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

www.elsevier.com/locate/heafai

The European Journal of Heart F

http://eurjhf.oxfoD

ownloaded from

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, Ake Hjalmarson d,

John V. McMurray e, Finn Waagstein d, Hans Wedel f, Peter Wessman c, John Wikstrand c,d

on behalf of the CORONA Study Group1

a Department of Cardiology, Rikshospitalet University Hospital, University of Oslo, Sognsvannsveien 20, Oslo 0027, Norwayb Department of Cardiology, Ampia Hospital, Breda, The Netherlands

c AstraZeneca R&D, Molndal, Swedend Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Goteborg, Sweden

e Department of Cardiology, Western Infirmary, Glasgow, UKf Nordic School of Public Health, Goteborg, Sweden

Received 4 June 2005; received in revised form 2 September 2005; accepted 15 September 2005

at Sana'a University on June 4, 2013

rdjournals.org/

Abstract

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.

D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Heart failure; Statins; Ischaemic heart disease; Death

1388-9842/$ - see front matter D 2005 European Society of Cardiology. Publishe

doi:10.1016/j.ejheart.2005.09.005

* Corresponding author. Tel.: +47 23073677; fax: +47 23073676.

E-mail address: [email protected] (J. Kjekshus).1 For members of the CORONA Study Group, see appendix.

1. CORONA—background and rationale

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

ailure 7 (2005) 1059 – 1069

d by Elsevier B.V. All rights reserved.

http://eurjhf.oxfordjournals.org/

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

Study Number randomized No. of deaths Yearly hazard rate (%),

deaths/pat years of follow-up

Risk

reduction

p-value

Placebo (n) Statin (n) Placebo (n) Statin (n) Placebo (n) Statin (n) %

4S (S) 2223 2221 256 182 1.8 1.3 30 0.0003

CARE (P) 2078 2081 196 180 1.9 1.7 9 0.37

LIPID (P) 4502 4512 633 498 2.3 1.8 22 <0.001

HPS (S) 10267 10269 1503 1328 2.9 2.6 12 <0.001

PROSPER (P) 2913 2891 240 219 2.6 2.4 3 0.74

ALLHAT-LLT (P)a 5185 5170 641 631 2.6 2.5 1 0.88

CORONA (R)b 2475 2475 706 613 9.4 8.0 15

Abb. S=simvastatin; P=pravastatin; R=rosuvastatin.a vs. usual care, not placebo.b Assumptions for CORONA.

J. Kjekshus et al. / The European Journal of Heart Failure 7 (2005) 1059–10691060


http://eurjhf.oxfordjournals.org/D

ownloaded from

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 pla-

cebo-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

Table 2

Ratio of number of non-fatal cardiovascular events per number of deaths (all-cause

assumed such data for CORONA

Study Non-fatal MI PTCA/CABG

Events/deaths ratio Events/deaths ratio

4S (S) 1.1 NP

CARE (P) 0.9 2.0

LIPID (P) NP 1.1

HPS (S) NP 0.8

PROSPER (P) 1.1 0.2

ALLHAT-LLT (P)a NP NP

CORONA (R)b <0.2 <0.1

Abb. S=simvastatin; P=pravastatin; R=rosuvastatin; NP=not published.a vs. usual care, not placebo.b Assumptions for CORONA.

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.

) in previous secondary prevention studies with statins (placebo group), and

Hospitalisations for

unstable angina

Hospitalisations for worsening

heart failure

Events/deaths ratio Events/deaths ratio

NP Very low (NP)

1.8 Very low (NP)

1.7 Very low (NP)

NP Very low (NP)

NP 0.51

NP Very low (NP)

<0.1 >1.3


J. Kjekshus et al. / The European Journal of Heart Failure 7 (2005) 1059–1069 1061



ownloaded from

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 inflamma-

tory 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 sup-

plemental 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 independ-

ent of their lipid lowering effect. These include inhibition

of pro-inflammatory cytokine activity, improvement of

endothelial NO production, neo-angiogenesis and regula-

tion 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 Multi-

national Study in Heart Failure (CORONA). The random-

ization 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

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.

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

CORONA is a multicentre, randomized, double-blind,

placebo-controlled study (Fig. 1). The inclusion and exclu-

sion criteria are listed in Panels 2 and 3. Briefly, patients aged

60 years or older with chronic symptomatic (NYHA func-

tional 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


Primary objective

The primary objective of CORONA is to determine whether rosuvastatin reduces the combined endpoint ofcardiovascular death or non-fatal myocardial infarction (MI) or non-fatal stroke (time to first event).

Secondary objectives

The secondary objectives are to evaluate the effects of rosuvastatin on:• Total mortality • Any coronary event defined as the combined endpoint of sudden death or fatal or non-fatal

MI or PTCA or CABG or defibrillation of ventricular fibrillation by an implantedcardioverter defibrillator (ICD) or resuscitation from a cardiac arrest or hospitalisation forunstable angina (time to first event)

• Cardiovascular mortality with cause-specific mortality for sudden death; fatal MI; and death from worsening heart failure

• Total number of hospitalisations for cardiovascular causes; for unstable angina; and forworsening heart failure

Tertiary objectives

The tertiary objectives are to evaluate the effects of rosuvastatin on: • Overall safety • Tolerability defined as overall discontinuation of study treatment• Functional state as evaluated by NYHA classification• Patient-Reported Outcomes as judged by the McMaster overall treatment evaluation

questionnaire (OTE) (in a subset of countries)• Health economics• Changes in lipids and lipoproteins• Changes in markers of inflammation• Newly diagnosed diabetes

Abbreviations: PTCA= Percutaneous Transluminal Coronary Angioplasty; CABG= Coronary Artery BypassGrafting

Panel 1. Pre-specified outcome variables in CORONA.




ownloaded from

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.

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 ‘‘opti-

mally’’ 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 Amol/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

(CrClMDRD) below 25 mL/min/1.73 m2 body surface area

(BSA) was developed (Panel 4, see supplementary data,

Appendix B) [35].


Single-blind placebo run-in

A stable condition for atleast 2 weeks prior to

randomization

Rosuvastatin

0-4 weeks

Placebo

Informed consentOptimal treatment for CHF

instituted

2-4 weeks

First post-randomization visit

Visit 5 scheduled 3 monthsafter randomization, then a

visit every 3rd month

Visit 1

Enrolment visit 1

Visit 2

Enrolment visit 2

Visit 3

Randomisation visit

Visit 4

Visit 5 to Last visit

Mean follow-up time approximately 3 years

6 weeks

Closing visit

6 weeks

• In subjects already on optimal heart failure treatment at the time of enrolment (visit 1), visit 1 and 2 may be combined into one visit.

• For hospitalised subjects, placebo run-in may be instituted at hospital discharge;however, subjects must be in a stable heart failure condition during the last twoweeks before randomisation, for further information see inclusion criterion No 6.

Assessed for Eligibility

Fig. 1. Study flow chart.




ownloaded from

3.3. Other study issues

Panel 5 gives details of treatments permitted, restricted

and prohibited in patients on blind study medication.

4. Determination of sample size

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% (b =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% (a =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.


All of the following criteria:

1. Provision of written informed consent, to be obtained before any study related procedures are performed.

2. Age >60 years at date of randomisation.

4. Chronic symptomatic systolic heart failure of ischaemic aetiology as judged by the investigator.

5. Left ventricular ejection fraction of:

• <0.40 for a subject in NYHA class III or IV or

• ≤0.35 for a subject in NYHA class II

within 6 months before enrolment visit 1; or measured between enrolment visit 1 and 2 (not measuredearlier than 3 months after an acute myocardial infarction or any invasive intervention such as PTCA orCABG).

6. Optimal therapy for chronic symptomatic systolic heart failure, as determined by the investigator.

7. A stable clinical condition over the two weeks before the randomisation visit with no change in symptomsnecessitating hospitalisation or adjustment of the heart failure medication (eg ACE inhibitor or beta-blockerdose). However, the dose of the diuretic may be varied according to the judgement of the investigator.

8. A state of health that allows future visits to an out-patient clinic according to the protocol, or visits in thesubject's home by the investigator/nurse.

Panel 2. Inclusion criteria in CORONA.




ownloaded from

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 col-

lected 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

The study was initiated by the investigators and the

scientific responsibility rests on the CORONA Study Group:

the International Steering Committee, International Execu-

tive 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 responsi-

bility 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 Coordinat-

ing 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


Any of the following criteria:

1. An acute myocardial infarction within 6 months before randomisation.

2. Treatment with any statin or other lipid lowering drug; or a medical condition that in the opinion of theinvestigator requires treatment with a statin or other lipid lowering drug. It is not allowed to stop lipidlowering treatment in order to randomise a subject.

3. History of statin induced myopathy, or serious hypersensitivity reactions to statins.

4. Unstable angina pectoris or stroke within 3 months before randomisation.

5. Any of the following concomitant conditions of clinical significance:

uncorrected, primary valvular heart disease; obstructive, hypertrophic cardiomyopathy; malfunctioning artificial heart valve; acute endo- or myocarditis or pericardial disease; systemic disease (eg uncorrected hyperthyroidism or amyloidosis)

6. The following invasive procedures:

planned PTCA, CABG or other angioplasty; planned implantation of ICD or biventricular pacemaker;or any of these or similar procedures performed within the last 3 months prior to randomisation. Asubject with any of these or similar procedures performed more than 3 months prior to randomisationmay be randomised.

previous heart transplant; or heart transplantation planned; previous cardiomyoplasty; orcardiomyoplasty planned

7. Unstable decompensated heart failure (e.g. pulmonary oedema or hypoperfusion) at enrolment orrandomisation. Subject in need of continuous or intermittent inotropic therapy (digitalis is permitted).

8. Acute or chronic liver disease or ALAT >2.0 x upper limit of normal (ULN) at enrolment visit 2.

9. Severe renal disease or serum creatinine above 220 µmol/L at enrolment visit 2.

10. Chronic muscle disease such as dermatomyositis or polymyositis or unexplained creatine kinase (CK)above 2.5 x ULN at enrolment visit 2. A subject with a value > 2.5 x ULN at enrolment visit 2, but witha value of < 2.5 x ULN if a new sample is taken may be randomised.

11. Uncontrolled hypothyroidism as indicated by a thyroid stimulating hormone (TSH) > 2 x ULN atenrolment visit 2 (this is due to the increased risk for myopathy in subjects with hypothyroidism treatedwith statins). In subjects receiving amiodarone, TSH testing is unreliable and other clinical judgementshould be used to exclude hypothyroid subjects.

12. Any other serious disease or condition which might affect life expectancy or make it difficult tosuccessfully manage and follow the subject according to the protocol, such as:

life threatening infectious disease; malignancy (NB: Subjects who have been in remission for at least 5 years with no signs of recurrence or whose malignancy has been basal or squamous cell skin carcinomamay be randomised); known or suspected alcohol or drug abuse

13. Treatment with cyclosporin.

14. If the number of tablets used during the single-blind placebo run-in treatment deviates more than 20%from the expected number of tablets or if poor compliance is suspected.

15. Participation in another clinical study during the last 30 days before enrolment into the study, oraccording to subject's local ethics committee requirements where a longer period is stipulated.

16. Previous randomisation in this study.

Panel 3. Exclusion criteria in CORONA.




ownloaded from

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


Prohibited treatments

Statins, gemfibrozil, and cyclosporin are prohibited treatments for patients on double blind study treatment.

Study medication should also be stopped if a decision is taken to start treatment with gemfibrozil or

cyclosporin.

Restricted treatments

Oral anticoagulants from the coumadin group (eg warfarin)AntacidsFibrates and niacin

Allowed treatment

Drug treatment to control concomitant diseases deemed necessary by the treating physician isacceptable, except for protocol-prohibited medications.

If an investigator identifies an absolute need for lipid lowering treatment during the study, and dietary advice has failed, it is allowed to add a lipid lowering drug, such as a resin, on top of thedouble-blind treatment.

If an investigator identifies an absolute need for statin treatment during the study and decides onprescribing open label treatment with a statin, study medication should be stopped without breakingthe code.

Panel 5. Listing of prohibited, restricted and allowed treatment for patients on blind study medicine in CORONA.


at Sana'ahttp://eurjhf.oxfordjournals.org/

Dow

nloaded from

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.

University on June 4, 2013

6. Statistical analysis plan and publications

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 respon-

sibility 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 inves-

tigators, and members of the DSMB and the Endpoint

Committee (see Appendix A).

7. Data management and the coordinating centre

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 collec-

tion and a fast turnaround time for data queries. The

Coordinating centre is located at AstraZeneca R&D, Moln-

dal, Sweden.

8. Recruitment

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

Selected baseline characteristics of all patients random-

ized (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%).

Dow

nloaded from

10. Discussion

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]. How-

ever, results from observational studies may be mislead-

ing, and results from large-scale randomized clinical

trials, rather than from observational studies, are neces-

sary to show that a treatment is better than placebo or an

alternative therapy [33]. It is interesting to note that

Table 3

Baseline characteristics in CORONA (data from COOL, not yet clean)

Variable

Mean age, years 72.6 (7.1)

Females (%) 24

NYHA class

II (%) 37

III (%) 62

IV (%) 1.4

Mean ejection fraction 0.31 (0.07)

Mean total cholesterol (mmol/L)a 5.2 (1.1)

Mean serum creatinine (umol/L)b 115 (30)

Mean systolic blood pressure (mm Hg) 130 (18)

Mean diastolic blood pressure (mm Hg) 77 (10)

Mean heart rate (beats/min) 72 (12)

Medical history

Myocardial infarction (%) 60

Hypertension (%) 63

Diabetes mellitus (%) 30

Atrial fibrillation (%) 24

Medications

Loop or thiazide diureticsc (%) 90

Aldosterone antagonists (%) 42

Any diuretic (%) 92

ACE inhibitor (%) 80

AT-I blocker (%) 13

Any ACE inhibitor or AT-I blocker (%) 91

Beta-blocker (%) 75

Digitalis glycoside (digoxin or digitoxin) (%) 32

ASA (%) 58

Anticoagulant (%) 35

ASA or anticoagulant (%) 89

For mean values, the standard deviation is given in parentheses.a To convert to mg/dL multiply by 38.3.b To convert to mg/dL multiply by 0.0113.c Including also thiazide-like diuretics.



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 atheroscler-

otic 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 CORONAwas 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.

Acknowledgement

The CORONA study is sponsored by AstraZeneca.



ownloaded from

Appendix A

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, Ake 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 (Roma-

nia), Vivencio Barrios (Spain), Michael Bohm (Germany),

John Cleland (UK), Jan Cornel (The Netherlands), Candida

Fonseca (Portugal), Assen Goudev (Bulgaria), Peer Grande

(Denmark), Lars Gullestad (Norway), Jaromir Hradec

(Czech Republic), Andras Janosi (Hungary), Gabriel

Kamensky (Slovakia), Michel Komajda (France), Jerzy

Korewicki (Poland), Timo Kuusi (Finland), Francois Mach

(Switzerland), Vyacheslav Mareev (Russia), Maria Schau-

felberger (Sweden), Johan Vanhaecke (Belgium), Dirk van

Veldhuisen (The Netherlands).

The Steering committee also includes one AstraZe-

neca monitor from each of the 21 participating countries

(non-voting): Mark Arnold (Spain), Margrethe Tvede-

gaard (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 (Bel-

gium), Lucia Szaboova (Slovakia), Nadine Schwarzmann

(Germany).

A.3. Data and safety monitoring board

Henry Dargie (chairman), David DeMets (DSMB bio-

statistician), 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

Supplementary data associated with this article can be

found, in the online version, at doi:10.1016/j.ejheart.2005.

09.005.

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:

1383–9.

[2] Shepherd J, Cobbe SM, 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:

1301–7.

[3] Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on

coronary events after myocardial infarction in patients with average

cholesterol levels. Cholesterol and Recurrent Events Trial investiga-

tors. N Engl J Med 1996;335:1001–9.

[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;339:1349–57.

[5] Downs JR, 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/Tex-

asCoronary Atherosclerosis Prevention Study. JAMA 1998;279:

1615–22.

[6] MRC/BHF Heart Protection Study Group. MRC/BHF Heart Protec-

tion Study of cholesterol lowering with simvastatin in 20,536 high-risk

individuals: a randomised placebo-controlled trial. Lancet 2002;360:

7–33.

[7] The ALLHAT Officers and Coordinators for the ALLHAT Collabo-

rative Research Group. Major outcomes in moderately hypercholes-

terolemic, 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.

[8] Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly

individuals at risk of vascular disease (PROSPER): a randomised

controlled trial. Lancet 2002;360:1623–30.

[9] Sever PS, Dahlof B, Poulter NR, 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;361:1149–58.

http://dx.doi.org/doi:10.1016/j.ejheart.2005.09.005

http://dx.doi.org/doi:10.1016/j.ejheart.2005.09.005





ownloaded from

[10] Colhoun HM, Betteridge DJ, Hitman GA, 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;364:685–96.

[11] Krum H, McMurray JJ. Statins and chronic heart failure: do we

need a large-scale outcome trial? J Am Coll Cardiol 2002;39:

1567–73.

[12] Bohm M, Hjalmarson A, Kjekshus J, Laufs U, McMurray J, van

Veldhuisen DJ. Heart failure and statins—why do we need a clinical

trial? Z Kardiol 2005;94:223–30.

[13] Weverling-Rijnsburger AWE, Blauw GJ, Lagaay AM, Knook DL,

Meinders AE, Westendorp RGJ. Total cholesterol and risk of mortality

in the oldest old. Lancet 1997;350:119–23.

[14] Richartz J, Radovancevic B, Frazier OH, et al. Low serum cholesterol

levels predict high perioperative mortality in patients supported by a

left-ventricular assist system. Cardiology 1998;89:184–8.

[15] Vredevoe DL, Woo MA, Doering LV, et al. Skin anergy in advanced

chronic heart failure secondary to either ischaemic or idiopathic

dilated cardiomyopathy. Am J Cardiol 1998;82:323–8.

[16] Horwich B, Hamilton MA, Maclellan WR, Fonarow GC. Low serum

total cholesterol is associated with marked increase in mortality in

advanced heart failure. J Card Fail 2002;8:216–24.

[17] Rauchhaus M, Clark AL, Doehner W, et al. The relationship between

cholesterol and survival in patients with chronic heart failure. J Am

Coll Cardiol 2003;42:1933–44.

[18] Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune

activation in chronic heart failure: a prospective cohort study. Lancet

1999;353:1838–42.

[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;76:125–33.

[20] Rauchhaus M, Coats AJ, Anker SD. The endotoxin– lipoprotein

hypothesis. Lancet 2000;356:930–3.

[21] Mortensen SA, 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:S137–44 [Suppl].

[22] Langsjoen PH, Langsjoen AM. The clinical use of HMGCoA-

reductase inhibitors and the associated depletion of coenzyme Q10.

A review of animal and human publications. BioFactors 2003;18:

101–11.

[23] Silver MA, Langsjoen PH, 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:

1306–10.

[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:

889–92.

[25] Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myo-

pathy with normal creatine kinase levels. Ann Intern Med 2002;137:

581–5.

[26] Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy

with statin therapy in high-risk patients. Arch Intern Med 2003;163:

553–64.

[27] Furman C, Copin C, Kandoussi M, et al. Rosuvastatin reduces MMP-7

secretion by human monocyte-derived macrophages. Atherosclerosis

2004;174:93–8.

[28] Jans DM, Keyzer W, Martinet W, Bult H, Herman AG, Meyer GR.

Effect of statins on macrophage activation after platelet phagocytosis.

Fundam Clin Pharmacol 2005;19:401.

[29] Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just

lower cholesterol. Lancet 1996;348:1079–82.

[30] Wolfrum S, Liao JK. The pleiotropic effects of statins: relevance to

their salutary effects. In: Metha JL, editor. Statins: understanding

clinical use. Saunders; 2004. p. 163–87.

[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;36:773–5.

[32] Mitchell LB, Powell JL, Gillis AM, Kehl V, Hallstrom APAVID

Investigators. Are lipid-lowering drugs also antiarrhythmic drugs? An

analysis of the antiarrhythmics versus implantable defibrillators

(AVID) trial. JACC 2003;42:88–92.

[33] Remme WJ, 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;26:1115–40.

[34] Tavazzi L, Tognoni G, Franzosi MF, 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 conges-

tive heart failure. Eur J Heart Fail 2004;6:635–41.

[35] Levey AS, Coresh J, Balk E, et al. National kidney foundation practice

guidelines for chronic kidney disease: evaluation, classification, and

stratification. Ann Intern Med 2003;139:137–47.

[36] Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyorala K. The

effects of simvastatin on the incidence of heart failure in patients with

coronary heart disease. J Card Fail 1997;3:249–54.

[37] Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin

therapy improves cardiac function and symptoms in patients with

idiopathic dilated cardiomyopathy. Circulation 2003;108:839–43.

[38] Horwich TB, MacLellan R, Fonarow GC. Statin therapy is associated

with improved survival in ischemic and non-ischemic heart failure.

J Am Coll Cardiol 2004;43:642–8.

[39] Ray GR, Gong Y, Sykora K, Tu JV. Statin use and survival outcomes

in elderly patients with heart failure. Arch Intern Med 2005;165:62–7.

[40] Uretsky BF, Thygesen K, Armstrong PW, 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;102:611–6.

[41] Ørn A, Cleland JGF, 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;118:752–8.


Documents

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