European Journal of Heart Failure

European Journal of Heart Failure 2004 6(5):635-641; doi:10.1016/j.ejheart.2004.03.001

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Tavazzi, L. Search for Related Content PubMed PubMed Citation Articles by Tavazzi, L. Social Bookmarking          What's this?

© 2004 European Society of Cardiology

Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure^*

Luigi Tavazzi^a, Gianni Tognoni^f, Maria Grazia Franzosi^b, Roberto Latini^b, Aldo Pietro Maggioni^c, Roberto Marchioli^f,*, Gian Luigi Nicolosi^d, Maurizio Porcu^e and on behalf of the GISSI-HF investigators

^a Policlinico San Matteo, IRCCS, Pavia Italy
^b Istituto di Ricerche Farmacologiche ‘Mario Negri Milano, Italy
^c Centro Studi ANMCO Firenze, Italy
^d Ospedale Santa Maria degli Angeli Pordenone, Italy
^e Ospedale San Michele ‘G. Brotzu’ Cagliari, Italy
^f Consorzio Mario Negri Sud Santa Maria Imbaro, Italy

^* Corresponding author. Present address: GISSI-HF Co-ordinating Centre, Centro Studi ANMCO, Via La Marmora 34, Firenze, Italy. E-mail address: gissihf{at}anmco.it

	Abstract

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 
Background: The GISSI Heart Failure project is a large-scale, randomized, double-blind study designed to investigate the effects of n-3 polyunsaturated fatty acids and rosuvastatin on mortality and morbidity in patients with symptomatic heart failure.

Methods and results: Patients with New York Heart Association classes II to IV heart failure, already receiving optimized recommended therapy, will be recruited in a nation-wide network of more than 300 cardiology and internal medicine services to be randomly allocated to treatment with n-3 polyunsaturated fatty acids (1 g daily) or the corresponding placebo. Patients with no clear indication or contraindication to cholesterol-lowering therapy will be further randomized to receive low-dose rosuvastatin (10 mg daily) or placebo. According to data available in heart failure registries, it is expected that 70% of the patients will be suitable to enter both components of the trial, which assume the same co-primary endpoints: (a) 15% reduction of all-cause mortality and (b) 20% reduction of all-cause mortality or cardiovascular hospitalizations. The trial is event-driven and will continue either until at least 1252 deaths have been recorded or a reduction of all-cause mortality will satisfy the significance boundaries, which have been established to stop the study. The recruitment of the planned sample size of approximately 7000 patients randomized in the n-3 PUFA trial is expected to be completed within 18 months from the trial start. As of February 29, 2004, 4624 heart failure patients have been included in the trial.

Conclusion: The GISSI-HF project, with its protocol articulated into two independent randomization schemes, has the aim and the power to verify the hypothesis that n-3 polyunsaturated fatty acids and rosuvastatin can favorably modify the prognosis of patients with symptomatic heart failure.

Key Words: Heart failure • Polyunsaturated fatty acids • Statins • Mortality

Received September 12, 2003; Revised September 19, 2003; Accepted March 1, 2004

	1. Introduction

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 
The important decline in mortality rates from acute coronary syndromes due to major advances in the prevention and treatment of cardiovascular disease has been paralleled by the growing morbidity and mortality burden due to cardiac failure, despite the substantial advances in its pharmacological treatment and control [1–7]. Heart failure is a complex clinical syndrome, which is the final common pathway for several types of cardiac damage. While pharmacological treatments specifically targeted to the cardio-circulatory system and pathophysiological mechanisms have been largely investigated, few controlled data are available on the role of interventions which aim to reduce mortality and morbidity through the modification of other pathophysiological mechanisms from inflammation to gene regulation, which are thought to be associated with ventricular remodeling as well as with heart failure progression [1].

The GISSI Heart Failure Study (GISSI-HF) is a randomized, large-scale, double-blind, placebo-controlled trial to test, in addition to prescribed treatments, two pharmacological agents never formally assessed in symptomatic heart failure. These are, n-3 polyunsaturated fatty acids (PUFA), which are expected to exert a beneficial effect mainly through their antiarrhythmic properties, and rosuvastatin, which is evaluated for the increasing emphasized pleiotropic effects of statins, beyond their well-established lipid-lowering action [8].

	2. Rationale

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 
2.1. The n-3 PUFA hypothesis
The GISSI-Prevenzione trial showed that 3-year treatment with low-dose n-3 PUFA was associated with a significant 21% reduction of total mortality in patients who survived a recent MI [9]. A secondary analysis of the causes of death showed that, among all cardiac causes, the most affected by n-3 PUFA was sudden cardiac death and that the benefit on sudden death was already significant after 4 months of therapy [10]. An unpublished, post-hoc analysis of the GISSI-Prevenzione trial showed that, in nearly 2000 post-infarction patients with left ventricular dysfunction enrolled in the trial, the effects of n-3 PUFA on all-cause and sudden mortality were similar to those observed in the total population of the trial. Experimental, epidemiological, as well as small size human studies are consistent with these findings and support the hypothesis that n-3 PUFA can exert antiarrhythmogenic or antifibrillatory effects [11–19].

In addition to the antiarrhythmic effects, n-3 PUFA have a number of pleiotropic effects which could be important in heart failure [20]. For instance, n-3 PUFA have been shown to have anti-inflammatory effects in healthy volunteers, among them the synthesis of IL-1beta, IL-1alpha and TNF by circulating monocytes was reduced [21]. Pepe et al. recently showed that n-3 PUFA directly influenced heart function and improved cardiac responses to ischemia and reperfusion [22,23]. In particular, the administration of n-3 PUFA reduced oxygen consumption at any given workload output, increased post-ischemic recovery, and prevented ventricular fibrillation in reperfusion [22]. Long-chain n-3 fatty acids can increase the ability of the cardiac muscle to take up fatty acids into the mitochondria for energy production by increasing the expression of carnitine palmytoiltransferase I (CPT-I) and activating peroxisome proliferator activated receptors (PPAR-a) [24].

Recently, a case–control study on fish consumption showed that n-3 PUFA are protective against non-fatal myocardial infarction, a cause of possible worsening of heart failure [25]. Therefore, the hypothesis that n-3 PUFA can improve the outcome of patients with heart failure of any aetiology and any level of left ventricular function merits formal testing.

2.2. The statin hypothesis
Several trials have shown that statin treatment is associated with a significant reduction of cardiovascular events in patients at high risk, mainly in patients with documented coronary artery disease [26–29]. Recently, the Heart Protection Study demonstrated that statin therapy is effective in patients at high risk of ischemic coronary heart disease, irrespective of baseline cholesterol levels [29]. A post-hoc analysis of the 4S study showed that the use of statins in patients with coronary artery disease, but without heart failure, could prevent the occurrence of congestive heart failure [30]. Since the prevalent aetiology of heart failure is coronary artery disease, preventing heart failure progression may be related to the prevention of coronary artery disease. To date, only post-hoc, non-randomized, underpowered sub-analyses have been performed on this issue. In the ELITE-2 trial a lower mortality rate in patients with heart failure of any aetiology treated with statins (non-randomized comparison) was shown [31]. Of 897 patients with LV dysfunction/failure enrolled in the statin arm of the GISSI-Prevenzione trial, no safety problems were observed in the patients allocated to pravastatin and the favorable trend in total mortality reduction was similar among patients with and without left ventricular dysfunction. Therefore, while there is no direct evidence from randomized clinical trials, the above observations are highly suggestive and supportive of a formal test of the benefit of statins in patients with heart failure.

The so-called pleiotropic effects of statins are considered important in determining the observed benefit [32]. It has been hypothesized that the inhibition of HMG-CoA reductase not only affects cholesterol but, by limiting the synthesis of mevalonate-derived molecules, interferes with the synthesis of anti-inflammatory components, thus down-regulating cytokine and chemokine production, which is activated in patients with advanced heart failure due to any aetiology [32]. Statin treatment can also improve endothelial function which is largely compromised in patients with heart failure, irrespective of the underlying aetiology, and it is considered co-responsible for the multi-organ failure [33,34]. Recent experimental data suggest that statins can reduce the negative effects of angiotensin II on left ventricular remodeling independently of cholesterol reduction [35].

Statins, however, may have detrimental effects in patients with heart failure, since low serum cholesterol levels are independently associated with a worse prognosis in these patients [36], and a meta-analysis found a lower efficacy of older cholesterol-lowering drugs in trials including subjects with heart failure as compared with those which excluded these patients [37]. There are some suggestions indicating that high levels of cholesterol can be beneficial in patients with heart failure on the basis of the ability of serum lipoproteins to modulate inflammatory immune function, since cholesterol-rich lipoproteins can bind and detoxify bacterial lipopolysaccharide (LPS), whose production is increased in heart failure patients (endotoxin-lipoprotein hypothesis) [38]. LPS is a very strong stimulator of the release of pro-inflammatory cytokines, which may contribute to the progression of heart failure. By inhibiting the synthesis of mevalonate, statins can depress the production of ubiquinone, which is a central compound of the mitochondrial respiratory chain. Thus, statins could affect mitochondrial function and worsen the skeletal or cardiac muscle function. It is worthwhile to recall that the main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction [39–42]. Therefore, the risk of myopathy associated with any statin administration could be a particular concern in patients with both an energy-inefficient, dilated failing heart with defective contractile function [1] and skeletal muscle structural and functional alterations creating a so-called ‘heart failure myopathy’.

	3. Methods, general design, and study population

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 
The primary objectives of GISSI-HF are to investigate whether long-term administration of n-3 PUFA and rosuvastatin is more effective than the corresponding placebo in the reduction of two co-primary end points: (a) all-cause mortality; and (b) all-cause mortality or hospitalizations for cardiovascular reasons.

The study is a multicentre, randomized, placebo-controlled design. Patients with symptomatic heart failure who are already being treated with optimal recommended therapies will be randomly allocated to the two following hypotheses:

Randomization 1 (R1): n-3 PUFA 1 g daily or corresponding placebo;

Randomization 2 (R2): rosuvastatin 10 mg daily or corresponding placebo.

The inclusion criteria are very broad: male and female patients with no age limitations can be admitted to the study if they have clinical evidence of heart failure of any aetiology classified according to the ESC guidelines as NYHA class II–IV [43], and provided they have their left ventricular EF measured within 3 months from enrolment. In case of ejection fraction >40%, at least one hospital admission for congestive heart failure in the previous year is required to meet the inclusion criteria.

The exclusion criteria shared by the two components of the study include (a) known hypersensitivity to study treatments; (b) conditions that in the opinion of the investigator would be associated with poor adherence to the protocol; (c) presence of any non-cardiac co-morbidity (e.g. cancer) unlikely to be compatible with a sufficiently long follow-up; (d) treatment with any investigational agent within 1 month before randomization; (e) acute coronary syndrome or revascularization procedure within 1 month; (f) planned cardiac surgery, expected to be performed within 3 months after randomization; (g) significant liver disease; and (h) pregnant or lactating women or women of childbearing potential who are not protected from pregnancy by an accepted method of contraception.

In addition to the aforementioned criteria, otherwise suitable patients will be excluded from the study if their background therapy includes: (a) for R1, an ongoing post-MI treatment with n-3 PUFA; (b) for R2, lipid-lowering therapy with statins.

Based on data available in the literature and in the IN-CHF database [44], it is estimated that up to 30% of R1 patients will be unsuitable to enter R2. Further, R1 patients cannot be randomized in R2 if the following conditions exist: (a) serum creatinine level >2.5 mg/dl; (b) ALT, AST level >1.5 times the upper normal limit; and (c) CPK levels above upper normal limit.

	4. Trial organization and procedures

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 
Patients will be randomized to receive one daily capsule of 1 g n-3 PUFA (850–882 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters in the average ratio of EPA/DHA 1:1.2) or matching placebo.

For patients randomized in R2, rosuvastatin and corresponding placebo will be supplied to the investigator in tablet formulation of 10 mg for oral use.

Allocation of patients to treatment groups will be accomplished via a telephone call-in system, and centrally approved at the study Coordinating Centre.

The ethical conduct of the study is regulated by the last revision of the Helsinki Declaration (2000) as well as the provisions of the Oviedo Convention (1997). The study complies with the Good Clinical Practice (GCP) principles and procedures, as described in the ICH Harmonized Tripartite Guidelines for Good Clinical Practice (1996), the Directive 91/507/EEC ‘The Rules Governing Medicinal Products in the European Community’, and the US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 concerning informed consent and IRB regulations). Following the initial approval by the Ethical Committee of the Chairman's institution, the protocol must be approved by the local committees of the participating centers. Each patient will be duly informed of the trial objectives, study design, and risks and benefits of study participation as well as on his/her rights to the full respect of privacy and confidentiality rules, as set out in Italian law, which comply with and implement European Union regulations. A signed consent form will be collected for all patients.

After randomization, patients will be required to return to their reference center half-yearly for drug supply and for the scheduled visits at 1, 3, 6, 12 months and then every 6 months until the trial end. A common core of assessments (cardiovascular examination, vital signs, 12-lead ECG, compliance check, drug dispensation, serious adverse events assessment, and blood chemistry) will be undertaken at the study visits.

All treatments proven effective for the treatment of congestive heart failure will be positively recommended (specifically: ACE-inhibitors, beta-blockers, diuretics, digitalis, spironolactone). Patients can be treated with amiodarone, aspirin and/or oral anticoagulants according to the clinical decision of the attending physician.

	5. Efficacy and safety evaluation

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 
Two co-primary outcome measures have been established: time to death and time to death or cardiovascular hospitalization. Secondary outcomes include cardiovascular mortality; cardiovascular mortality or hospitalization for heart failure or for any reason; sudden cardiac death; hospitalization for any reason; hospitalization for cardiovascular reasons; hospitalization for heart failure; myocardial infarction; stroke.

All events recorded in the study will be adjudicated blindly by an ad-hoc Committee on the basis of pre-agreed definitions and procedures. Each report will include narrative summaries with supporting documentation for all events.

Serious adverse events (defined as fatal, life-threatening, requiring or prolonging hospitalization, permanently disabling or incapacitating, which may jeopardize the subject or which may require medical or surgical intervention) and which are suspected by the Investigator to be related to study medication will be reported to the study Coordinating Center within 24 h of notification of their occurrence. Serious adverse events not suspected by the Investigator to be related to study medication will be reported with the CRF and/or end-point documentation.

A policy of surveillance will be specifically focused on renal dysfunction (creatinine), liver dysfunction (ALT and AST enzymes, symptoms), myopathy (CK, symptoms), and gastrointestinal disorders (symptoms).

Specific attention will be focused on patients at high risk of adverse events and drug reactions, such as those with a serum creatinine level between 1.5 and 2.5 mg/dl, NYHA class IV, or aged more than 70 years. In addition to the planned clinical visits, two telephone calls 2 and 9 months after randomization are planned for these patients, in order to assess their health status. Specific tables containing information on safety aspects of these subgroups of high-risk patients will be periodically reviewed by the Data and Safety Monitoring Board (DSMB).

	6. Statistical aspects

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 
Due to the different inclusion criteria in R1 and R2 the patient samples will be different, the two hypotheses explored in GISSI-HF will, therefore be tested independently.

Since it is expected that 70% of R1 patients will be also enrolled in R2, the latter randomized cohort is taken as reference for sample size calculations. The expected 3-year death rate in the placebo group has been used for sample size calculation, since death is the harder and more conservative component of the established outcome measures (Table 1). As two co-primary efficacy end points will be analyzed, an adjustment for the overall =0.05 will be made by setting an of 0.045 for all-cause mortality and an of 0.01 for the composite end point of all-cause mortality or cardiovascular hospitalization.

View this table: [in this window] [in a new window]   Table 1 Statistical assumptions to calculate the sample size of the trial

 
According to an event-driven sample size calculation, to detect a 15% reduction in an expected mortality rate of 25% in the placebo arm with 90% power and a two-sided significance at the 0.045 level, at least 1252 deaths will be required [45,46].

The expected cumulative rate of death or hospitalization for cardiovascular reasons during 3 years of follow-up is expected to be between 40 and 45%. The minimum clinically relevant beneficial effect of the tested treatments on the cumulative endpoint is set at a 20% reduction of risk (Table 1). The number of patients to be recruited in both R1 and R2 will also be adequate to test the efficacy of n-3 PUFA and rosuvastatin for the analysis of the co-primary combined end point.

Efficacy in terms of all-cause mortality will be monitored using the sequential procedure of Peto [47]. There will be one interim analysis to assess efficacy, scheduled at approximately 1/2 of expected deaths. Accordingly, the corresponding significance level for evidence to stop the trial will be <0.001. In case the level of significance set to stop, the trial at the interim analysis will be reached for one of the two cohorts, the study will be carried on only for the cohort in which the level of significance has not been reached [45]. Since the trial is event driven, follow-up will be continued until at least 1252 patient deaths have occurred in R2 or the reduction of all-cause mortality either in n-3 PUFA or rosuvastatin studies satisfies the significance level of P<0.001 which has been established as the efficacy criterion to stop the study prematurely.

The expected duration of follow-up is 4 years and the approximate expected number of patients to be recruited to test the efficacy of experimental treatments is 7000 for R1 and 5250 for R2 along an accrual period of at least 18 months.

Safety aspects will be monitored. No formal boundaries will be proposed, but clear, consistent, and persistent evidence of net harm that overwhelms any benefit will be made apparent to the DSMB.

The main analysis will be performed according to an intention-to-treat approach; therefore all patients randomized in the study will be included in the analysis. Baseline characteristics will be presented by treatment groups. Any unbalance for baseline characteristics thought to be of prognostic importance will be considered for multivariate adjustment in the subsequent analyses by using a Cox proportional hazards model with terms for fish-oil and rosuvastatin treatment. Results will be presented in terms of hazards ratios at their respective confidence intervals (i.e. 95.5 and 99%). Plots of the Kaplan–Meier estimates of the survival curves will be presented [48].

The existence of an effect modification in patients receiving both treatments, however, will be explored by fitting to the data a Cox proportional hazards model with terms for fish-oil, rosuvastatin and their interaction. If the term for interaction is non-significant, it will be removed from the model.

The consistency of the effect of tested treatments according to the risk profile of enrolled patients will be explored by: (a) carrying out subgroup analyses; (b) assessing the degree of the expected benefit through the categories of a score system taking into account all major prognostic indicators.

By using the combined outcome measure of all-cause mortality or hospital admission for cardiovascular reasons, the effects of the study drugs will be evaluated in the following predefined subgroups of patients: age (above/below the median value); left ventricular function (EF%>40% vs. 40%); aetiology (ischemic vs. non-ischemic); functional capacity (NYHA class II vs. III–IV); diabetes (yes vs. no); baseline total cholesterol levels (above/below the median value). The test of interaction between tested treatments and the predefined subgroups of patients (consisting in a model including each of the aforementioned variables, treatment and their interaction with treatment) will be carried out at the 5% significance level, being in the context of exploratory analyses in the framework of multivariate models allowing for possible unbalance for relevant prognostic covariates.

	7. Discussion

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 
Following its first formal presentation to the Italian cardiologic community in Summer 2001, the GISSI-HF protocol has successfully completed its feasibility and regulatory phases. Patient recruitment commenced in September 2002 and as of 29 February 2004, 4624 heart failure patients have been recruited in 345 centers. GISSI-HF has therefore translated into an ongoing program to investigate what the most recent literature [49] indicates is an interesting hypothesis.

Rosuvastatin testing is ‘nested’ into the broader population of symptomatic heart failure patients randomized to assess the efficacy of another innovative approach with n-3 PUFA.

Following the long tradition of GISSI studies [50], the evaluation of the two experimental treatments incorporates a recruitment strategy extended to a highly representative sample of the hospital and ambulatory care facilities where heart failure patients are treated.

To ensure that the trial is truly testing an add-on benefit with respect to the existing evidence-based treatments, the trial is framed in a program of optimization of the background care, which is promoted and supported with ad hoc information and educational material provided to all participating centers. Along this line, patients who have a positive indication for either of the experimental treatments are excluded from randomization. The legitimacy of testing a primarily non-lipid lowering indication for a statin against placebo, is in concordance with the position and recommendations of the British National Institute for Clinical Excellence (NICE), which underline the absence of data directly supporting an indication for statins in heart failure patients, even for those with ischemic aetiology.

A few carefully selected and designed sub-projects have been incorporated into the main study to explore: (a) ventricular remodeling, with a protocol centered on echocardiography and a planned sample size of 800 subjects; (b) the behavior and the role of biohumoral markers (BNP, CRP, PTX3, lipids including n-3 and n-6 PUFA; planned size, 800 patients); (c) the incidence and the profile of arrhythmias and autonomic profile (Holter monitoring in a sample of 750 patients); (d) exercise capacity (in 400 patients). Further, a comprehensive assessment of the prevalence, incidence, and impact on outcomes of quality of life, depression, cognitive function (measured at each clinical visit with the Kansas City Cardiomyopathy Questionnaire, the Geriatric Depression Scale, and the Mini mental State Evaluation) in patients aged >70 years is foreseen in a subpopulation of at least 3000 patients.

It is proposed that, through modification of lipids in cell membranes for n-3 PUFA and in the blood for rosuvastatin, the treatments tested in GISSI-HF can decrease the risk of arrhythmic and ischemic events which in turn can decrease mortality and morbidity in heart failure. In addition, the pleiotropic effects of n-3 PUFA and rosuvastatin can favorably affect various mechanisms involved in the progression of heart failure [1] from abnormalities in energy metabolism, through altered expression or function of contractile proteins and abnormalities of excitation–contraction coupling, to ventricular hypertrophy, remodeling and neurohormonal changes. Such actions of n-3 PUFA and statins, however, have only been shown in bench research using different experimental conditions, with in vitro or ex vivo experimental models. Their relevance in humans is still unknown, particularly so in heart failure patients who are already treated with a number of drugs of proven efficacy and with possibly overlapping mechanisms of action.

Several interventions have been shown in controlled clinical trials to be useful in limited cohorts of patients with heart failure (e.g. aldosterone antagonists, angiotensin receptor blockers, hydralazine and isosorbide dinitrate, and exercise training). GISSI-HF will help to clarify whether the management of heart failure might justifiably be expanded to include n-3 PUFA and rosuvastatin in addition to the aforementioned treatments.

7.1. Organization
The GISSI-HF study is sponsored by the GISSI group who has, therefore the full responsibility not only for the formulation, but also for the overall conduct of the study, including onsite monitoring, and the utilization of the results. A pool of financial grants has been assured by the companies which are the owners and the suppliers of the study drugs (Pharmacia-Upjohn, Sigma-Tau, and Società Prodotti Antibiotici supply capsules containing 850-882 mg EPA/DHA ethyl esters; Rosuvastatin is supplied by Astra-Zeneca).

7.1.1. Steering committee
Luigi Tavazzi (chair), Gianni Tognoni (co-chair), Maria Grazia Franzosi, Roberto Latini, Aldo Pietro Maggioni, Roberto Marchioli, GianLuigi Nicolosi, and Maurizio Porcu.

7.1.2. Trial management and secretariat
Barbara Bartolomei Mecatti, Elisa Bianchini, Marco Gorini, Andrea Lorimer, Giampietro Orsini, Paola Priami (Centro Studi ANMCO); Giuseppina Di Bitetto, Luisa Galbiati, (Istituto Mario Negri); Barbara Ferri, Anna Flamminio, Carla Pera (Consorzio Mario Negri Sud).

7.1.3. Statistics
Simona Barlera, Donata Lucci, Roberto Marchioli.

7.1.4. Monitoring activities
Francesca Bianchini, Ilaria Cangioli, Martina Ceseri, Arianna Tafi (Centro Studi ANMCO).

7.1.5. End point evaluation committee
Enrico Geraci (chair), Marino Scherillo (co-chair), Franco Cobelli, Gianna Fabbri (Coordinator), Claudio Fresco, Giacomo Levantesi, Cristina Opasich, Franco Rusconi, Gianfranco Sinagra, Fabio Turazza, and Alberto Volpi.

7.1.6. Data and safety monitoring board
Salim Yusuf (chair), Fulvio Camerini, Jay N. Cohn, Adriano De Carli, Bertram Pitt, Philip Poole-Wilson, and Peter Sleight.

	Notes

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 
GISSI-HF Investigators: GISSI—Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca—is endorsed by Associazione Nazionale Medici Cardiologi Ospedalieri—ANMCO—and by Istituto di Ricerche Farmacologiche ‘Mario Negri’.

	References

Top Notes Abstract 1. Introduction 2. Rationale 3. Methods, general design,... 4. Trial organization and... 5. Efficacy and safety... 6. Statistical aspects 7. Discussion References

 

1. Braunwald E. Congestive heart failure: a half century perspective. Eur Heart J (2001) 22:825–836.[Free Full Text]
2. The CONSENSUS Trial Study Group. Effects of enalapril in severe congestive heart failure. N Engl J Med (1987) 316:1429–1435.[Abstract]
3. Cohn J.N., Johnson G., Ziesche S., et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med (1991) 325:303–310.[Abstract]
4. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med (1991) 325:293–302.[Abstract]
5. Packer M., Bristow M.R., Cohn J.N., Colucci W.S., et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med (1996) 334:1349–1355.[Abstract/Free Full Text]
6. CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]
7. MERIT-HF Study Group. Effects of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure. (MERIT-HF). J Am Med Assoc (2000) 283:1295–1302.[Abstract/Free Full Text]
8. Maggioni A.P., Tavazzi L., Marchioli R., Tognoni G., Avanzini F. Roncaglioni MC on the behalf of the GISSI-Group. Perspectives on n-3 PUFA: primary prevention, antiarrhythmic effects, congestive heart failure. Eur Heart J (2001) 3:D106–D109.[CrossRef]
9. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet (1999) 354:447–455.[CrossRef][Web of Science][Medline]
10. Marchioli R., Barzi F., Bomba E., Chieffo C., Di Gregorio D., Di Mascio R., et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation (2002) 105:1897–1903.[Abstract/Free Full Text]
11. Harper C.R., Jacobson T.A. The fats of life: the role of omega-3 fatty acids in the prevention of coronary heart disease. Arch Intern Med (2001) 161:2185–2192.[Abstract/Free Full Text]
12. Nordoy A., Marchioli R., Arnesen H., Videbæk J. n-3 polyunsaturated fatty acids and cardiovascular diseases. Lipids (2001) 36:S127–S129.[CrossRef][Web of Science][Medline]
13. Billman G.E., Kang J.X., Leaf A. Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs. Circulation (1999) 99:2452–2457.[Abstract/Free Full Text]
14. Leaf A. The electrophysiological basis for the antiarrhythmic actions of polyunsaturated fatty acids. Eur Heart J (2001) 3:D98–D105.[CrossRef]
15. Curtis B.M., O'Keefe J.H. Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight. Mayo Clin Proc (2002) 77:45–54.[Abstract/Free Full Text]
16. Sellmayer A., Witzgall H., Lorenz R.L., Weber P.C. Effects of dietary fish oil on ventricular premature complexes. Am J Cardiol (1995) 76:974–977.[CrossRef][Web of Science][Medline]
17. Christensen J.H., Korup E., Aaroe J., Toft E., Moller J., Rasmussen K., et al. Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction. Am J Cardiol (1997) 79:1670–1673.[CrossRef][Web of Science][Medline]
18. Albert C.M., Campos H., Stampfer M.J., Ridker P.M., Manson J.E., et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med (2002) 346:1113–1118.[Abstract/Free Full Text]
19. Hu F.B., Bronner L., Willett W., et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. J Am Med Assoc (2002) 287:1815–1821.[Abstract/Free Full Text]
20. Demaison L., Moreau D. Dietary n-3 polyunsaturated fatty acids and coronary heart disease-related mortality: a possible mechanism of action. Cell Mol Life Sci (2002) 59:463–477.[CrossRef][Web of Science][Medline]
21. Endres S., Ghorbani R., Kellev V.E., Georgilis K., Lonnemann G., van der Meer J.W., et al. 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.[Abstract]
22. Pepe S., McLennan P.L. Cardiac membrane fatty acids composition modulates myocardial oxygen consumption and postischemic recovery of contractile function. Circulation (2002) 105:2303–2308.[Abstract/Free Full Text]
23. Pepe S., McLennan P.L. Dietary fish oil exerts direct antiarrhythmic action in myocardium of the rat. J Nutr (1996) 126:34–42.[Abstract/Free Full Text]
24. De Windt L.J., Cox K., Hofstra L., Doevedans P.A. Molecular and genetic aspects of cardiac fatty acids homeostasis in health and disease. Eur Heart J (2001) 23:774–787.[CrossRef][Web of Science]
25. Tavani A., Pelucchi C., Negri E., Bertuzzi M., La Vecchia C. n-3 Polyunsaturated fatty acids, fish, and nonfatal acute myocardial infarction. Circulation (2001) 104:2269–2272.[Abstract/Free Full Text]
26. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet (1994) 344:1383–1389.[CrossRef][Web of Science][Medline]
27. Sacks F.M., Pfeffer M.A., Moye L.A., et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med (1996) 335:1001–1009.[Abstract/Free Full Text]
28. LIPID Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med (1998) 339:1349–1357.[Abstract/Free Full Text]
29. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet (2002) 360:7–22.[CrossRef][Web of Science][Medline]
30. Kjekshus J., Pedersen T.R., Olsson A.G., Faergeman O., Pyorala K. The effects of simvastatin on the incidence of heart failure with coronary heart disease. J Card Fail (1997) 3:249–254.[CrossRef][Medline]
31. Segal R., Pitt B., Pode-Wilson P., Sharma D., Bradstreet D.C., Ikeda L.S. Effects of HMG-COA reductase inhibitors (statins) in patients with heart failure. Eur J Heart Fail (2000) 2(Suppl. 2):96. (on behalf of the ELITE. II).[Free Full Text]
32. Vaughan C.J., Murphy M.B., Buckley B.M. Statins do more than just lower cholesterol. Lancet (1996) 348:1079–1082.[CrossRef][Web of Science][Medline]
33. Koh K.K. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res (2000) 47:648–657.[Abstract/Free Full Text]
34. Drexler H., Hornig B.D. Endothelial dysfunction in human disease. J Mol Cell Cardiol (1999) 31:51–60.[CrossRef][Web of Science][Medline]
35. Dechend R., Fiebeler A., Park J.K., et al. Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Circulation (2001) 104:576–581.[Abstract/Free Full Text]
36. Horwich T.B., Hamilton M.A., Maclennan W.R., Fonorow G.C. Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure. J Card Fail (2002) 8:216–224.[CrossRef][Web of Science][Medline]
37. Marchioli R., Marfisi R.M., Carinci F., Tognoni G. Meta-analysis, clinical trials, and transferability of research results into practice: The case of cholesterol-lowering interventions in secondary prevention of coronary heart disease. Arch Intern Med (1996) 156:1158–1172.[Abstract/Free Full Text]
38. Rauchhaus M., Coats A.J.S., Anker S.D. The endotoxin-lipoprotein hypothesis. Lancet (2000) 356:930–933.[CrossRef][Web of Science][Medline]
39. Marz W., Siekmeier R., Muller H.M., Wieland H., Gross W., Olbrich H.G. Effects of lovastatin and pravastatin on the survival of hamsters with inherited cardiomyopathy. J Cardiovasc Pharmacol Ther (2000) 5:275–279.[Abstract/Free Full Text]
40. De Lorgeril M., Salen P., Bontemps L., Belicghard P., Geyssant A., Itti R. Effects of lipid-lowering drugs on left ventricular function and exercise tolerance in dyslipidemic coronary patients. J Cardiovasc Pharmacol (1999 March) 33(3):473–478.[CrossRef][Web of Science][Medline]
41. Permanetter B., Rossy W., Klein G., Weingartner F., Seidl K.F., Blomer H. Ubiquinone (coenzyme Q10) in the long-term treatment of idiopathic dilated cardiomyopathy. Eur Heart J (1992) 13:1528–1533.[Abstract/Free Full Text]
42. Louis A., Cleland J.G., Crabbe S., Ford S., Thackray S., Houghton T., et al. Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail (2001) 3(3):381–387.[Abstract/Free Full Text]
43. Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527–1560.
44. Pulignano G., Del Sindaco D., Tavazzi L., Lucci D., Gorini M., Leggio F., et al. Clinical features and outcomes of elderly outpatients with heart failure followed up in hospital cardiology units: data from a large nationwide cardiology database (IN-CHF Registry). Am Heart J (2002) 143:45–45.[CrossRef][Web of Science][Medline]
45. Marubini E., Valsecchi M.G. Analysing survival data from clinical trials and observational studies (1995) New York: John Wiley and Sons Inc.
46. Collett D. Modelling survival data in medical research (1994) Chapman and Hall.
47. Geller N.L., Pocock S.J. Interim analyses in randomized clinical trials: ramifications and guidelines for practitioners. Biometrics (1987) 43:213–223.[CrossRef][Web of Science][Medline]
48. Kalbfleisch J.D., Prentice R.L. The statistical analysis of failure time data (1980) New York: John Wiley and Sons Inc.
49. Krum H., McMurray J.J. Statins and chronic heart failure: do we need a large-scale outcome trial? JACC (2002) 39:1567–1573.[Abstract/Free Full Text]
50. Tognoni G., Fresco C., Maggioni A.P., Turazza F. The GISSI Story (1983–1996): a comprehensive review. J Intervent Cardiol (1997) 10:3–28.[CrossRef][Web of Science]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				S. Masson, R. Latini, E. Carbonieri, L. Moretti, M. G. Rossi, S. Ciricugno, V. Milani, R. Marchioli, J. Struck, A. Bergmann, et al. The predictive value of stable precursor fragments of vasoactive peptides in patients with chronic heart failure: data from the GISSI-heart failure (GISSI-HF) trial Eur J Heart Fail, January 22, 2010; (2010): hfp206v1 - hfp206. [Abstract] [Full Text] [PDF]

				S. Masson, R. Latini, V. Milani, L. Moretti, M. G. Rossi, E. Carbonieri, A. Frisinghelli, C. Minneci, M. Valisi, A. P. Maggioni, et al. Prevalence and Prognostic Value of Elevated Urinary Albumin Excretion in Patients With Chronic Heart Failure: Data From the GISSI-Heart Failure Trial Circ Heart Fail, January 1, 2010; 3(1): 65 - 72. [Abstract] [Full Text] [PDF]

				A. P. Maggioni, G. Fabbri, D. Lucci, R. Marchioli, M. G. Franzosi, R. Latini, G. L. Nicolosi, M. Porcu, F. Cosmi, S. Stefanelli, et al. Effects of rosuvastatin on atrial fibrillation occurrence: ancillary results of the GISSI-HF trial Eur. Heart J., October 1, 2009; 30(19): 2327 - 2336. [Abstract] [Full Text] [PDF]

				H.J. Dargie Current controversies in drug use Eur J Heart Fail Suppl, April 1, 2009; 8(suppl_1): i15 - i20. [Full Text] [PDF]

				Y. Yang, Y. Mou, S.-J. Hu, and M. Fu Beneficial effect of rosuvastatin on cardiac dysfunction is associated with alterations in calcium-regulatory proteins Eur J Heart Fail, January 1, 2009; 11(1): 6 - 13. [Abstract] [Full Text] [PDF]

				A. P. Coletta, D. Cullington, A. L. Clark, and J. G.F. Cleland Clinical trials update from European Society of Cardiology meeting 2008: TIME-CHF, BACH, BEAUTIFUL, GISSI-HF, and HOME-HF Eur J Heart Fail, December 1, 2008; 10(12): 1264 - 1267. [Abstract] [Full Text] [PDF]

				T. D. Filippatos and D. P. Mikhailidis Statins and Heart Failure Angiology, August 1, 2008; 59(2_suppl): 58S - 61S. [Abstract] [PDF]

				D. Mozaffarian Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death Am. J. Clinical Nutrition, June 1, 2008; 87(6): 1991S - 1996S. [Abstract] [Full Text] [PDF]

				D. J.A. Jenkins, A. R. Josse, P. Dorian, M. L. Burr, R. LaBelle Trangmar, C. W.C. Kendall, and S. C. Cunnane Heterogeneity in Randomized Controlled Trials of Long Chain (Fish) Omega-3 Fatty Acids in Restenosis, Secondary Prevention and Ventricular Arrhythmias J. Am. Coll. Nutr., June 1, 2008; 27(3): 367 - 378. [Abstract] [Full Text] [PDF]

				V. G. Athyros, A. I. Kakafika, K. Tziomalos, A. Karagiannis, and D. P. Mikhailidis CORONA, Statins, and Heart Failure: Who Lost the Crown? Angiology, March 1, 2008; 59(1): 5 - 8. [PDF]

				J. H. Lee, J. H. O'Keefe, C. J. Lavie, R. Marchioli, and W. S. Harris Omega-3 Fatty Acids for Cardioprotection Mayo Clin. Proc., March 1, 2008; 83(3): 324 - 332. [Abstract] [Full Text] [PDF]

				K. Ramasubbu, J. Estep, D. L. White, A. Deswal, and D. L. Mann Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 415 - 426. [Abstract] [Full Text] [PDF]

				H. M. Den Ruijter, G. Berecki, A. O. Verkerk, D. Bakker, A. Baartscheer, C. A. Schumacher, C. N.W. Belterman, N. de Jonge, J. W.T. Fiolet, I. A. Brouwer, et al. Acute Administration of Fish Oil Inhibits Triggered Activity in Isolated Myocytes From Rabbits and Patients With Heart Failure Circulation, January 29, 2008; 117(4): 536 - 544. [Abstract] [Full Text] [PDF]

				J. G.F. Cleland, A. P. Coletta, A. T. Abdellah, D. Cullington, A. L. Clark, and A. S. Rigby Clinical trials update from the American Heart Association 2007: CORONA, RethinQ, MASCOT, AF-CHF, HART, MASTER, POISE and stem cell therapy Eur J Heart Fail, January 1, 2008; 10(1): 102 - 108. [Abstract] [Full Text] [PDF]

				F. A. Masoudi Statins for Ischemic Systolic Heart Failure N. Engl. J. Med., November 29, 2007; 357(22): 2301 - 2304. [Full Text] [PDF]

				J. Kjekshus, E. Apetrei, V. Barrios, M. Bohm, J. G.F. Cleland, J. H. Cornel, P. Dunselman, C. Fonseca, A. Goudev, P. Grande, et al. Rosuvastatin in Older Patients with Systolic Heart Failure N. Engl. J. Med., November 29, 2007; 357(22): 2248 - 2261. [Abstract] [Full Text] [PDF]

				S. Pepe and P. L. McLennan (n-3) Long Chain PUFA Dose-Dependently Increase Oxygen Utilization Efficiency and Inhibit Arrhythmias after Saturated Fat Feeding in Rats J. Nutr., November 1, 2007; 137(11): 2377 - 2383. [Abstract] [Full Text] [PDF]

				J. G.F. Cleland, A. T. Abdellah, O. Khaleva, A. P. Coletta, and A. L. Clark Clinical trials update from the European Society of Cardiology Congress 2007: 3CPO, ALOFT, PROSPECT and statins for heart failure Eur J Heart Fail, October 1, 2007; 9(10): 1070 - 1073. [Abstract] [Full Text] [PDF]

				B. London, C. Albert, M. E. Anderson, W. R. Giles, D. R. Van Wagoner, E. Balk, G. E. Billman, M. Chung, W. Lands, A. Leaf, et al. Omega-3 Fatty Acids and Cardiac Arrhythmias: Prior Studies and Recommendations for Future Research: A Report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop Circulation, September 4, 2007; 116(10): e320 - e335. [Full Text] [PDF]

				V. Zaca, S. Rastogi, M. Imai, M. Wang, V. G. Sharov, A. Jiang, S. Goldstein, and H. N. Sabbah Chronic Monotherapy With Rosuvastatin Prevents Progressive Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure J. Am. Coll. Cardiol., August 7, 2007; 50(6): 551 - 557. [Abstract] [Full Text] [PDF]

				M. Metra, P. Ponikowski, K. Dickstein, J. J.V. McMurray, A. Gavazzi, C.-H. Bergh, A. G. Fraser, T. Jaarsma, A. Pitsis, P. Mohacsi, et al. Advanced chronic heart failure: A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology Eur J Heart Fail, June 1, 2007; 9(6-7): 684 - 694. [Abstract] [Full Text] [PDF]

				J. G. Ray, C. M. Norris, J. A. Udell, R. T. Tsuyuki, F. A. McAlister, M. L. Knudtson, and W. A. Ghali Lipid-Lowering Therapy and Outcomes in Heart Failure Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2007; 12(1): 27 - 35. [Abstract] [PDF]

				K. K. Khush, D. D. Waters, V. Bittner, P. C. Deedwania, J. J.P. Kastelein, S. J. Lewis, and N. K. Wenger Effect of High-Dose Atorvastatin on Hospitalizations for Heart Failure: Subgroup Analysis of the Treating to New Targets (TNT) Study Circulation, February 6, 2007; 115(5): 576 - 583. [Abstract] [Full Text] [PDF]

				Heart Protection Study Collaborative Group,* N-Terminal Pro-B-Type Natriuretic Peptide, Vascular Disease Risk, and Cholesterol Reduction Among 20,536 Patients in the MRC/BHF Heart Protection Study J. Am. Coll. Cardiol., January 23, 2007; 49(3): 311 - 319. [Abstract] [Full Text] [PDF]

				C. von Schacky and W. S. Harris Cardiovascular benefits of omega-3 fatty acids Cardiovasc Res, January 15, 2007; 73(2): 310 - 315. [Abstract] [Full Text] [PDF]

				R. Fiaccavento, F. Carotenuto, M. Minieri, L. Masuelli, A. Vecchini, R. Bei, A. Modesti, L. Binaglia, A. Fusco, A. Bertoli, et al. {alpha}-Linolenic Acid-Enriched Diet Prevents Myocardial Damage and Expands Longevity in Cardiomyopathic Hamsters Am. J. Pathol., December 1, 2006; 169(6): 1913 - 1924. [Abstract] [Full Text] [PDF]

				A. S. Go, W. Y. Lee, J. Yang, J. C. Lo, and J. H. Gurwitz Statin therapy and risks for death and hospitalization in chronic heart failure. JAMA, November 1, 2006; 296(17): 2105 - 2111. [Abstract] [Full Text] [PDF]

				J. Floras and A. Bagai Polyunsaturated Fatty Acids and the Post-Infarct Patient: A Recipe for Baroreflex Health? J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1607 - 1609. [Full Text] [PDF]

				A. P. Coletta, L. Tin, P. H. Loh, A. L. Clark, and J. G.F. Cleland Clinical trials update from the European Society of Cardiology heart failure meeting: TNT subgroup analysis, darbepoetin alfa, FERRIC-HF and KW-3902 Eur J Heart Fail, August 1, 2006; 8(5): 547 - 549. [Abstract] [Full Text] [PDF]

				P. van der Harst, A. A. Voors, W. H. van Gilst, M. Bohm, and D. J. van Veldhuisen Statins in the treatment of chronic heart failure: Biological and clinical considerations Cardiovasc Res, August 1, 2006; 71(3): 443 - 454. [Abstract] [Full Text] [PDF]

				P. Jhund and J. J.V. McMurray Does Aspirin Reduce the Benefit of an Angiotensin-Converting Enzyme Inhibitor?: Choosing Between the Scylla of Observational Studies and the Charybdis of Subgroup Analysis Circulation, June 6, 2006; 113(22): 2566 - 2568. [Full Text] [PDF]

				L. Tavazzi, A. P. Maggioni, D. Lucci, G. Cacciatore, G. Ansalone, F. Oliva, M. Porcu, and on behalf of the Italian survey on Acute Heart Fai Nationwide survey on acute heart failure in cardiology ward services in Italy Eur. Heart J., May 2, 2006; 27(10): 1207 - 1215. [Abstract] [Full Text] [PDF]

				J. G.F. Cleland, A. P. Coletta, N. P. Nikitin, and A. L. Clark Clinical trials update from the American College of Cardiology: Darbepoetin alfa, ASTEROID, UNIVERSE, paediatric carvedilol, UNLOAD and ICELAND Eur J Heart Fail, May 1, 2006; 8(3): 326 - 329. [Abstract] [Full Text] [PDF]

				R. de Silva, N. P. Nikitin, K. K.A. Witte, A. S. Rigby, K. Goode, S. Bhandari, A. L. Clark, and J. G.F. Cleland Incidence of renal dysfunction over 6 months in patients with chronic heart failure due to left ventricular systolic dysfunction: contributing factors and relationship to prognosis Eur. Heart J., March 1, 2006; 27(5): 569 - 581. [Abstract] [Full Text] [PDF]

				J. G.F. Cleland, N. Freemantle, A. P. Coletta, and A. L. Clark Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE Eur J Heart Fail, January 1, 2006; 8(1): 105 - 110. [Abstract] [Full Text] [PDF]

				J. Kjekshus, P. Dunselman, M. Blideskog, C. Eskilson, A. Hjalmarson, J. V. McMurray, F. Waagstein, H. Wedel, P. Wessman, J. Wikstrand, et al. A statin in the treatment of heart failure? Controlled rosuvastatin multinational study in heart failure (CORONA): Study design and baseline characteristics Eur J Heart Fail, October 1, 2005; 7(6): 1059 - 1069. [Abstract] [Full Text] [PDF]

				J. G.F. Cleland, A. P. Coletta, M. Lammiman, K. K. Witte, H. Loh, M. Nasir, and A. L. Clark Clinical trials update from the European Society of Cardiology meeting 2005: CARE-HF extension study, ESSENTIAL, CIBIS-III, S-ICD, ISSUE-2, STRIDE-2, SOFA, IMAGINE, PREAMI, SIRIUS-II and ACTIVE Eur J Heart Fail, October 1, 2005; 7(6): 1070 - 1075. [Abstract] [Full Text] [PDF]

				H. Rosolova, J. Cech, J. Simon, J. Spinar, R. Jandova, J. Widimsky sen, L. Holubec, and O. Topolcan Short to long term mortality of patients hospitalised with heart failure in the Czech Republic--a report from the EuroHeart Failure Survey Eur J Heart Fail, August 1, 2005; 7(5): 780 - 783. [Abstract] [Full Text] [PDF]

				A. Macchia, G. Levantesi, M. G. Franzosi, E. Geraci, A. P. Maggioni, R. Marfisi, G. L. Nicolosi, C. Schweiger, L. Tavazzi, G. Tognoni, et al. Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids Eur J Heart Fail, August 1, 2005; 7(5): 904 - 909. [Abstract] [Full Text] [PDF]

				J. G.F. Cleland, A. P. Coletta, N. Freemantle, P. Velavan, L. Tin, and A. L. Clark Clinical trials update from the American College of Cardiology meeting: CARE-HF and the Remission of Heart Failure, Women's Health Study, TNT, COMPASS-HF, VERITAS, CANPAP, PEECH and PREMIER Eur J Heart Fail, August 1, 2005; 7(5): 931 - 936. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Tavazzi, L. Search for Related Content PubMed PubMed Citation Articles by Tavazzi, L. Social Bookmarking          What's this?

Online ISSN 1879-0844 - Print ISSN 1388-9842

Copyright © 2010 European Society of Cardiology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics