GISSI-Prevenzione Study Research Articles

The debate on omega 3: recent developments

Long-chain omega 3 fatty acids EPA and DHA entered the nutrition and cardiovascular pharmacology fields quite recently, after the now famous studies of Bang and Dyrberg were published in the second half of the XX century. These molecules have a wide spectrum of activities, whose precise nature is often difficult to classify. For example they can be derived from food (in particular from appropriate diets) and yet they sometimes need to be taken as supplements: some of their favorable effects on the cardiovascular system, on the other hand, can only be obtained following pharmacological treatments that supply up to ten-twenty times the amounts usually present in Western diets. The triple connotation of EPA and DHA (food components, supplements, and drugs) translates into the positive effects that have been attributed to their regular consumption. It is not rare to read scientific papers in which a hypotriglyceridemic action is ascribed to “dietary” doses, whereas only pharmacological treatment can achieve this result. Yet, even at appropriate doses omega 3 fatty acids have been recently criticized. Some trials and a meta-analysis did negate the cardioprotective activities of omega 3 fatty acids that had been previously reported by, e.g., the famous GISSI-Prevenzione study carried out in Italy in the ’90s. The review by Connye N. Kuratko, Coleen C. Nolan, and Norman Salem Jr. published in this issue of Nutrafoods delivers an in-depth analysis of these complex issues and provides readers with information necessary to interpret the manifold physiological and functional actions of omega 3 fatty acids. Indeed, their effects recently extended to areas that are being now explored. As an example, in addition to the anti-arrhythmic activities and those on triglyceridemia and heart rate control, actions on inflammation and on endothelial function have been explored. In addition, recent data suggest that omega 3 fatty acids stabilize atherosclerotic plaques via increased fibrous cap thickness and reduction of inflammatory infiltration. How can we reconcile this increasing knowledge of omega 3-mediated cardioprotective mechanisms with the disappointing results stemming from clinical trials of pharmacological use we mentioned above? One potential answer can be found after careful analysis of how randomized, double-blind, placebocontrolled studies are carried out. In these protocols the drug at study is added “on top” of an established “best treatment”. In fact, this model may underestimate the effects of a compound added to pharmacological treatment, especially if the tested molecule (as in the case of omega 3 fatty acids) shares effects such as anti-inflammation, amelioration of endothelial function, plaque stabilization with established therapeutic agents, i.e. statins.

Omega-3 in Antiarrhythmic Therapy

The association between omega-3 (n-3 polyunsaturated fatty acids) and the clinical outcome of patients with cardiovascular diseases such as coronary heart disease is currently unclear, especially regarding its possible antiarrhythmic effects and the not quite understood mechanisms of action. In the last 15 years, several epidemiological studies have shown a lower incidence of sudden cardiac death with a diet rich in omega-3 or fish consumption. The antiarrhythmic properties related to omega-3 have been related to modulation of sodium-dependent ion channels or sodium-calcium exchangers of myocytes through a reduction of their excitability especially in ischaemic or damaged myocardial tissue. However, the results of experimental studies have not always been consistent. Although the role of omega-3 in preventing sudden cardiac death has been evaluated in several clinical trials that included patients with coronary artery disease (particularly in patients with post-myocardial infarction), the interpretation of such data must be treated with extreme caution. In particular, while a reduction in cardiac death was demonstrated by a meta-analysis of several randomized clinical trials, a reduced risk of sudden cardiac death has been described only in the GISSI-Prevenzione study, while in other studies the evidence that emerged is more controversial, with wide confidence intervals that support the possibility of heterogeneity in the distribution of the factors involved in the efficacy of treatment. Omega-3 is probably involved in the prevention of cardiovascular mortality through different mechanisms, and it is crucial to study its association with other drugs such as ACE inhibitors or calcium channel blockers. The study of antiarrhythmic drugs has been divided into prevention of supraventricular and ventricular arrhythmias. In these conditions, the role of omega-3 seems to be more pronounced in atrial tachyarrhythmias such as atrial fibrillation, but does not have a role in ventricular arrhythmias. In summary, the antiarrhythmic effect of omega-3 is not clearly evident and further studies are needed to investigate its beneficial effect in cardiac mortality compared with arrhythmic death.

Omega-3 Ethylester Concentrate

Oral omega-3 ethylester concentrate (omega-3 EEC) [Omacor; Lovaza] is indicated as an adjuvant therapy in adult patients for secondary prevention post-myocardial infarction (MI) and the treatment of hypertriglyceridaemia in the majority of European countries, and for the treatment of hypertriglyceridaemia (serum triglyceride levels > or =5.6 mmol/L [> or =500 mg/dL]) in the US. Each 1000 mg capsule of omega-3 EEC consists of 460 mg of ethyl eicosapentaenoic acid and 380 mg of ethyl docosahexaenoic acid. The addition of omega-3 EEC 1000 mg/day to standard medical therapy in the GISSI-Prevenzione study provided secondary prevention benefits in post-MI adult patients. The benefits were attributable to reductions in death and cardiovascular death (including sudden death). Additional data examining the extent and mechanisms of the cardiovascular benefit conferred by omega-3 EEC in secondary prevention would be useful. As an adjunct to diet, monotherapy with omega-3 EEC 4000 mg/day significantly reduced triglyceride levels in patients with hypertriglyceridaemia, although limited data suggest it was less effective than gemfibrozil. In addition, omega-3 EEC 4000 mg/day plus simvastatin or atorvastatin reduced triglyceride, non-high-density lipoprotein cholesterol (non-HDL-C) and/or very-low-density lipoprotein cholesterol (VLDL-C) levels to a significantly greater extent than placebo plus simvastatin or atorvastatin. Omega-3 EEC was generally well tolerated both as secondary prevention post-MI and in the treatment of hypertriglyceridaemia. Thus, omega-3 EEC is a useful option both in secondary prevention post-MI and the treatment of hypertriglyceridaemia.

Role of n−3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease

n−3 Fatty acids (FAs) when used in doses of 3–4 g/d eicosapentaenoic acid and docosahexaenoic acid have profound effects on triacylglycerol (TG) concentrations. The mechanism for their TG reduction relates to their favorable effects on reducing hepatic production and secretion of VLDL and VLDL apolipoprotein B particles, along with favorable effects on plasma lipolytic activity through lipoprotein lipase–mediated clearance, as well as stimulation of β-oxidation of other FAs in the liver. Their hypotriglyceridemic properties are related to both the dose of n−3 FAs used and the baseline TG concentrations of the population. In patients with TG concentrations >500 mg/dL, 4 g n−3 FAs have been shown to reduce TGs by 45%, VLDL by 42%, and non-HDL by 10.2%. A recent pooled meta-analysis with multiple doses of n−3 FAs ranging from 0.8 to 5.4 g revealed changes in TGs of −27 mg/dL (95% CI: −33, −20), in HDL of +1.6 mg/dL (95% CI: + 0.8, +2.3), and in LDL cholesterol of +6 mg/dL (95% CI: + 3, +8). The clinical uses of n−3 FAs include treatment of severe and moderate hypertriglyceridemia, use in statin-treated patients with elevated TG concentrations or non–HDL cholesterol (mixed hyperlipidemia), and use in the secondary and primary prevention of cardiovascular disease. Existing large-scale clinical trials such as the GISSI-Prevenzione Study and JELIS with low doses of n−3 FAs (1–2 g) show clinical benefit in reducing coronary heart disease without substantial changes in concentrations of TGs or other lipids. Future clinical trials need to determine whether the TG-lowering doses of n−3 FAs (3-4 g/d) result in additional risk reduction.

Alcohol consumption and risk of heart failure in the GISSI-PREVENZIONE Study

Alcohol consumption and risk of heart failure in the GISSI-PREVENZIONE Study

Apolipoprotein E polymorphisms influence effect of pravastatin on survival after myocardial infarction in a Mediterranean population: the GISSI-Prevenzione study

Controversy exists with regard to the influence of APOE polymorphisms on coronary heart disease development and on the efficacy of statin treatment. we investigated the relationship between apoe, mortality and the response to treatment in Mediterranean myocardial infarction (mi) survivors. We analysed 3304 Italian patients with MI randomized to pravastatin or no treatment in the GISSI-Prevenzione study, with a mean follow-up time of 23.0 +/- 6.7 months (median 24.3 months). Mortality curves were calculated using Kaplan-Meier method, and differences in survival were tested using the log-rank test. There were 109 deaths during follow-up. Patients treated with pravastatin showed a significant decrease in mortality compared with non-treated patients (HR 0.67, 95% confidence interval 0.45-0.97, P = 0.038). Among the 3304 patients, 554 (16.8%) were epsilon4 carriers and 2750 (83.2%) were non-epsilon4 carriers. No significant difference in terms of mortality was observed between the epsilon4 and the non-epsilon4 carriers (3.61% vs. 3.24%, P = 0.67). However, although in non-epsilon4 carriers no significant difference in mortality was observed between patients treated with pravastatin and non-treated (2.81% vs. 3.67%, P = 0.21), among the epsilon4 carriers a significant reduction in mortality was observed in patients treated compared with non-treated (1.85% vs. 5.28%, P = 0.023). We found that epsilon4 allele is a determinant of pravastatin response in terms of survival. Though in the entire population investigated,we found a beneficial effect of pravastatin in terms of survival, only the epsilon4 carriers seemed to have gained a significant benefit from this treatment. We suggest that the effect of statins is of particular interest in this fraction of the population. Genetic markers can help in identifying patients that benefit more from statin treatment.

Oral Omega n3-PUFA Therapy (Omacor) Has No Impact on Indices of Heart Rate Variability in Stable Post Myocardial Infarction Patients

To determine the effects of n3-PUFA supplementation, in the dose used in the GISSI-Prevenzione study, on indices of heart rate variability (HRV) in patients following myocardial infarction (AMI). Open label randomised single blind controlled trial. Thirty eight patients post AMI, stable on standard secondary prevention drug therapy were single blind randomised to receive either Omacor 1 g/day (n = 21) or usual care (n = 17). HRV indices (time and frequency-domain) were measured at baseline and following 3 months of treatment. At baseline there were no significant differences in clinical, biochemical or HRV indices between patient groups. After 3 months therapy there were no observed changes in measured HRV indices in either the Omacor supplemented or 'usual care' groups. Three month supplementation of omega 3 PUFA (Omacor) 1 g/day has no effect on HRV is patients post AMI.

Omega-3-Fettsäuren in der Sekundärprävention nach Myokardinfarkt

The ESC (European Society of Cardiology) recommends treatment with highly concentrated omega-3 fatty acids after myocardial infarction. By daily application of 1 g 84% EPA/DHA-ethyl ester the mortality rate is significantly reduced as shown in the GISSI-Prevenzione study. The main reason for this protective effect is the serum concentration of EPA/DHA which can be adjusted by this dosage. On account of this fact the number of fatal arrhythmias decreases. Concerning secondary prevention omega-3 fatty acids must be given in this form continuously, otherwise a clinically effective level of fatty acids cannot be achieved. Therefore the application of EPA/DHA-ethyl esters should be preferred, because in this case the serum's level can be kept on a sufficiently high level as a result of their more prolonged release.

A clinically practicable diagnostic score for metabolic syndrome improves its predictivity of diabetes mellitus: The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)–Prevenzione scoring

Metabolic syndrome (MS) is associated with late-onset diabetes. However, diagnostic criteria for individual components of MS are based on categorical/arbitrary cut points and, therefore, do not exploit the information yield of each factor. We aimed to generate a diagnostic score for MS (MS-Score), aimed at predicting diabetes by giving appropriate weight to the individual components of MS. Of 11,323 patients with prior myocardial infarction and followed up for 3.5 years in the GISSI-Prevenzione study, 3855 subjects with diabetes at baseline or missing information for relevant variables were excluded. A Cox proportional hazards model including age, sex, glycemia, high-density lipoprotein cholesterol, triglycerides, hypertension, and body mass index was fitted to create a diagnostic score. A cutoff point of 28 of the score was the best compromise between sensitivity and specificity for MS diagnosis (MS-Score). The prognostic performance of the MS-Score was compared with that of the diagnostic criteria of MS, as defined by National Cholesterol Education Program Adult Treatment Panel III (MS-ATP). Of 7468 patients, 940 developed diabetes. The risk of getting diabetes significantly and progressively increased in the quintiles of the score reaching > 6-fold higher risk in the last one. The predictive capability of MS-Score was significantly higher than that of the MS-ATP (AUC = 0.650 vs 0.587, sensitivity 67% vs 52%, specificity 63% vs 66%, P = .0002). The MS-Score, but not the MS-ATP, was significantly associated with mortality. MS-Score improves the prediction of diabetes development by using the full informative content of individual components for diagnosis of MS.

Analysis of the Benefits of a Mediterranean Diet in the GISSI-Prevenzione Study: A Case Study in Imputation of Missing Values from Repeated Measurements

The problem of missing values has increasingly being recognized in epidemiology. New methods allow for the analysis of missing data that can provide valid estimates of epidemiological quantities of interest. The GISSI-Prevenzione study was aimed to reliably assess the long-term relationship between the consumption of foods typical of the Mediterranean diet and the risk of mortality amongst 11,323 Italians with prior myocardial infarction. Food intake frequencies were recorded repeatedly over the 4.5 years of follow-up and missing values affected each food variable at increasing rates over the course of the study. Comparisons were made between the results obtained from the analysis of the complete data and those obtained after imputing the missing data with simple imputation methods and with various implementations of the multiple imputation (MI) method. MI appeared to best address the issue of missing data on the food intake frequencies, preserving the observed distributions and relationships between variables whilst producing plausible estimates of variability. Given its theoretical properties and flexibility to different types of data, MI is more likely to provide valid estimates, compared to complete data analysis and imputation by simple methods, and is thus worthy of wider consideration amongst epidemiological researchers.

Omega-3 long-chain PUFA and triglyceride lowering: minimum effective intakes

Early studies on the cardioprotective effects of high doses (up to 20 g of eicosapentaenoic and docosahexaenoic acids, EPA and DHA, per day) of omega-3 fatty acids (FAs) suggested that these FAs primarily lowered triglyceride levels. These supraphysiological intake studies soon gave way to trials using lower and lower intakes of omega-3 FAs such that it is now clear that up to 45% lowering of serum triglyceride levels can be achieved with 3–4 g of EPA + DHA. This is an intake that can hardly be achieved by dietary means; direct supplementation is required. This is a public health challenge since implementing wide-scale supplementation programmes would be difficult. Relatively few investigators have examined the effects of low (<2 g) EPA+DHA on serum lipid profiles, presumably because until recently there was little expectation that any benefit would be detectable. With the publication of the DART study and more recently the GISSI-Prevenzione Study, it is becoming clear that small intakes of omega-3 FAs can significantly impact CHD risk. A review of the studies on the effects of small doses (<2 g · day−1) of omega-3 FAs on serum triglyceride levels suggests that serum triglyceride levels decreased in every study (compared with control or placebo treatment). The decreases were often not statistically significant, but this is to be expected with small doses given for short time-periods. Four of the five studies that examined postprandial lipids (PPL) reported significant reductions in this parameter even when fasting levels were not altered. This suggests that chronic intake of small amounts of omega-3 FAs may reduce overall (day-long) triglyceride-rich lipoprotein levels which could have long-term implications for the reduction of CHD risk. Whilst the cardioprotective effects of omega-3 FAs are becoming well documented, the question of whether such beneficial effects of omega-3 FAs are at least partially mediated by changes in serum levels of triglyceride-rich lipoproteins or their remnants remains open. Further studies to examine the effects of this low level of intake are clearly needed to determine the relative contribution of hypolipidaemic mechanisms versus those involving diminished platelet function, altered adhesion molecule expression, improvements in endothelial function and antiarrhythmic or hypotensive effects.