European Journal of Heart Failure

European Journal of Heart Failure 2005 7(6):1059-1069; doi:10.1016/j.ejheart.2005.09.005

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© 2005 European Society of Cardiology

A statin in the treatment of heart failure? Controlled rosuvastatin multinational study in heart failure (CORONA): Study design and baseline characteristics

John Kjekshus^a,*, Peter Dunselman^b, Malin Blideskog^c, Christina Eskilson^c, Åke Hjalmarson^d, John V. McMurray^e, Finn Waagstein^d, Hans Wedel^f, Peter Wessman^c, John Wikstrand^c,d and on behalf of the CORONA Study Group¹

^a Department of Cardiology, Rikshospitalet University Hospital, University of Oslo Sognsvannsveien 20, Oslo 0027, Norway
^b Department of Cardiology, Ampia Hospital Breda, The Netherlands
^c AstraZeneca R&D Mölndal, Sweden
^d Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital Göteborg, Sweden
^e Department of Cardiology, Western Infirmary Glasgow, UK
^f Nordic School of Public Health Göteborg, Sweden

^* Corresponding author. Tel.: +47 23073677; fax: +47 23073676. E-mail address: john.kjekshus{at}medisin.uio.no

	Abstract

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
Background: Previous prospective outcome studies of statins have not provided any guidance on benefit-risk in patients with heart failure.

Aim: The primary objective is to determine whether rosuvastatin (10 mg) reduces the combined endpoint of cardiovascular mortality, non-fatal myocardial infarction or non-fatal stroke (time to first event). The first secondary endpoint is all-cause mortality.

Methods: CORONA is a randomized, double-blind, placebo-controlled trial. Briefly, men and women, aged 60 years with chronic symptomatic systolic heart failure of ischemic aetiology and ejection fraction 0.40 (NYHA class III and IV) or 0.35 (NYHA class II) were eligible if they were not using or in need of cholesterol lowering drugs.

Results: Mean age was 73 years (n=5016; 24% women), with 37% in NYHA II and 62% in NYHA III, ejection fraction 0.31, total cholesterol 5.2 mmol/L. Sixty percent have a history of myocardial infarction, 63% hypertension, and 30% diabetes. Patients are well treated for heart failure with 90% on loop or thiazide diuretics, 42% aldosterone antagonists, 91% ACE inhibitor or AT-I blocker, 75% beta-blockers, and 32% digitalis.

Conclusion: CORONA is important for three main reasons: (1) A positive result is very important because of the high risk of the population studied, the increasing prevalence of elderly patients with chronic symptomatic systolic heart failure in our society, and the health economic issues involved. (2) If negative, new mechanistic questions about heart failure have to be raised. (3) If neutral we can avoid unnecessary polypharmacy.

Key Words: Heart failure • Statins • Ischaemic heart disease • Death

Received June 4, 2005; Revised September 2, 2005; Accepted September 15, 2005

	1. CORONA—background and rationale

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
Mortality and morbidity remain high in patients with chronic symptomatic systolic heart failure despite treatment with angiotensin converting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers (ARBs). Thus, there is a clinical need for further agents which, when added to best available treatment, will further improve prognosis. One such agent may be a statin.

A series of internationally conducted randomized placebo-controlled clinical trials, which included more than 80,000 individuals with or without verified coronary artery disease, definitely established the benefit of statins in a variety of patient groups [1–10]. The Scandinavian Simvastatin Survival Study (4S), and all subsequent studies, with the exception of the Heart Protection Study (HPS) [6], excluded symptomatic patients requiring treatment for systolic heart failure. In HPS, ejection fraction and whether heart failure was present were not recorded at baseline, but patients with severe heart failure were excluded (R. Collins, personal communication, 2002). Therefore, no study so far has provided outcome data for statins in patients with heart failure [11,12].

1.1. Differences between patients with heart failure and those randomized in prior statin trials
Patients with symptomatic systolic heart failure differ in several important aspects from those included in previous secondary prevention studies with statins. Patients with heart failure have a three- to five-fold higher annual mortality risk (see Table 1). Sudden death and death from worsening heart failure are more likely and death from myocardial infarction much less likely, as a proportion of total mortality, than in patients without heart failure. Furthermore patients with heart failure have many fewer non-fatal coronary events, as a proportion of all-cause mortality, and more hospitalisations for worsening heart failure, than patients without heart failure (Table 2). Given that the main effect of statins in previous trials was to reduce fatal and non-fatal coronary events, this action of these drugs may be less prominent in patients with heart failure. Patients with heart failure, especially if severe, may also have normal or low plasma cholesterol concentrations, further reducing the potential for statins to exert a beneficial effect. In addition, patients with heart failure are older and have more comorbidities than the patients enrolled in the earlier statin trials. PROSPER–the only statin trial focussed on the elderly–did not show a reduction in all-cause mortality [8]. Furthermore, polypharmacy is the norm in patients with heart failure, which may further complicate long-term treatment with statins. Lastly, reduced renal and hepatic function are confounding factors in these patients, which may result in as yet undefined interactions with statins.

View this table: [in this window] [in a new window]   Table 1 Number of subjects randomized, number of deaths and yearly mortality risk (deaths per patient years of follow-up), risk reduction and p-value for previous secondary prevention studies with statins, and assumed such data for CORONA

 

View this table: [in this window] [in a new window]   Table 2 Ratio of number of non-fatal cardiovascular events per number of deaths (all-cause) in previous secondary prevention studies with statins (placebo group), and assumed such data for CORONA

 
1.2. Theoretical harmful effects of statins in heart failure
Low and decreasing concentrations of LDL and total cholesterol are associated with a worse prognosis in patients with heart failure [13–17]. This association may reflect the onset of cardiac cachexia and a causal link between these two processes has been proposed. The hypothesis suggests that reduced concentrations of LDL cholesterol result in impaired neutralisation of inflammatory cytokines and endotoxins entering the circulation via the intestines, particularly in patients with advanced heart failure and oedema [18–20]. Furthermore, statins inhibit the synthesis of mevalonate and depress the production of ubiquinone (co-enzyme Q10) [21–24], an essential component of the mitochondrial respiratory chain and necessary for production of ATP. Co-enzyme Q10 may also have antioxidant and membrane stabilising properties (i.e. a reduction in co-enzyme Q10 may exacerbate oxidative stress which may play a role in the pathogenesis of heart failure). Through these effects, statins could affect mitochondrial function, cause myocardial and skeletal muscle dysfunction, and worsen heart failure generally [23,25,26]. There is some evidence that supplemental co-enzyme Q10 has beneficial effects in heart failure.

1.3. Theoretical beneficial effects of statins in heart failure
Statins reduce the incidence of fatal and non-fatal myocardial infarction and sudden death, furthermore, statins also reduce the risk of fatal and non-fatal strokes and the need for coronary revascularisation [1–10]. In addition, statins may reduce the complications of peripheral arterial disease and prevent the development of heart failure. Statins are thought to confer these clinical benefits through favourable effects on lipoproteins and the atherosclerotic process, probably by reducing both plaque burden and stabilising vulnerable plaques. The importance of this action in heart failure is uncertain because of the low risk of recognised myocardial infarction.

Statins, including rosuvastatin, have effects independent of their lipid lowering effect. These include inhibition of pro-inflammatory cytokine activity, improvement of endothelial NO production, neo-angiogenesis and regulation of AT1 receptors [27–30]. Statins have been shown to alter regulation of DNA transcription, regulate natural-killer-cell cytotoxicity, and inhibit antibody-dependent cellular cytotoxicity [29,30]. Irrespective of their exact mechanism of action, these non-lipid, "pleiotrophic" actions may also contribute to the clinical benefits of statins, but this hypothesis is not proven. Furthermore, statins may beneficially restore autonomic functions and reduce the risk for ventricular fibrillation and sudden death [31,32]. For example, in the 4S study, in post-myocardial infarction patients, simvastatin reduced total mortality by 30% (256 deaths on placebo, 182 deaths on simvastatin), with a substantial reduction in sudden death (85 vs. 46 deaths; relative risk 0.53; 95% CI 0.37–0.76; p=0.0006) (John Kjekshus, personal communication, 2002).

In summary, the benefit-risk balance of this class of agents in patients with chronic symptomatic systolic heart failure is unclear and the earlier prospective outcome studies with statins have not provided any guidance in this category of patients. Current European guidelines for patients with heart failure consequently do not include any recommendations on statins [33]. Taken together there is a need for randomized studies with statins in patients with chronic symptomatic systolic heart failure. Two such studies are now running with rosuvastatin, the GISSI Heart Failure Trial [34], and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA). The randomization phase has been completed in both trials. The hypothesis is that the beneficial effects of rosuvastatin will outweigh any theoretical hazards and, when added to current standard therapy for heart failure, lead to improved survival, reduced morbidity, and increased well-being in patients with chronic symptomatic systolic heart failure. The purpose of this paper is to describe the design, methods and some selected baseline characteristics of CORONA.

	2. Methods—pre-specified outcome variables

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
The primary objective of CORONA is to determine whether rosuvastatin, when added to other medications prescribed for patients with heart failure, reduces the risk of the combined endpoint of death from a cardiovascular cause, non-fatal myocardial infarction (MI) or non-fatal stroke, analysed as time to the first event (Panel 1). The first secondary endpoint is death from any cause. Other pre-specified outcomes are listed in Panel 1.

View larger version (27K): [in this window] [in a new window] [Download PowerPoint slide]   Panel 1 Pre-specified outcome variables in CORONA.

 
There are also a number of sub-studies including measurements of lipoproteins, BNP, hsCRP, inflammatory markers, and co-enzyme Q10, as well as one focusing on genetics.

	3. Study design

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
CORONA is a multicentre, randomized, double-blind, placebo-controlled study (Fig. 1). The inclusion and exclusion criteria are listed in Panels 2 and 3. Briefly, patients aged 60 years or older with chronic symptomatic (NYHA functional class II–IV) systolic heart failure of ischemic aetiology and with an ejection fraction of 0.40 (0.35 if NYHA class II) were eligible. Subjects already on a statin (or other lipid lowering drug) or considered by their own doctor to need (or have a contraindication to) a statin were not randomized. No upper limit of serum cholesterol was included as an exclusion criterion because survival data with statins were lacking in subjects with chronic symptomatic systolic heart failure, and because there was no consensus about what threshold would be appropriate in these subjects. Lipid lowering treatment could not be stopped to make the subject eligible for inclusion. Subjects who had been treated with a statin previously were not eligible for randomization until 6 months after withdrawal of the statin.

View larger version (15K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Study flow chart.

 

View larger version (21K): [in this window] [in a new window] [Download PowerPoint slide]   Panel 2 Inclusion criteria in CORONA.

 

View larger version (34K): [in this window] [in a new window] [Download PowerPoint slide]   Panel 3 Exclusion criteria in CORONA.

 
3.1. Enrolment, randomization and follow-up
Patients who fulfilled the enrolment criteria at visit 2 (Fig. 1) received single-blind treatment with placebo once daily for 2 to 4 weeks. Thereafter, patients who complied with the inclusion and exclusion criteria (Panels 2 and 3) were randomly allocated to rosuvastatin (10 mg) or matching placebo in a ratio of 1:1. The randomization was computer-based and centralised via an interactive web-based response (IWR) system, and based on an optimum assignment procedure (minimisation method), with a random element included. The method obtains an "optimally" balanced allocation with respect to important covariates for each new subject accrued. The variables used were: age; sex; previous acute MI; diabetes mellitus; hypertension; ejection fraction; NYHA class; beta-blocker use; and total cholesterol. Centre and study level constraints were used in order to preserve the allocation ratio. Balance with respect to important covariates was emphasised by the addition of a score containing information on age, ejection fraction, and diagnosis of diabetes mellitus, previous myocardial infarction, and NYHA class. This procedure used the information of these variables from all previously randomized subjects allocating them dynamically as they were accrued into the study, but the actual treatment allocation was not deterministic.

For follow-up visits after randomization, see Fig. 1.

3.2. Follow-up of laboratory values outside range
Since rosuvastatin is partly excreted via the kidneys, the plasma concentration of rosuvastatin may increase in patients with renal failure. Consequently, a new simple scheme for follow-up of patients with serum creatinine values above 220 µmol/L (2.5 mg/dL) or a glomerular filtration rate estimated from the abbreviated formula from the Modification of Diet in Renal Disease (MDRD) study (CrCl_MDRD) below 25 mL/min/1.73 m² body surface area (BSA) was developed (Panel 4, see supplementary data, Appendix B) [35].

3.3. Other study issues
Panel 5 gives details of treatments permitted, restricted and prohibited in patients on blind study medication.

View larger version (18K): [in this window] [in a new window] [Download PowerPoint slide]   Panel 5 Listing of prohibited, restricted and allowed treatment for patients on blind study medicine in CORONA.

 

	4. Determination of sample size

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
The sample size was estimated in order to provide the number of events (based upon the combined primary endpoint of cardiovascular death, non-fatal MI or stroke) needed to give power of at least 90% (β=0.10) to detect a significant difference between the treatment arms (for size of treatment effect, see below). The difference will be tested using a two-sided significance level of 5% (=0.05), allowing for the alpha spent in three interim analyses before the final analysis. The withdrawal rate is expected to be around 15% during the first year and 5% yearly thereafter (excluding all discontinuations occurring within 5 days of death). About half of the subjects withdrawing are expected subsequently to be prescribed active treatment with a lipid lowering drug. A mean yearly hazard rate in the placebo group of 10.4% for the combined endpoint of cardiovascular death, non-fatal MI or non-fatal stroke on an intention-to-treat basis has been assumed, with a delay of 10 months in obtaining the full risk reducing effect of active treatment. Thereafter a mean risk-reducing effect of rosuvastatin on the primary endpoint of 22% has been assumed in the intention-to-treat population (taking into account withdrawals from randomized treatment). Based on assumptions of a 16-month recruitment period and 35 months of continued follow-up (a total study time of 51 months), it was estimated that 4950 subjects needed to be randomized.

The mean follow-up time has been estimated to be 36.4 months for placebo and 37.1 months for rosuvastatin, corresponding to approximately 15,200 patient years collected for the intention-to-treat population. The total expected number of subjects with an event contributing to the combined primary endpoint has been estimated to be 1422, with 766 of these on placebo and 656 on rosuvastatin. The mean risk reducing effect over the whole study period is estimated to be 16.1% for the primary endpoint (intention to treat). The number of assumed deaths is 1319 (Table 1), 706 on placebo and 613 on rosuvastatin.

4.1. Closing rules for the study
The study is expected to be closed when the accrued number of events contributing to the combined primary endpoint agrees with estimated numbers. Alternatively, the Steering Committee may take a decision to close the study following a recommendation from the Data and Safety Monitoring Board (see below).

	5. CORONA study management

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
The study was initiated by the investigators and the scientific responsibility rests on the CORONA Study Group: the International Steering Committee, International Executive Committee, the Data and Safety Monitoring Board, and the Independent Endpoint Committee. The sponsor is providing matching placebo and active study drug, economic and scientific support, and a coordination centre (see below).

5.1. Steering committee
The International Steering Committee consists of the members in the Executive Committee, all the National Coordinating investigators and one representative from each of the participating marketing companies of the sponsor (non-voting). The Steering Committee is responsible for the study design and the scientific execution of the study.

5.2. Executive committee
The International Executive Committee consists of nine voting members, six international experts on survival studies in heart failure and three representatives of the sponsor (Study Team Leader, Study Team Physician and Study Team Biostatistician). The Executive Committee has the responsibility for the day-to-day scientific aspects of the study.

5.3. Data and safety monitoring board (DSMB)
The DSMB consists of five external members, two biostatisticians and three physicians. The Statistical and Data Analysis centre (SDAC) at the University of Wisconsin, USA provides the DSMB with all analyses decided upon, based on data received from the Coordinating centre.

The assigned SDAC biostatistician in the DSMB is the only person with access to the randomization code and who is permitted to merge the randomization code and the data on clinical events/adverse events and other study variables while the study is ongoing.

The DSMB will review and evaluate all serious adverse events and all suspected clinical events during the study. It is the responsibility of the DSMB to immediately alert the Executive Committee if data, when unblinded by the DSMB, would lead to any concern regarding drug safety.

5.3.1. Interim analyses
The formal interim analyses of the primary endpoint (time to first event) and of total mortality are scheduled when 25%, 50% and 75%, respectively, of total number of expected events has been reached. The procedures are described in the document Guideline for Interim Analyses. Fig. 2 (see supplementary data, Appendix B) illustrates theoretical information times and monitoring bounds for the combined primary endpoint of cardiovascular mortality or non-fatal MI or non-fatal stroke (time to first event), and for total mortality.

5.4. Independent endpoint committee
The Endpoint Committee consists of five members. The adjudication process is web based via a specially designed electronic endpoint handling information system (ePHiS) and governed by an Event Classification Manual. Each event will be classified by two independent persons, who will be blinded to any information relating to randomization group, dosing of blind medicine and open treatment with lipid-lowering drugs. The Independent Endpoint Committee will use all available information such as relevant eCRF pages, copies of hospital records, physician's records, discharge letters, police reports, death certificates and autopsy reports, blinded to patient ID.

5.4.1. Comments on classifying cause-specificity
All pre-defined clinical events will be classified following a pre-specified hierarchical order. Initially all deaths where a non-cardiovascular reason has not been identified will be classified as cardiovascular. Cardiovascular death will then be classified into three subgroups: cardiac, cerebrovascular and other. Cardiac death will then be classified into four groups: sudden cardiac death; death due to heart failure; death due to acute myocardial infarction; and other. Similarly a hospitalisation will be classified as being due to a cardiovascular cause if a non-cardiovascular cause has not been identified. In all cases, one single cause of death or cause for hospitalisation, respectively, will be stated.

	6. Statistical analysis plan and publications

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
SDAC and the sponsor will independently perform key analyses of the study according to a predefined Statistical Analysis Plan. Any discrepancies should be resolved before submission of any manuscript for publication.

The Executive Committee will serve as a Publication Committee for CORONA. The main paper will clearly state that results presented in the paper are based on analyses performed by SDAC independently of the sponsor. The Executive Committee assumes the responsibility for all publication matters in close collaboration with the Steering Committee. Papers will be published on behalf of the CORONA Study Group, which includes members of the Steering Committee, all Principal investigators, and members of the DSMB and the Endpoint Committee (see Appendix A).

	7. Data management and the coordinating centre

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
Data entry is made at each local study centre by authorised personnel into the eCRF in the web-based data capture system, COOL (Clinical Operations On-line). COOL is a web-based data capture (WBDC) system developed by AstraZeneca. A WBDC system enables all of the involved parties in the clinical study to access the study data through the Internet as soon as it has been entered into the eCRF by the authorised centre personnel. This enables faster data collection and a fast turnaround time for data queries. The Coordinating centre is located at AstraZeneca R&D, Mölndal, Sweden.

	8. Recruitment

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
The study is ongoing at 378 centres in 21 countries (see Appendix A). Recruitment was based on a web-based screening system in 20 of the 21 participating countries. Nine thousand and fourteen patients were pre-screened and 5759 patients were enrolled for visit 1 between 1 September 2003 and 25 February 2005, and 5016 were randomized (the last patient was randomized on 21 April 2005).

	9. Baseline characteristics

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
Selected baseline characteristics of all patients randomized (n=5016) are presented in Table 3. Compared to those screened, randomized patients were 1.7 years younger (72.6 vs. 74.3 years), included a lower proportion of women (23.6 vs. 30.2%) and more patients in NYHA class II (37% vs. 29%). Both groups had a similar mean ejection fraction (0.31 vs. 0.32), mean total cholesterol (5.2 mmol/L or 199 mg/dL in both groups), and proportion with a history of MI (60% vs. 61%).

View this table: [in this window] [in a new window]   Table 3 Baseline characteristics in CORONA (data from COOL, not yet clean)

 

	10. Discussion

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
An abundance of clinical evidence supports the use of statin treatment in patients with atherosclerotic vascular disease. However, as summarised above, the effect of statins on clinical outcomes in patients with systolic heart failure has not been tested previously in an adequately designed and powered prospective trial. Results from some observational, non-randomized studies with statins have suggested improved survival in patients with both ischemic and non-ischemic heart failure [36–39]. However, results from observational studies may be misleading, and results from large-scale randomized clinical trials, rather than from observational studies, are necessary to show that a treatment is better than placebo or an alternative therapy [33]. It is interesting to note that outcome in the observational studies was independent of cholesterol level, and other observational studies have reported that low cholesterol levels are associated with a poor prognosis in heart failure patients and in the elderly [13–17]. Heart failure patients are in general different from non-heart failure patients in that they are older and at higher risk.

Furthermore mode of death is different, in that more patients are dying from progressive heart failure. The most obvious beneficial effect of a statin is a reduction in acute coronary events. It is believed that these may underlie many of the deaths that occur so commonly in patients with heart failure, though they may not be recognised as acute coronary events. The best evidence for this comes from the ATLAS and the OPTIMAAL autopsy studies in heart failure patients, in which recognised myocardial infarcts were rare [40,41]. Autopsy showed that unrecognised coronary events were common (i.e. coronary thrombus, a ruptured atherosclerotic plaque or myocardial infarction) especially in patients dying suddenly, but also in those dying from progressive pump failure. Patients with signs and symptoms of heart failure have a high risk of death, re-hospitalisation and disability, so that even small relative risk reductions will lead to large absolute risk reductions, which have the potential to translate into important personal, societal and health economic benefits. The lipid hypothesis therefore needs to be properly tested in patients with coronary disease and with chronic symptomatic systolic heart failure.

Despite the constraints of the inclusion and exclusion criteria and the widespread use of lipid lowering therapy, enrolment of patients in CORONA was very successful. The age, gender, NYHA functional class, previous history, lipoprotein profile and concurrent treatment of these patients are very much in accord with other cohorts of patients with heart failure (Table 3) [33].

There are now two randomized trials evaluating the risk-benefit of statins in heart failure. The two trials differ in several respects. In GISSI-HF patients have first been randomized to receive omega III fatty acids or placebo (n=7057) [34]. Of these, 4642 were eligible to be randomized to the rosuvastatin/placebo arm of the study regardless of aetiology of heart failure or ejection fraction. In contrast CORONA includes only patients with systolic heart failure, and of ischaemic aetiology. Hopefully the two trials will shed light on the important question: Should a statin be used to treat heart failure? From an ethical standpoint this is a very important question for three main reasons: (1) a positive result is very important because of the high risk of the population studied, the increasing prevalence of elderly patients with chronic symptomatic systolic heart failure in our society, and the health economic issues involved. (2) If negative, new mechanistic questions about heart failure have to be raised. (3) If neutral we can avoid unnecessary polypharmacy.

The hypothesis is that the beneficial effects of rosuvastatin will outweigh any theoretical hazards and, when added to current standard therapy for heart failure, lead to improved survival, reduced morbidity, and increased well-being.

	Appendix A

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
Members of the CORONA Study Group. A list of all Investigators can be found in the online version of this paper at doi:10.1016/j.ejheart.2005.09.005.

A.1. Executive committee
Malin Blideskog (Study team leader, replaced Christina Eskilson 1 April 2005), Peter Dunselman, Åke Hjalmarson (chairman of the Executive Committee), John Kjekshus (chairman of the Steering Committee), John McMurray, Finn Waagstein, Hans Wedel (Independent biostatistician), Peter Wessman (Study team biostatistician), John Wikstrand (Study team physician).

A.2. Steering committee
Executive committee members and the following National coordinating investigators: Eduard Apetrei (Romania), Vivencio Barrios (Spain), Michael Böhm (Germany), John Cleland (UK), Jan Cornel (The Netherlands), Candida Fonseca (Portugal), Assen Goudev (Bulgaria), Peer Grande (Denmark), Lars Gullestad (Norway), Jaromir Hradec (Czech Republic), András Jánosi (Hungary), Gabriel Kamensk (Slovakia), Michel Komajda (France), Jerzy Korewicki (Poland), Timo Kuusi (Finland), François Mach (Switzerland), Vyacheslav Mareev (Russia), Maria Schaufelberger (Sweden), Johan Vanhaecke (Belgium), Dirk van Veldhuisen (The Netherlands).

The Steering committee also includes one AstraZeneca monitor from each of the 21 participating countries (non-voting): Mark Arnold (Spain), Margrethe Tvedegaard (Denmark), Lubica Cernakova (Czech Republic), Anne Compagnon (France), Ruth Coy (UK), Beatrice Costea (Romania), Stephanie Detert (South Africa), Judit Farkas (Hungary), Georgi Georgiev (Bulgaria), Juha Halme (Finland), Arild Hildebrandt (Norway), Pernilla Isberg (Sweden), Melanie LaVita (Portugal), Katrin Leichner (Switzerland), Katarzyna Milczarek (Poland), Larisa Plekhova (Russia), Edel Shaw (Ireland), Arlette Sijbers (The Netherlands), Philippe Spinewine (Belgium), Lucia Szaboova (Slovakia), Nadine Schwarzmann (Germany).

A.3. Data and safety monitoring board
Henry Dargie (chairman), David DeMets (DSMB biostatistician), Rory Collins, Jan Feyzi (SDAC biostatistician), Barry Massie.

A.4. Independent endpoint committee
Bengt-Olov Fredlund, Mikael Holmberg, Katarina Saldeen, Ola Samuelsson (secretary), Karl Swedberg (chairman).

	Appendix B. Supplementary data

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ejheart.2005.09.005.

	Acknowledgement

 
The CORONA study is sponsored by AstraZeneca.

	Notes

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 
¹ For members of the CORONA Study Group, see appendix.

	References

Top Notes Abstract 1. CORONA--background and... 2. Methods--pre-specified... 3. Study design 4. Determination of sample... 5. CORONA study management 6. Statistical analysis plan... 7. Data management and... 8. Recruitment 9. Baseline characteristics 10. Discussion Appendix A Appendix B. Supplementary data References

 

1. 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]
2. Shepherd J., Cobbe S.M., Ford I., et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med (1995) 333:1301–1307.[Abstract/Free Full Text]
3. 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. Cholesterol and Recurrent Events Trial investigators. N Engl J Med (1996) 335:1001–1009.[Abstract/Free Full Text]
4. The Long-Term Intervention with Pravastatin in Ischaemic Disease (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]
5. Downs J.R., Clearfield M., Weis S., et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA (1998) 279:1615–1622.[Abstract/Free Full Text]
6. MRC/BHF Heart Protection Study Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet (2002) 360:7–33.[CrossRef][Web of Science][Medline]
7. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs. usual care, the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT). JAMA (2002) 288:2998–3007.[Abstract/Free Full Text]
8. Shepherd J., Blauw G.J., Murphy M.B., et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet (2002) 360:1623–1630.[CrossRef][Web of Science][Medline]
9. Sever P.S., Dahlöf B., Poulter N.R., et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have an average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet (2003) 361:1149–1158.[CrossRef][Web of Science][Medline]
10. Colhoun H.M., Betteridge D.J., Hitman G.A., et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet (2004) 364:685–696.[CrossRef][Web of Science][Medline]
11. Krum H., McMurray J.J. Statins and chronic heart failure: do we need a large-scale outcome trial? J Am Coll Cardiol (2002) 39:1567–1573.[Abstract/Free Full Text]
12. Böhm M., Hjalmarson A., Kjekshus J., Laufs U., McMurray J., van Veldhuisen D.J. Heart failure and statins—why do we need a clinical trial? Z Kardiol (2005) 94:223–230.[CrossRef][Web of Science][Medline]
13. Weverling-Rijnsburger A.W.E., Blauw G.J., Lagaay A.M., Knook D.L., Meinders A.E., Westendorp R.G.J. Total cholesterol and risk of mortality in the oldest old. Lancet (1997) 350:119–123.
14. Richartz J., Radovancevic B., Frazier O.H., et al. Low serum cholesterol levels predict high perioperative mortality in patients supported by a left-ventricular assist system. Cardiology (1998) 89:184–188.[CrossRef][Web of Science][Medline]
15. Vredevoe D.L., Woo M.A., Doering L.V., et al. Skin anergy in advanced chronic heart failure secondary to either ischaemic or idiopathic dilated cardiomyopathy. Am J Cardiol (1998) 82:323–328.[CrossRef][Web of Science][Medline]
16. Horwich B., Hamilton M.A., Maclellan W.R., Fonarow 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]
17. Rauchhaus M., Clark A.L., Doehner W., et al. The relationship between cholesterol and survival in patients with chronic heart failure. J Am Coll Cardiol (2003) 42:1933–1944.[Abstract/Free Full Text]
18. Niebauer J., Volk H.D., Kemp M., et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet (1999) 353:1838–1842.[CrossRef][Web of Science][Medline]
19. Rauchhaus M., Koloczek V., Volk H., et al. Inflammatory cytokines and the possible immunological role for lipoproteins in chronic heart failure. Int J Cardiol (2000) 76:125–133.[CrossRef][Web of Science][Medline]
20. Rauchhaus M., Coats A.J., Anker S.D. The endotoxin–lipoprotein hypothesis. Lancet (2000) 356:930–933.[CrossRef][Web of Science][Medline]
21. Mortensen S.A., Leth A., Agner E., Rohde M. Dose-related decrease of serum co-enzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med (1997) 18:S137–S144. [Suppl].[CrossRef][Web of Science][Medline]
22. Langsjoen P.H., Langsjoen A.M. The clinical use of HMGCoA-reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications. BioFactors (2003) 18:101–111.[Web of Science][Medline]
23. Silver M.A., Langsjoen P.H., Szabo S., Patil H., Zelinger A. Effect of atorvastatin on left ventricular diastolic function and ability of coenzyme Q10 to reverse that dysfunction. Am J Cardiol (2004) 94:1306–1310.[CrossRef][Web of Science][Medline]
24. Rundek T., Naini A., Sacco R., Coates K., DiMauro S. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol (2004) 61:889–892.[Abstract/Free Full Text]
25. Phillips P.S., Haas R.H., Bannykh S., et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med (2002) 137:581–585.[Abstract/Free Full Text]
26. Ballantyne C.M., Corsini A., Davidson M.H., et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med (2003) 163:553–564.[Abstract/Free Full Text]
27. Furman C., Copin C., Kandoussi M., et al. Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages. Atherosclerosis (2004) 174:93–98.[CrossRef][Web of Science][Medline]
28. Jans D.M., Keyzer W., Martinet W., Bult H., Herman A.G., Meyer G.R. Effect of statins on macrophage activation after platelet phagocytosis. Fundam Clin Pharmacol (2005) 19:401.[Web of Science]
29. 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]
30. Wolfrum S., Liao J.K. The pleiotropic effects of statins: relevance to their salutary effects. In: Statins: understanding clinical use—Metha J.L., ed. (2004) Saunders. 163–187.
31. De Sutter J., Tavernier R., De Buyzere M., Jordaens L., De Backer G. Lipid lowering drugs and recurrences of life-threatening ventricular arrhythmias in high-risk patients. JACC (2000) 36:773–775.[Free Full Text]
32. Mitchell L.B., Powell J.L., Gillis A.M., Kehl V., Hallstrom A.P. AVID Investigators. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the antiarrhythmics versus implantable defibrillators (AVID) trial. JACC (2003) 42:88–92.[Free Full Text]
33. Remme W.J., Swedberg K. The 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 (2005) 26:1115–1140.[Free Full Text]
34. Tavazzi L., Tognoni G., Franzosi M.F., et al. 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. Eur J Heart Fail (2004) 6:635–641.[Abstract/Free Full Text]
35. Levey A.S., Coresh J., Balk E., et al. National kidney foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med (2003) 139:137–147.[Abstract/Free Full Text]
36. Kjekshus J., Pedersen T.R., Olsson A.G., Faergeman O., Pyorala K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail (1997) 3:249–254.[CrossRef][Medline]
37. Node K., Fujita M., Kitakaze M., Hori M., Liao J.K. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation (2003) 108:839–843.[Abstract/Free Full Text]
38. Horwich T.B., MacLellan R., Fonarow G.C. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol (2004) 43:642–648.[Abstract/Free Full Text]
39. Ray G.R., Gong Y., Sykora K., Tu J.V. Statin use and survival outcomes in elderly patients with heart failure. Arch Intern Med (2005) 165:62–67.[Abstract/Free Full Text]
40. Uretsky B.F., Thygesen K., Armstrong P.W., et al. Acute coronary findings at autopsy in heart failure patients with sudden death. Results from the assessment of treatment with lisinopril and survival (ATLAS) trial. Circulation (2000) 102:611–616.[Abstract/Free Full Text]
41. Ørn A., Cleland J.G.F., Romo M., Kjekshus J., Dickstein K. Recurrent infarction is the most common cause of death in patients with left ventricular dysfunction following myocardial infarction. Am J Med (2005) 118:752–758.[CrossRef][Web of Science][Medline]

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