of perindopril-base blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033-1041

United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: (UKPDS 38): BMJ 1998;317:703-713

United Kingdom Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39: BMJ 1998;317:713-720

Adler AI, Stratton IM, Neil AW et al on behalf of the UK Prospective Diabetes Study Group Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study BMJ 2000;321:412-419


Synergy Between Omega-3 Fatty Acids and Cardiovascular Drugs

Peter R. C. Howe, Ph.D., University of Wollongong, Wollongong, North South Wales, Australia 

Potential health benefits of bioactive nutrients such as long-chain omega-3 polyunsaturated fatty acids (n-3) LC-PUFA can be classified as a) health development, b) risk prevention, c) risk factor management or d) treatment of disease, where a) and b) are nutritional and c) and d) are therapeutic. The nutritional role of n-3 LC-PUFA in relation to cardiovascular health has been acknowledged1, although the evidence for this role comes largely from intervention trials demonstrating improvement, not prevention, of pre-existing risk factors for cardiovascular disease (CV) disease, thus highlighting a therapeutic role for n-3 LC-PUFA. Therapeutic applications of nutrients may be equally, if not more, beneficial than nutritional roles, but their exploitation requires more rigorous, hence costly, substantiation. This may be justified in the case of n-3 LC-PUFA supplementation, especially if one considers its additional potential as an adjunct to drug therapy.

Apart from improving a range of recognized CV risk factors, including thrombotic tendency, hypertriglyceridemia, hypertension, reduced arterial compliance and endothelial dysfunction, there is increasing evidence that n-3 LC-PUFA supplementation can augment the efficacy of CV drugs and provide broader risk benefit. An example is the ability of n-3 supplementation to further reduce blood pressure (BP) in hypertensives treated with diuretics or b-blockers and, at the same time, counteract the adverse effects of these drugs on plasma lipids (fig 1)2,3. However, the antihypertensive effect of n-3 LC-PUFA is not additive to that of the drug; it will depend on the class of drug and mechanistic interactions. Interactions with other nutrients may also influence the overall therapeutic effect, e.g. sodium restriction can potentiate the antihypertensive effect of n-3s. 

Another important example of synergy is the use of n-3 LC-PFA with statins. The hypotriglyceridemic effect of n-3s can complement the hypocholesterolemic effect of statins, which has obvious application in the treatment of persistent hypertriglyceridemia or combined hyperlipidemia and may prove a safer alternative to the combination of fibrates with statins. There is a pressing need for large-scale trials to demonstrate the efficacy and safety of this promising therapeutic strategy. An additional benefit awaiting confirmation is the potential for n-3 LC-PUFA supplementation in patients taking statins to further reduce plasma cholesterol (mainly VLDL) and shift LDL toward a less atherogenic profile, effects not seen with n-3 alone (fig 2)4,5. 

Additionally, n-3 LC-PUFA may counteract arterial disease by enhancing endothelial function and counteracting the inflammatory mechanisms mediating end organ damage. There is increasing recognition that such mechanisms are also a major factor in the efficacy of ACE inhibitors, angiotensin receptor blockers and statins in reducing coronary outcomes. Hence prudent combinations of n-3 LC-PUFA with these drugs may have potent effects on cardiac mortality, independent of their effects on risk factor modulation. Combining n-3 with aspirin is another important example. Rather than being redundant (in terms of cyclooxygenase products), it appears that n-3 can be converted into a new array of eicosanoids with potent anti-inflammatory effects in blood vessels6. It has been suggested that such n-3 to drug synergies may account for the impressive reduction of cardiac outcomes seen in recent secondary intervention trials in drug-treated subjects supplemented with n-3 LC-PUFA.

Clearly, prudent combinations of w3 and CV drugs have great therapeutic potential that should be systematically evaluated. As a minimum consideration, such synergies should be considered as possible confounders in attributing benefit for CV risk reduction in intervention trials utilizing n-3 LC-PUFA supplements.


Fig 1: Omacor (4g/d) potentiates BP reduction and improves lipid profiles in hypertensives treated with diuretics or b-blockers (from reference 2)

Fig 1: Omacor (4g/d) potentiates BP reduction and improves lipid profiles in hypertensives treated with diuretics or b-blockers (from reference 2)

Fig 2: Effects of fish oil supplementation (4 or 8 g/day of DHA rich tuna oil) on plasma lipids (averaged values after 3 & 6 mths) in statin-treated subjects (from reference 4)

Fig 2: Effects of fish oil supplementation (4 or 8 g/day of DHA rich tuna oil) on plasma lipids (averaged values after 3 & 6 mths) in statin-treated subjects (from reference 4)

Aspirin in Primary and Secondary Prevention of Vascular Disorders: Implications for N-3 Fatty Acids

Howard R. Knapp, MD, PhD. Deaconess Billings Clinic, Billings Montana, U.S.A.

When making decisions about preventive pharmacotherapy for vascular disease considering primary and secondary prevention is very important. These days patients entering clinical trials are likely to have been engaging in primary prevention—doing things like ingesting omega-3 or taking aspirin before entering a study, even before onset of cardiovascular dysfunction, because they were considered to be at high risk of vascular disease.Vascular disease endpoints (i.e. definite events) can result from several different biological actions, and specific drugs, such as aspirin, may influence only part of the disease process. We wanted to explore the safety of giving aspirin to cardiac patients already ingesting omega-3s.Platelet aggregation is slowed by aspirin (ASA) and is certainly involved in thrombotic events, but ASA may have little or no influence on atherogenesis per se. New recommendations for the treatment of high cholesterol (NCEP-III study) and blood pressure (JNC VI study) to prevent vascular events are now being based more on quantitative estimates of the risk of future events, rather than whether or not an individual patient has already had an event. We can now justify cholesterol-lowering with statins for patients with a predicted event-rate over 2% per year, for example.

Similar recommendations for the preventive use of ASA are a logical progression of evidence-based practice guidelines. The Antiplatlet Trialists Collaboration has updated its recommendations based upon results from 287 studies involving over 212,000 patients (BMJ 324:71-86, 2002). Their conclusion was that “high risk” groups with >2%/year event rates would benefit from aspirin, including patients with stable angina, claudication, or asymptomatic carotid disease. The USPS Task force (Annals Int Med 136:157-176, 2002) suggests that patients with >1%/year vascular risk would benefit from aspirin therapy. They did take care to note that benefits are not seen in patients with sub-optimally treated blood pressure, that women likely have less benefit than men, and that the chance of a serious/fatal G.I. bleed from even low-dose ASA is two to three times greater in patients over age 70.We expect that most patients at vascular risk will be treated with aspirin in future studies, so the question arises as to what influence this might have on the risk or benefit of omega-3 PUFA in clinical studies. Interestingly, aspirin therapy has been shown, in at least four studies (>1600 patients), to increase bleeding during CABG, while three studies in which patients received omega-3 PUFA (>4.4g/d for 4 weeks) before CABG failed to detect any bleeding problems. Added effects of omega-3 PUFA and ASA on prolongation of template bleeding time has been noted in three papers, but safety of the combination can be inferred from three sets of observations: 

All patients in angioplasty studies involving omega-3 PUFA were also taking aspirin, and in the 7 largest such studies involving 1309 patients, there was no evidence of problems with bleeding during angioplasty or in those patients requiring CABG (Table 1).

Large studies of omega-3 PUFA levels in women with pregnancy-induced hypertension who were also given ASA did not find any increase in blood loss at parturition.

Women in the Faroe Islands, Greenland, and Northern Canada, where daily omega-3 PUFA intakes range from 1.5-8g/day have no problems with bleeding at delivery, nor did those in a Danish study of 535 women given 2.8g/day omega-3 PUFA from their 30th week of pregnancy onward. 

Overall, we can make a strong case for the essential safety of providing omega-3 PUFA at low doses (<2g/day) to patients at vascular risk who are taking aspirin.

Table 1: Combined Use Of ASA & N-3 PUFA In Angioplasty Trials


Total=1309 patients, all took 325mg ASA/d except Griggs et al.

Markers and Surrogate Parameters

Trevor A. Mori, Ph.D., et al., University of Western Australia, Perth, Australia

Effects of the long chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFA), eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) on factors for cardiovascular disease (CVD), such as systolic and diastolic blood pressure, overweight and obesity, dislipidemia, insulin resistance, platelett aggregation, thrombolysis, C-reactive protein and oxidative stress were discussed. Recently published results of two studies by Mori et al. were used to illustrate these effects. The main purpose of the presentation was not to be all encompassing or to establish priorities, but rather to stimulate discussion.

One study1,2 examined the potential effects of both dietary fish rich in n-3 LC-PUFA and a weight loss regimen on 24-hour blood pressure (BP) levels (systolic/diastolic or S/D), on 24-hour heart rate (beats/min or bpm), fasting insulin and glucose levels, HDL and LDL cholesterol, total cholesterol and fasting triacylglycerols (Tg). A factorial design was used and 69 obese and hypertensive subjects on single or dual therapy with ACE inhibitors or beta-blockers were randomized to a daily fish meal (3.65 g n-3 LC-PUFA), weight reduction, a combination of both or a control regimen for 16 weeks. Sixty three subjects completed the study. Weight fell by 5.6 kgs in the reduced energy intake groups. Both dietary fish and weight loss had independent and additive effects on ambulatory 24-hour BP (S/D=6.0/3.0 mm Hg reduction with dietary fish alone, 5.5/2.2 mm Hg with weight reduction alone and 13.0/9.3 mm Hg with both combined). Dietary fish reduced 24-hour ambulatory and daytime heart rates (HR) by 3.1 bpm and 4.2 bpm respectively. Weight reduction had an HR-lowering effect during night only (3.2 bpm). Thus, a combination of dietary fish intake and weight-reducing program could have additive positive effects suggesting reduced cardiovascular risks and a potential reduced need for antihypertensive medication. Fasting insulin levels decreased in the weight loss group with an even greater decrease in both insulin and glucose levels (the area under curve during a glucose tolerance test) in the combined fish + weight loss group. The fish meal group alone showed no reduction in fasting insulin and glucose levels. Fish increased HDL2 cholesterol and decreased HDL3 cholesterol. It did not alter total cholesterol, LDL or HDL cholesterol. Weight loss had no effect on these variables. Fish meals lowered fasting Tg levels significantly by 29% and weight loss lowered fasting Tg levels by 26%. The fish + weight loss group showed the greatest improvements in lipids: Tg decreased by 38% and HDL cholesterol increased by 24% compared with the control group. 

The second study3,4 was aimed at identifying the potential significant differences between EPA and DHA in regard to their physiological effects on the above risk factors. Fifty-nine overweight and mildly hyperlipidemic men were randomized to 4.0 g/day of purified EPA and DHA, or olive oil (as placebo) for 6 weeks in a parallel design, double blind, placebo-controlled trial. Fifty six subjects completed the study. When compared with the placebo group DHA reduced 24 hour and daytime ambulatory BP (S/D) by 5.8/3.3 and 3.5/2.0 mm. Hg respectively; decreased 24-hour HR, daytime and nighttime HR by 5 bpm, 3.7 bpm and 2.8 bpm respectively. EPA had no significant effect on either of these parameters. Both DHA and EPA reduced Tg levels by 20% and 18% respectively, Neither EPA, nor DHA had any effect on total cholesterol. EPA reduced HDL3 cholesterol only (by 6.7%) and had no effect on LDL, HDL and HDL2. DHA increased HDL2 significantly (by 29%). DHA increased LDL cholesterol by 8% but also increased LDL cholesterol particle sizes by 0.25 nm. EPA had no effect on particle size. Both EPA and DHA increased fasting insulin levels significantly.

These results indicate that EPA and DHA have differential effects on the above risk factors and that these differences should be taken into account. They also emphasise the importance of connecting omega-3 LC-PUFA consumption with life style changes for a potentially optimal CV benefit. This is particularly true for those vegan and vegetarian forms, such as Omega 3 from algae oil. Vegan and vegetarian forms of Omega 3 would therefore be preferential for this demonstration.

In regard to vascular effects, DHA appears to have significant vasodilatory effects, while EPA does not. Similarly, DHA reduces platelet aggregation and thrombolitic effects while EPA does not appear to do so in a significant fashion. Presently, C-reactive protein appears non-reactive to n-3 LC-PUFA. Effects due to the presence or absence of oxidative stress are difficult to evaluate due to limitations in measuring methodologies. The increasing importance of measuring urinary F(2)-isoprostanes5 as markers of in vivo lipid peroxidation was emphasised. Diabetes, especially type 2 diabetes should be included in considerations of any long-term primary prevention trial.


  1. Bao D.Q. et al, Effect of dietary fish and weight reduction on ambulatory blood pressure in overweight hypertensives, Hypertension, 1998; 32, 710-7
  2. Mori T.A., et al., Dietary fish as a major component of weight-loss: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects, Am J Clin Nutr. 1999; 70(5), 817-25
  3. Mori T.A. et al., Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans, Hypertension, 1999; 34 (2), 253-60
  4. Mori T.A. et al., Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men, Am J Clin Nutr. 2000; 71 (5): 1085-94
  5. Proudfoot J., et al., Measurement of urinary F(2)-isoprostanes as markers of in vivo lipid peroxidation-A comparison of enzyme immunoassay with gas chromatography/mass spectrometry, Anal Biochem. 1999; 272(2), 209-15

Patient Populations and Clinical Endpoints for an Omega 3 Fatty Acid Cardioprotection Study

Ernst J. Schaefer, M.D., Tufts University, Boston, Massachusetts, U.S.A.

In the Diet and Reinfarction Trial (DART), fish or two fish oil capsules per day were administered to 2033 men with coronary heart disease (CHD). This reduced risk of CHD mortality by 29% (Lancet 2:757-761, 1989). No other dietary advice or practice (e.g. high fiber, low saturated fat) had any significant effect. In the large Italian study know as GISSI, 11324 men and women with CHD took 0.850 gram per day of long chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFA). This reduced CHD mortality 15% (Lancet 345:447-455, 1999). 

Death rates from CHD in United States (U.S.) for men ages 65-74 are approximately 898 out of 100,000 per year. In men ages 75-84 the death rate was 2130 out of 100,000 per year. Therefore, over five years, the projected number of deaths would be 4490 out of 100,000 for the younger age group, and 10650 out of 100,000 for the older group, or 449 out of 10,000 in the younger group and 1065 out of 10,000 for the older group. Death rates of women in the U.S. was 415 and 1288/100,000 or 42 and 128/10,000 per year in the 65-74 and 75-84 age groups respectively or 210 and 640/10,000 over 5 years. The over-75 age group is the fastest growing segment of society in the United States (National Center for Health Statistics, US, 2000), so considering the elderly in cardioprotection studies is of growing importance.

If we consider people who are being treated for hypertension the death rate increases by a factor of 1.66 for men and 2.75 for women. (National Cholesterol Education Program Adult Treatment Panel III guidelines JAMA 285: 2486-2497, 2001). Selecting people for total cholesterol over 200 mg/dl adds no increased risk for men and very little increased risk for women. Selecting for patients with HDL cholesterol below 40 mg/dl would add risk, but it would be difficult to recruit women for such a trial. Age is the overwhelmingly important CHD risk factor, therefore selecting subjects 75 years of age or older greatly increases the risk of CHD death versus younger groups, especially in women. 

In a primary prevention study for CHD mortality, comprised of a total of 10,000 people with equal numbers of men and women all 75 years of age and older with treated hypertension one could assume the following: 

  • 426 CHD deaths over 5 years in the 5000 randomized to the placebo group 
  • 30% reduction in CHD mortality 
  • 298 deaths in the 5000 placed in the fish oil group. 

Power calculations assuming an 8.52% death rate in the placebo group and a 5.97% death rate in the treatment group indicate that about 2300 subjects per group would be sufficient to detect this difference. Therefore 5000 per group should be more than sufficient to show that fish oil supplementation has a significantly beneficial effect in reducing CHD mortality in the primary prevention setting in the elderly. The concept of what constitutes "general population" was discussed in great detail.

National Recommendations Regarding Omega N-3 Fatty Acids

William S. Harris, PhD., University of Missouri-Kansas City, MO, and the Mid America Heart Institute, Kansas City, Missouri, U.S.A.


Both the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)-III and the American Heart Association (AHA) have issued recommendations regarding the role of diets in reducing risk for coronary heart disease (CHD). Both groups specifically addressed n-3 fatty acids (FA). 

The NCEP ATP-III report1 first discusses n-3 FA under Other factors that may reduce baseline risk for CHD. The Evidence Statement of this report is, “The mechanisms whereby n-3 fatty acids might reduce coronary events are unknown and may be multiple. Prospective data and clinical trial evidence in secondary CHD prevention suggests that higher intakes of n-3 fatty acids reduce risk for coronary events or coronary mortality.” The NCEP ATP-III report recommends that, “higher dietary intakes of n-3 fatty acids in the form of fatty fish or vegetable oils are an option for reducing risk for CHD,” but also states that, “this recommendation is optional because the strength of the evidence is only moderate at present. ATP-III supports the AHA recommendation that fish be included as part of a CHD risk-reduction diet… a dietary recommendation for a specific amount of n-3 fatty acids is not being made,” because of the lack of understanding of the actual mechanisms of n-3 fatty acids.In the section entitled, “Other Drugs” the NCEP ATP also mentions n-3 FA.“N-3 FA have two potential uses. In higher doses (3-12 g/d), EPA and DHA lower serum triglycerides. They represent alternatives to fibrates or nicotinic acid for the treatment of hypertriglyceridemia, especially chylomicronemia.

Recent clinical trials also suggest that relatively high intakes of n-3 FA (1.0-2.0 g/d) in the form of fish, fish oils, or high linolenic acid oils will reduce risk for major coronary events in persons with established CHD. Although this usage falls outside the realm of “cholesterol management,” the ATP-III panel recognizes that n-3 FA can be a therapeutic option in secondary prevention. In the view of the ATP-III panel, more definitive clinical trials are required before relatively high intakes (1.0-2.0 g/d) can be strongly recommended for either primary or secondary prevention.”In the AHA Dietary Guidelines1 n-3 FA are first mentioned under Specific Guidelines. “Because of the beneficial effects of omega-3 fatty acids on risk of coronary artery disease as well as other diseases such as inflammatory and autoimmune diseases, the current intake, which is generally low, should be increased. Food sources of omega-3 fatty acids include fish, especially fatty fish such as salmon, as well as plant sources such as flaxseed and flaxseed oil, canola oil, soybean oil and nuts. At least 2 servings of fish per week are recommended to confer cardioprotective effects.”Another reference is found in the section entitled Issues that Merit Further Research. “Consumption of one fatty fish meal per day (or alternatively a fish oil supplement) could result in an omega-3 fatty acid intake (i.e., EPA and DHA) of about 900 mg/d, an amount shown to beneficially affect coronary heart disease mortality rates in patients with coronary disease.”The Table in this abstract lists the approximate amount of EPA and DHA contained in a variety of common fish and fish oils, as well as how much of each one would need to consume in order to obtain 900 mg of these two n-3 FA daily. 


Obtaining 900 mg a day of EPA and DHA from fish is practically impossible for most people consuming a Western diet as it would require the daily consumption of at least 1.5 oz of oily fish like sardines, mackerel or herring per day. Capsules may be the only practical way for patients with CHD who are unwilling or unable to consume a more Mediterranean-style diet to consistently achieve this intake. Both the AHA and the NCEP generally endorse the consumption of 2 fish meals per week [(preferably oily fish (AHA)] for cardioprotection. This amount is inferred from epidemiological studies, not randomized trials. NCEP believes “strong recommendations for either primary or secondary prevention” must await further clinical trials evidence. AHA suggests daily fatty fish (or n-3 FA capsule) intake for secondary prevention in the context Issues that merit further study, but does not extend these recommendations to the primary prevention setting. 

  2. Krauss et al. Revision 2000: A Statement for Healthcare Professionals from the Nutrition Committee of the AHA. Circulation 2000;102:2284-2299.



Different sources of Omega 3 and subsequent weights required to reach 0.9g DHA + EPA.

Different sources of Omega 3 and subsequent weights required to reach 0.9g DHA + EPA.




Data from USDA Nutrient Data Laboratory. The intakes of fish given above are rough estimates since oil content can vary markedly (>300%) with species, season, diet, and packaging and cooking methods. 

 This intake of cod liver oil would provide about the Recommended Dietary Allowance of vitamins A and D.

 Not currently available in the USA.