Ebook: Cardiovascular Benefits of Omega-3 Polyunsaturated Fatty Acids
During the last decades progress has been made in the treatment of patients who survived myocardial infarction. Nevertheless, patients who survive an acute myocardial infarction are at high risk, with life expectancy half that of their peers who have not experienced similar events, and with increased risk for subsequent cardiovascular events and death. The risk of sudden death increases with severity of systolic dysfunction after myocardial infarction. In recent years, it has become clear that in addition to risk factors such as overweight, lack of exercise, smoking, hypertension and hypercholesterolemia, psychosocial factors play a key role for prognosis in patients with myocardial infarction. Therefore, there is high medical need for drugs which lower the incidence of sudden death and have an effect on other risk factors such as depression. OMACOR®, a pharmaceutical preparation of highly purified and concentrated Ω-3 polyunsaturated acids, may present such a drug. It lowers the incidence of sudden death in patients with myocardial infarction and decreases depression. This publication focuses on the effect of Ω-3 polyunsaturated fatty acids on different risk factors in patients with cardiovascular disease. In addition, aspects of prevention of cardiovascular disease, risk factors and pharmacokinetics of Ω-3 fatty acids ethyl esters are considered.
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Therapy for Sudden Death Still Awaited
During the last decades progress has been made in the treatment of patients who survived myocardial infarction. The implementation of coronary care units and evolution of public education to encourage rapid response, development of catheter-based revascularization techniques, greater emphasis on cardiac rehabilitation, and improved therapy have contributed to improvement of prognosis for patients with myocardial infarction. The introduction of aspirin, thrombolytics, ß-blockers, ACE-inhibitors and statins led to reduction in both short-term and immediate mortality rates among patients suffering from myocardial infarction. Nevertheless, patients who survive an acute myocardial infarction are at high risk, with life expectancy half that of their peers who have not experienced similar events, and with increased risk for subsequent cardiovascular events and death. The risk of sudden death increases with severity of systolic dysfunction after myocardial infarction. Sudden death has proved to be more difficult to treat than coronary disease.
In recent years, it has become clear that in addition to risk factors such as overweight, lack of exercise, smoking, hypertension and hypercholesterolemia, psychosocial factors play a key role for prognosis in patients with myocardial infarction. Depression, anxiety, perceived social support and social desirability may have an effect on mortality and morbidity in such patients. Therefore, there is high medical need for drugs which lower the incidence of sudden death and have an effect on other risk factors such as depression.
A pharmaceutical preparation of highly purified and concentrated Ω-3 polyunsaturated acids, OMACOR®, may represent such a drug. It lowers the incidence of sudden death in patients with myocardial infarction and decreases depression.
This volume summarizes lectures delivered during the symposium entitled “Effect of Ω-3 polyunsaturated fatty acids on different risk factors in patients with cardiovascular disease” presented during the European Cardiology Society Congress in Stockholm (Sweden) in 2005. In addition, aspects of prevention of cardiovascular disease, risk factors, and pharmacokinetics of Ω-3 fatty acids ethyl esters have been considered.
W. Cautreels, C. Steinborn, L. Turski
Atherosclerotic disease is considered to be the leading cause of death and loss of disability-adjusted life-years worldwide. Major differences are between different countries, mainly because of the variation of risk factors for atherosclerosis between populations. Over 300 risk factors have been associated with atherosclerosis and its major complications, coronary heart disease and stroke. However, between 70% and 90% of the risk of atherosclerotic disease can be explained by different associations between conventional risk factors, such as smoking, abnormal lipids, hypertension, diabetes, obesity, psychosocial factors, unhealthy diet, and lack of physical activity. Because risk factors can have multiplicative effects, their assessment in an individual subject needs application of different models for total risk estimation. Effective cardiovascular prevention needs a global strategy, based on knowledge of the importance of different risk factors, conventional and newly-described, and of the best model that can be applied to assess risk for atherosclerotic disease in an individual subject.
The therapeutic options for interfering with the electrical instability of a pathologically remodeled or ischaemic heart remain limited. Of increasing importance become interventions which target the fatty acid composition of blood and membrane lipids. In particular, the long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provide parameters for stratification of risks associated with severe arrhythmia disorders and sudden cardiac death. Since EPA and DHA appear to have their anti-arrhythmogenic actions when present as free fatty acids, the parameters which determine a critical free fatty acid concentration are of great interest. In the present study, conclusions on EPA and DHA incorporation in blood lipids are derived from the administration of OMACOR® which contains highly purified (84%) EPA and DHA ethyl esters and reduced the risk of sudden cardiac death by 45% in post-myocardial infarction patients (GISSI-Prevention study). The “EPA+DHA level” is described as risk identifying parameter for severe arrhythmia disorders, particularly if they are associated with myocardial ischaemia. It appears essential not only to build up body stores for release of EPA and DHA but to provide also a sustained uptake of EPA and DHA in the form of ethyl esters. In contrast to more rapidly absorbed triacylglycerols from fish, ethyl esters are taken up slowly within 24 h. For the administration of 1 g/day OMACOR® to healthy volunteers, it is shown that in whole blood EPA is increased from 0.6% to 1.4% within 10 days while DHA is increased from 2.9% to 4.3%. After withdrawal, the EPA and DHA levels approach baseline values within 10 days. A gas chromatographic procedure was established which requires only 10 μl of whole blood for the identification of more than 30 fatty acids. Evidence is summarized strengthening the concept that a low “EPA+DHA level” presents a risk for severe arrhythmia disorders and sudden cardiac death. The administration of 840 mg/day of EPA and DHA ethyl esters raises the “EPA+DHA level” to approximately 6% that is associated with protection from sudden cardiac death. The pharmacological effects of ethyl esters are compared with the naturally occurring EPA and DHA triacylglycerols present in fish or fish oils which are of interest in primary prevention of cardiovascular disorders.
Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione was the first large randomized trial to produce evidence that a pharmaceutical preparation of highly purified omega-3 polyunsaturated fatty acids (PUFAs), administered as an adjunct to other accepted interventions, had a favorable effect on hard clinical end-points in post-myocardial infarction patients. Much of the 20% all-cause mortality benefit recorded during the study could be attributed to a 45% reduction in sudden death - a fatal outcome that traditionally has proved resistant to medical intervention. These results were obtained with an omega-3 PUFA dose of 1 g/day, which is much lower than was routinely being used at the time the study was initiated (e.g. 4 g/day for hypertriglyceridemia). One consequence of this low-dose regimen was that the tolerability profile of omega-3 PUFAs during GISSI-Prevenzione was considered highly satisfactory, with low adverse event incidence rates and low rates of discontinuation due to adverse events. Time-course analysis established that much of the survival benefit of omega-3 PUFA treatment in GISSI-Prevenzione was realized during the early months of the trial. The beneficial effects of omega-3 PUFA treatment were observed on top of standard, secondary pharmacological prevention therapy like anti-platelet agents, statins, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. The benefits of omega-3 PUFA therapy were also apparent in patients at all standards of adherence to a healthy diet and may have been augmented in patients with the best dietary profile. Patients with diabetes mellitus ( ≈15% of the study cohort) appeared to benefit from omega-3 PUFAs to at least the same extent as the general study population; the treatment effect on sudden death was progressively more pronounced as left ejection fraction declined. Cost-effectiveness analyses undertaken from a third-party payer perspective for Italy revealed that the cost of low-dose treatment with highly purified omega-3 PUFAs was approximately Euro 25,000 per life-year gained.
30 years ago the observation of a lower incidence of cardiovascular diseases in Inuits (Eskimos) was related to the higher fish consumption when compared to the residual Danish population. Clinical studies confirmed this finding. It was explained by the higher content of polyunsaturated fatty acids (PUFA) in fish, especially of omega-3 PUFAs. Experimental studies in cell cultures and also in animals with and without infarction models verified the anti-arrhythmic effect of omega-3 PUFAs among other possible contributing factors when compared to other fatty acids. In clinical studies a significant reduction (ca. 40%) of sudden cardiac deaths (SCD) could be found in patients after an acute myocardial infarction (AMI), if they were treated with at least 1 g omega-3 PUFAs daily, either by consumption of fish twice weekly or of a highly purified preparation omega-3 PUFAs in capsules. These findings led to recommendations of the American Heart Association and the European Society of Cardiology (ESC) to a higher fish consumption and/or the daily intake of 1 g O-3 PUFAs for primary and especially for secondary prevention of cardiovascular diseases. The much fewer side-effects, and the standardised dosage on one hand and the negative effect of the sometimes higher mercury content of fish make the intake of omega-3 PUFAs as capsules the better choice.
Prevention of Sudden Death after Acute Myocardial Infarction Cardiovascular disease is the leading cause of death in developed countries. In Canada, in 1999, cardiovascular disease was responsible for 36% of all deaths. Ischemic heart disease accounts for the greatest percentage of these deaths (20% of all deaths), half of which are due to the acute effects of myocardial infarction. The other half are related to the late manifestations and complications of myocardial infarction . Once coronary arteriosclerosis has reached the point where it results in myocardial infarction, two main complications can ensue, loss of myocardial function and disturbance of cardiac rhythm. Progressive loss of myocardial pump function results in the syndrome of congestive heart failure. Abnormalities of the heart rhythm result in ventricular fibrillation, which is the direct cause of sudden death. Congestive heart failure rates have been easy to track because of the frequent need for hospitalization and we know from analysis of administrative databases that the annual rate of death from heart failure is about 2.5% in Canada . Sudden death, however most often occurs at home and without warning, making it much more difficult to quantitate its impact. However, the most conservative estimates suggest that no less than 25% of deaths in patients with a diagnosis of ischemic heart disease are due to ventricular fibrillation [2,3].
Studies in patients recovering from myocardial infarction, episodes of unstable angina, coronary bypass surgery and coronary angioplasty, show that between 12 and 20% of hospitalized cardiac patients meet psychiatric criteria for current major depression. A similar percentage report elevated levels of depressive symptoms on paper and pencil self-report measures. These rates of depression are about three times higher than in the general community. On a practical basis this means that about one in three hospitalized CAD patients has some degree of depression. Despite its high prevalence in patients with CAD, depression is not a normal reaction to cardiac disease. Both major depression and elevated depressive symptoms are associated with at least a doubling in risk of subsequent cardiac events, even when standard cardiac risk factors, including left ventricular ejection fraction and number of blocked coronary arteries, are taken into account. In fact, several large, longitudinal community-based studies show that depression precedes the development of clinically evident CAD by many years. There is substantial evidence that depression is a potentially modifiable cardiac risk factor of as much importance as diabetes or lack of exercise. Although the precise mechanisms explaining the link between depression and CAD remain unknown, there is evidence that changes in autonomic regulation, sub-chronic inflammation, endothelial dysfunction, enhanced platelet responsiveness and reduced omega-3 free fatty acid levels may all be involved. Intriguingly, the mechanisms that have been hypothesized to explain the link between depression and CAD prognosis are the same as those suggested to explain the favorable impact of omega-3 supplements in CAD patients. Additional clinical trials to assess the impact of omega-3 supplements on depression are clearly warranted both in CAD patients and in individuals free of heart disease.
Depression is characterised by depressed mood or/and the loss of interest or pleasure in nearly all activities for a substantial period of time, causing significant distress. Depression is a potentially life-threatening disease. It is a major risk factor for suicide as well as coronary artery disease (CAD) and sudden cardiac death (SCD). It also may be associated with impaired endothelial dysfunction and decreased heart rate variability (HRV). Both conditions seem to persist in patients with depression despite successful antidepressant treatment. During the last few years epidemiological studies as well as clinical trials have suggested a significant role of omega-3 fatty acids in the pathogenesis of depression. As omega-3 fatty acids have been demonstrated to also beneficially influence many of the conditions depression is a risk factor for (CAD, SCD) or may be associated with (decreased HRV, endothelial dysfunction), they may well represent a major advance in the treatment of depression. However more large randomized clinical trials are clearly needed to substantiate that claim.
Patients who survive an acute myocardial infarction (MI) are at increased risk of subsequent major cardiovascular events and cardiac (often sudden) death. The use of highly concentrated and purified omega-3 polyunsaturated fatty acids (n-3 PUFAs), in addition to standard secondary prevention after MI, results in a significant reduction in the risk of sudden death. This study assessed the cost-effectiveness of adding n-3 PUFAs to the current secondary prevention treatment after acute MI in 5 countries: Australia, Belgium, Canada, Germany, Poland.
Based on the clinical outcomes of GISSI-Prevenzione (MI, stroke, revascularisation rate and mortality), a decision-model was built in DataPROTM. The implications of adding n-3 PUFAs to standard treatment in patients with a recent history of MI were analysed from the health care payer's perspective. The time horizon was 3.5 years (identical to GISSI-Prevenzione). Event costs were based on literature data. Life expectancy data for survivors of cardiac disease were taken from the Saskatchewan database and then country-adjusted. Results are expressed as extra cost (
Treatment with highly concentrated n-3 PUFAs yielded between 0.260 (Poland) and 0.284 (Australia) LYG, at an additional cost of
Adding highly concentrated n-3 PUFAs to standard treatment in the secondary prevention after MI appears to be cost-effective in the 5 countries studied.
OMACOR® is the focus of an extensive and ambitious clinical development program that seeks to build on the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione study. Studies currently in progress include very large clinical outcome trials designed to evaluate the impact of OMACOR® on death and major morbid events in defined patient populations such as individuals with heart failure or diabetes, specialist investigations in very high-risk populations such as patients requiring hemodialysis, and a range of specialized studies concerned with mechanisms of action and effects on biochemical and laboratory indices. The emergence of results from these studies can be expected to define a spectrum of indications for OMACOR® in the management of cardiovascular and renal disease.