European Journal of Heart Failure

European Journal of Heart Failure 2004 6(4):493-500; doi:10.1016/j.ejheart.2003.12.016

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© 2004 European Society of Cardiology

Comparison of treatment initiation with bisoprolol vs. enalapril in chronic heart failure patients: rationale and design of CIBIS-III

Ronnie Willenheimer^a,*, Erland Erdmann^b, Ferenc Follath^c, Henry Krum^d, Piotr Ponikowski^e, Bernard Silke^f, Dirk J. van Veldhuisen^g, Louis van de Ven^h, Patricia Verkenne^h, Philippe Lechatⁱ and on behalf of the CIBIS-III investigators

^a Department of Cardiology, University Hospital S-205 02 Malmö, Sweden
^b Medizinische Klinik III, University of Cologne Germany
^c Medicine A, University Hospital Zürich Switzerland
^d Departments of Epidemiology and Preventive Medicine and Medicine, Monash University, Alfred Hospital Melbourne, Australia
^e Cardiology Department, Clinical Military Hospital Wroclaw, Poland
^f Department of Pharmacology and Therapeutics, Trinity Centre, St James’ Hospital Dublin, Ireland
^g Thoraxcenter, Department of Cardiology, University Hospital Groningen The Netherlands
^h Merck KgaA Darmstadt, Germany
ⁱ Service de Pharmacologie, Hopital Pitié-Salpetriere Paris, France

^* Corresponding author. Tel.: +46-40-33-10-00; fax: +46-40-33-62-09. E-mail address: ronnie.willenheimer{at}medforsk.mas.lu.se

	Abstract

Top Abstract 1. Introduction 2. Rationale 3. Study design and... 4. Discussion 5. Conclusion and implications Appendix A References

 
Background: Angiotensin-converting-enzyme (ACE) inhibitors and β-blockers are standard therapy for chronic heart failure (CHF). β-blockers are recommended to be initiated after ACE-inhibitors, but this order is not evidence based. The initiation order may be important since many, especially elderly CHF patients cannot tolerate target doses of both. Data suggest that β-blockers may be more important to CHF patients than ACE-inhibitors, especially in early stages of CHF.

Aims: To compare the effect on combined death or hospitalisation of initial monotherapy with either bisoprolol or enalapril, followed by combination therapy.

Methods: One-thousand CHF patients without ACE-inhibitor, β-blocker or angiotensin-receptor-blocker therapy will be randomised 1:1 to monotherapy with either enalapril or bisoprolol for 6 months, followed by combined therapy for 6–18 months. The primary objective is to show non-inferiority for bisoprolol-first vs. enalapril-first regarding combined death or hospitalisation. If that is shown, superiority for bisoprolol-first will be tested.

Conclusions: If the trial shows non-inferiority for bisoprolol-first vs. enalapril-first, the first CHF therapy may be chosen based on individual judgement in each patient. If bisoprolol-first is superior to enalapril-first, a β-blocker should be given prior to an ACE-inhibitor in CHF, and the paradigm of testing CHF compounds against a background of ACE-inhibitor therapy will be challenged.

Key Words: Chronic heart failure • Therapy • β-blocker • ACE-inhibitor • Order of initiation

Received July 25, 2003; Revised November 4, 2003; Accepted December 11, 2003

	1. Introduction

Top Abstract 1. Introduction 2. Rationale 3. Study design and... 4. Discussion 5. Conclusion and implications Appendix A References

 
The important role of neurohormones in the pathophysiology of CHF is well recognised [1]. CHF is characterised by an increased activity of neurohormonal systems, such as the sympathetic nervous system, the renin-angiotensin-aldosterone system (RAAS), and a non-osmotic release of vasopressin. These neuroendocrine changes associated with CHF are an important target for the drug treatment in CHF. Blocking the RAAS by angiotensin-converting enzyme (ACE) inhibitors has been shown to effectively prevent or delay the progression of CHF and improve the prognosis in terms of mortality and morbidity [2,3]. The addition of a β-blocker on top of an ACE inhibitor further improves survival and decreases morbidity [4–9].

	2. Rationale

Top Abstract 1. Introduction 2. Rationale 3. Study design and... 4. Discussion 5. Conclusion and implications Appendix A References

 
Guidelines for the treatment of CHF recommend that treatment be started with an ACE inhibitor and that a β-blocker be given on top of this treatment [10,11]. However, this sequence is not evidence-based but solely due to chance: ACE inhibitors simply happened to be documented with regard to mortality and morbidity in CHF before β-blockers. Although the combination of an ACE inhibitor and a β-blocker has not been examined vs. monotherapy with a β-blocker with regard to mortality/morbidity in prospective, randomised trials, combination therapy most likely is more efficacious than monotherapy with either agent. This is suggested by post-hoc, non-randomised survival analysis of the SOLVD prevention trial [12], and by the results with regard to echocardiography variables in the surrogate endpoint study CARMEN [13]. Nevertheless, the order of initiation of treatment may be very important. Patients often cannot tolerate optimum doses of both an ACE inhibitor and a β-blocker. This is especially common among the elderly patients, who constitute the majority of CHF patients. Usually, CHF therapy is not started with both an ACE inhibitor and a β-blocker simultaneously, especially not in elderly patients. The first treatment (i.e. an ACE inhibitor) stands a better chance to be up-titrated to target dose, whereas the second agent (i.e. a β-blocker) will be given in addition as tolerated. Due to patient intolerance, the second agent stands a risk of not being given at all. Inadequate routines for up-titration also adds to this problem, Indeed, β-blockers are given to substantially fewer patients compared to ACE inhibitors and, when given at all, they are often given in suboptimal doses [14–16]. Therefore, it is imperative to know which one of these therapies is most important to the patients. Today, we do not have any instruments for individualising CHF therapy with regard to the effect on survival [17]. Therefore, we must base our treatment on the mean results of large intervention studies.

On average, ACE inhibitors have been shown to decrease mortality by approximately 25% in CHF [2,3]. The mortality/morbidity trials with β-blockers in CHF performed to date included patients receiving standard therapy, i.e. diuretics and ACE inhibitors. The addition of β-blockers led to a reduction in mortality of approximately 35% as documented by recent large outcome studies [4–6] and several meta-analyses of β-blocker mortality studies [7–9]. This suggests that β-blockers may be superior to ACE inhibitors in terms of improved survival and may favour giving β-blockers priority.

It is also important to know which of the therapies is most important to receive early on in the course of CHF. The sympathetic nervous system is activated prior to the RAAS during the development of CHF [1], and plasma norepinephrine is one of the most powerful predictors of mortality in early CHF [18]. Since β-blockers probably have a more pronounced protective effect against elevations in norepinephrine than ACE inhibitors, this suggests that a β-blocker should be initiated prior to an ACE inhibitor following the diagnosis of CHF. Furthermore, in the early course of CHF, as well as in mildly symptomatic CHF, sudden death is the most prevalent mode of death [19,20]. Although the question is quite controversial, there is limited evidence that ACE inhibitors prevent sudden death in CHF patients, whereas this effect of β-blockers is well documented [2–9,21]. β-blockers have a renin-inhibiting effect and therefore inhibit the sympathetic system as well as the RAAS. Indeed, the suppression of angiotensin II by an ACE inhibitor is more effective in patients who are also treated with a β-blocker, and the escape of angiotensin II from ACE inhibition is attenuated in patients treated with a β-blocker [22,23]. There is evidence that the initiation of a β-blocker prior to an ACE inhibitor prevents renal insufficiency as a side effect of the ACE inhibitor [24,25]. All of these circumstances may favour initiating β-blockers prior to ACE inhibitors.

Thus, before recommending in which order CHF therapy should be initiated, the optimal order should be investigated. This is the objective of the CIBIS III trial: in ACE inhibitor and β-blocker naïve patients with CHF, initial monotherapy with bisoprolol followed by combination therapy with enalapril will be compared to initial monotherapy with enalapril followed by combination therapy with bisoprolol, with regard to the effect on the combined endpoint of death or hospitalisation.

	3. Study design and population

Top Abstract 1. Introduction 2. Rationale 3. Study design and... 4. Discussion 5. Conclusion and implications Appendix A References

 
3.1. Design
CIBIS-III is a prospective, randomised, non-inferiority, open, blinded endpoint evaluation (PROBE) trial [26], with two parallel groups. The trial utilises a central telephone randomisation procedure. The open design allows for separate adjustment of the doses of the respective agents in the combined phase. The protocol enables the early introduction of the second drug, if needed. The design utilises a strict randomisation procedure to allocate patients to the two treatment regimes and a blinded evaluation of the end points by an independent Endpoint committee.

The design is outlined in Fig. 1. Following randomisation, bisoprolol or enalapril will be initiated at a dose of 1.25 mg o.d. for bisoprolol and 2.5 mg b.i.d. for enalapril, and progressively up-titrated with 2-week intervals. Titration is mandatory, unless prohibited due to intolerance. However, according to the individual tolerability titration may be slower. Titration steps for bisoprolol are 1.25 mg o.d., 2.5 mg o.d., 3.75 mg o.d., 5 mg o.d., 7.5 mg o.d., followed by a maintenance dose of 10 mg o.d. Titration steps for enalapril are 2.5 mg b.i.d. and 5 mg b.i.d., followed by 10 mg b.i.d. as maintenance dose. The titration phase is followed by an observational period of 16 weeks for the bisoprolol group and 22 weeks for the enalapril group on the maintenance dose. During the monotherapy phase, initiation of adjuvant therapy with an angiotensin-receptor blocker or an aldosterone-receptor blocker is not allowed. Pre-existing aldosterone-receptor blocker therapy is, however, allowed. At the end of the monotherapy phase the combination therapy phase will begin. The complementary drug will be up-titrated in a manner similar to the monotherapy initiation of the respective drug. Thereafter the patients will be followed on maintenance doses of the combination therapy. Diuretics may be adjusted at the investigators’ discretion at any time point after randomisation. Study medication may be up- or down-titrated at any time point at the investigators’ discretion. There will be 17 visits for the last recruited patient and 21 for the first recruited patient. In total, the duration of the monotherapy phase is 6 months and the combination therapy is given for between 6 months (26 weeks, for the last recruited patient) and 1.5 years (78 weeks, for the first recruited patient). Since patients will be recruited during 1 year, the study will end when the first enrolled patient concludes the 104-week visit, i.e. 2 years in total.

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 The design of CIBIS III.

 
3.2. Inclusion criteria
Adult male or female patients with CHF, NYHA Class II–III, aged at least 65 years, are required to meet the following criteria:

• Left ventricular ejection fraction 35% or less, based on echocardiography, determined within 3 months prior to randomisation.
  
• CHF must have been stable and without fluid retention within the last 7 days prior to randomisation.
  
• If the patient has received diuretic treatment, the drug and dosage must have remained unchanged within the last 7 days prior to randomisation.
  
• The patient must give written informed consent prior to enrolment into this study.
  

3.3. Major exclusion criteria
Patients are not eligible for this study if they have been on treatment with an ACE inhibitor, an angiotensin-receptor blocker and/or a β-blocker for more than 7 days during the 3 months prior to randomisation, or fulfil one or more of the following exclusion criteria:

• Stroke within 1 month prior to randomisation or stroke with permanent neurological sequelae within 12 months prior to randomisation.
  
• Participation in another clinical study within the past 30 days.
  
• Previous participation in any CHF outcome trial.
  
• Need for concurrent treatment with a non-permitted medication.
  
• Significant disease, which in the investigator's opinion would exclude the patient from the study.
  
• Known hypersensitivity to the study treatments.
  
• Current drug or alcohol abuse.
  
• Legal incapacity or limited legal capacity.
  
• Heart rate at rest <60 beats per minute, unless a pacemaker is functioning.
  
• Supine systolic blood pressure <100 mmHg at rest.
  
• Hyponatraemia <130 mmol/l
  
• Hyperkaliemia >5.5 meq
  
• Known stenosis of both renal arteries.
  
• AV block greater than 1st degree without a functioning pacemaker.
  
• Obstructive lung disease, which in the opinion of the investigator would contraindicate bisoprolol.
  
• Hyper- or hypothyroidism not controlled by treatment.
  
• Pheochromocytoma.
  
• Significant renal impairment defined as a creatinine value 220 µmol/l.
  
• Significant hepatic impairment defined as ALAT or ASAT value >three-fold the upper normal limit.
  
• History of angioneurotic oedema.
  
• Mandatory medical indication for therapy with an ACE inhibitor or a β-blocker.
  
• Uncontrolled hypertension.
  
• Acute coronary syndrome within 3 months prior to randomisation.
  
• Planned percutaneous coronary intervention or coronary by-pass surgery.
  
• Percutaneous coronary intervention or coronary by-pass surgery performed within 3 months prior to randomisation.
  
• Obstructive or restrictive cardiomyopathy.
  
• Ongoing myocarditis.
  
• Haemodynamically significant organic valvular disease requiring surgery.
  
• Previous heart transplant or currently awaiting heart transplant surgery.
  
• Congenital heart disease.
  

3.4. Objectives
The primary objective of the study is to compare the effect on the combined endpoint of long term all-cause mortality or all-cause hospitalisation for initial therapy with bisoprolol vs. enalapril, both initiated and up-titrated as monotherapy, followed by the combined therapy of both. In a first step, non-inferiority for bisoprolol-first vs. enalapril-first will be examined. If this is shown, superiority of bisoprolol-first vs. enalapril-first will be explored in a second step.

The secondary objectives are to compare the efficacy and safety of bisoprolol and enalapril on all-cause death, all-cause hospitalisation, cardiovascular causes of death and cardiovascular causes of hospitalisation.

3.5. Primary endpoint
The primary endpoint is the combined endpoint of mortality (death from any cause) and first all-cause hospitalisation at study end. For the time to event analysis, the event, which occurs first will be used.

3.6. Secondary endpoints

• Primary endpoint at the end of the monotherapy phase.
  
• Early introduction of the second drug due to poor control of CHF.At the end of the monotherapy phase and at study end:
  
• Individual components of the primary endpoint.
  
• Cardiovascular death (sudden death, fatal myocardial infarction, worsening of CHF, other cardiovascular deaths).
  
• Cardiovascular hospitalisation (myocardial infarction, worsening of CHF, other cardiovascular hospitalisation).
  

3.7. Further variables of interest

• Number of premature treatment withdrawals.
  
• Changes in NYHA class.
  

3.8. Safety endpoints

• Incidence and type of adverse events/serious adverse events.
  
• Premature treatment withdrawals due to side effects of either study drug.
  
• Blood pressure and heart rate.
  
• Biochemistry parameters:
  • Serum creatinine at visit 1 (baseline), at visit 9 (end of monotherapy) and at study end.
    
  • Number of patients with serum creatinine>220 µmol/l (2.5 mg/dl).
    
  • Number of patients with serum creatinine increase by>45 µmol/l (0.5 mg/dl).
    
  
  

3.9. Study organisation
The study will be performed under the responsibility of an independent Steering committee (Appendix A). The sponsor is represented at the steering committee meetings by two non-voting members. A data safety monitoring board (DSMB) will continuously supervise the trial for misbalance of serious adverse events. The DSMB consists of three permanent members, two cardiologists and one statistician, who are not associated with the operative conduct of the study or with the sponsor (Appendix A). The DSMB periodically reviews the safety reports and makes relevant recommendations for the conduct of the study. The endpoint evaluation will be made by an entirely independent endpoint committee, which will review, validate and classify the endpoints under blinded conditions. The endpoint committee consists of three cardiologists, independent of the operative conduct of the study and of the sponsor (Appendix A). There is an independent clinical trial data centre: The Nottigham Clinical Research Limited (NCRL), Nottingham, UK. The study database will be maintained by NCRL, who will perform statistical analysis and also be responsible for providing regular safety reports to the DSMB. The sponsor of the study is Merck KgAa, Darmstadt, Germany. The sponsor is responsible for the site monitoring of the trial through employees or freelance monitors. The sponsor also provides a trial statistician.

The study will be performed at approximately 150 centres in 17 European countries and in Australia: Australia, Austria, Belgium, Croatia, Czech Republic, Germany, Finland, France, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovak Republic, Sweden, Switzerland and the UK.

3.10. Statistical analysis and sample size
Non-inferiority and superiority analyses will be performed. The preferred study population is for the non-inferiority analysis the per-protocol-population, and for the superiority analysis the intention-to-treat-population. The intention-to-treat-population includes all randomised patients. The per-protocol-population includes all patients who have been treated according to protocol, excluding those who:

– were not clinically stable for at least 7 days prior to randomisation;

– were treated with an ACE inhibitor, an angiotensin-receptor blocker or a β-blocker for more than 7 days during the 3 months prior to randomisation;

– showed inadequate compliance on three consecutive visits;

– illegitimately received the second agent prior to 6 months following randomisation;

– illegitimately withdrew randomised therapy prematurely.

Parametric methods will be applied for the evaluation of all continuous endpoints. The primary endpoint will be analysed by the log-rank test. Differences in time to event (in days from randomisation) of mortality, the combined endpoint of mortality and hospital admission, and of relevant serious adverse events not covered by the primary endpoint will be assessed by the log-rank test. Survival curves will be calculated using Kaplan–Meier estimates. Additionally, the proportion of patients with events will be analysed by Fisher's exact test.

Subgroup analyses will be performed with regard to:

• NYHA class II/III (prior to randomisation).
  
• Gender.
  
• Age<71 years vs. 71 years or more.
  
• Left ventricular ejection fraction <28% vs. 28% or more.
  
• Concomitant digitalis or not.
  
• Heart rate at baseline <80 vs. 80 or more beats per minute.
  
• Systolic blood pressure at baseline <140 vs. 140 mmHg or more.
  
• Serum creatinine at baseline <180 vs. 180 umol/l or more.
  

The first objective of this study is to reject the hypothesis that initiation of therapy with bisoprolol is inferior in efficacy to initiation of therapy with enalapril (first null hypothesis). We assume an event rate of 40% in the enalapril-first arm. Bisoprolol is considered as being non-inferior to enalapril regarding the primary endpoint if the entire 95% confidence interval of the bisoprolol-first group event rate is below hazard ratio 1.125 (12.5% risk increase in relative terms, equivalent to less than 5% in absolute terms) vs. that of the enalapril-first group (Fig. 2). We assume that bisoprolol-first will actually reduce the primary endpoint rate by at least 15% compared to enalapril-first, i.e. to 34%. In such case, there is a probability of at least 92% at the 2.5% significance level (one-sided, two-sample problem, binominal distribution) to show non-inferiority of bisoprolol-first vs. enalapril-first with 450 patients per study group available for the per-protocol-analysis. Since 10% of the randomised patients are expected not to fulfil the criteria for the per-protocol analysis, 1000 patients will be included into the trial. If the event rate (pooled data) is lower than expected after the inclusion of 500 patients, there is an option to increase the sample size.

View larger version (4K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Various possible outcomes of the CIBIS III trial. The horizontal lines show various 95% confidence intervals for the effect of the bisoprolol-first group on the primary endpoint vs. the enalapril-first group. The enalapril-first group result is defined as hazard ratio 1.000. The bars indicate the various point estimates. The figure clearly demonstrates that 95% confidence interval, rather than the point estimate, decides if the result is superior or non-inferior for bisoprolol-first vs. enalapril-first.

 
If non-inferiority is proven, the objective is to show superiority in a second step. Assuming that bisoprolol-first reduces the event rate of the primary endpoint by 25%, i.e. from 40% (in the enalapril-first group) to 30%, the power to show superiority in the intention-to treat population (500 patients per study group) is 90% at the 5% (two-sided test) significance level.

	4. Discussion

Top Abstract 1. Introduction 2. Rationale 3. Study design and... 4. Discussion 5. Conclusion and implications Appendix A References

 
Guidelines for the treatment of CHF recommend that treatment be started with an ACE inhibitor and that a β-blocker be given on top of this treatment [10,11]. However, this sequence is not evidence-based but solely due to the fact that ACE inhibitors happened to be documented with regard to mortality and morbidity in CHF before β-blockers. The order of initiation of treatment may be very important and the aim of CIBIS III is to investigate the optimal order. There is much to support the introduction of a β-blocker prior to an ACE inhibitor: the early activation of the sympathetic nervous system in CHF [1]; the seemingly superior effect of β-blockers on sudden death [2–9,21], especially important in early stages of CHF [19,20]; the dual inhibitory effect of β-blockers on renin and the sympathetic nervous system; and the prevention by β-blockers of renal insufficiency as a side effect of ACE inhibitors [24,25].

An important feature of CIBIS III is that elderly patients will be included. Most patients with CHF are elderly and they have usually been poorly represented in mortality/morbidity trials. Therefore, our knowledge about the best treatment for CHF in general is limited in this majority of CHF patients. Although there is limited data, it is evident that elderly CHF patients commonly do not tolerate target doses of both an ACE inhibitor and a β-blocker [27,28]. The first initiated therapy (i.e. an ACE inhibitor) stands the better chance to be given long term and in an adequate dose, as seen in clinical practice [14–16]. Thus, notwithstanding that the question about the optimum order of initiating CHF therapy has relevance for all CHF patients, it is particularly important to examine this among the elderly. Since the effect on mortality and morbidity seems more pronounced for β-blockers than for ACE inhibitors [2–9], this speaks in favour of giving β-blockers priority.

We chose an open design for several reasons. It would have been practically impossible to carry out the trial, had we masked both treatments: In a long-term trial like CIBIS III there will frequently be a need for separate adjustment of the doses of the respective agents during the combined study phase, e.g. in response to side effects. An obvious advantage with the open design is that it allows for that. Another advantage of the open design is that it resembles clinical practice and offers a practice-oriented approach that adheres to accepted clinical principles and medical practice. The design is especially relevant for β-blocker studies in CHF, where the titration schedule is depending on individual response to treatment. Allowing for individual variation must not necessarily jeopardise the result of the study. In retrospective analysis of MERIT-HF and CIBIS-II, the effect on mortality and morbidity, as compared to placebo, was the same among those who received a small dose and those who received a large dose, when the β-blocker was up-titrated according to what the patient could tolerate [29,30].

The primary endpoint chosen reflects the fact that it is equally important to decrease hospitalisation and improve survival in CHF patients. Among the elderly it may even be considered a primary target to decrease hospitalisation. In accordance with this, the guidelines of the European Society of Cardiology for the treatment of CHF, have stated that improved quality of life is an equally important treatment goal to improved survival [10]. Therefore, despite the open design and the possible bias with regard to hospitalisation, we did not consider mortality alone to be the primary endpoint. Furthermore, the central telephone randomisation procedure and the blinded evaluation of the endpoints by the independent endpoint committee limits any possible investigator bias and also allows for valid non-inferiority analysis, despite the open design.

The relatively long maintenance period on monotherapy was chosen due to the fact that patients in the trial will be elderly. In our experience, it is easier and safer to add the second agent in any patient, if the patient is allowed to stabilise on the first agent for some time. We expect this stabilisation time to be longer in elderly than in younger patients.

During the monotherapy phase, initiation of supplementary therapy with an aldosterone-receptor blocker or an angiotensin-receptor blocker is not allowed. Not only would this be non-evidence-based treatment, but it would also potentially bias the result of the CIBIS III trial.

Non-inferiority will be assessed based on the per-protocol population. Non-inferiority analysis based on the intention-to-treat population may introduce a bias; the fewer patients who actually take study medication the more likely it is that non-inferiority will be shown.

The expected event rate in CIBIS III is based on data from the ELITE II trial [31], in which 85% of the included patients were 65 years or older. These patients were not previously treated with an ACE inhibitor or an angiotensin-receptor blocker and were, thus, similar to the expected CIBIS III population also in this respect. During a median time of follow-up of approximately 1.5 years the event rate of combined mortality/hospitalisation for all causes was approximately 45%. We expect patients in CIBIS III to be on average older than in ELITE II, since we do not allow any inclusion of patients below the age of 65 years. We also expect the majority of patients to have quite recently discovered CHF, since they will not have been treated with an ACE inhibitor or a β-blocker. We also expect most patients to be included in connection with a hospitalisation for new-onset CHF. These three factors may increase the event rate compared to ELITE II. However, in CIBIS III, patients will receive combined enalapril/bisoprolol therapy for approximately 1 year median, which is likely to decrease the event rate compared to the ELITE II trial. Therefore, the event rate of combined all-cause mortality/hospitalisation is estimated to be 40% during 1.5 years of median follow-up, rather than 45%. Based on the data suggesting that a β-blocker is superior to an ACE inhibitor as first treatment for CHF, we believe that it is fair to assume that bisoprolol-first will reduce the event rate of the primary endpoint by at least 15% compared to enalapril-first. In such case, the trial has an excellent statistical power to show non-inferiority for bisoprolol vs. enalapril. It does not seem unreasonable to expect a 25% reduction of the primary endpoint in the bisoprolol-first group, in which case there is also a power of more than 90% to show superiority of bisoprolol.

	5. Conclusion and implications

Top Abstract 1. Introduction 2. Rationale 3. Study design and... 4. Discussion 5. Conclusion and implications Appendix A References

 
The order of initiating therapy for CHF may be important, not least because many patients cannot tolerate optimum doses of both an ACE inhibitor and a β-blocker. Today, it is recommended to start treatment with an ACE inhibitor, up-titrate this to target dose and then add a β-blocker. This order is not evidence based. There is much to support the theory that starting with a β-blocker rather than an ACE inhibitor is superior. The CIBIS III trial is designed to provide evidence for the best order of initiating therapy. If superiority for either treatment regimen is shown we will know if we should start CHF therapy with an ACE inhibitor or a β-blocker. If the trial shows non-inferiority for bisoprolol-first vs. enalapril-first, there is evidence supporting a free choice with regard to the first therapy, based on individual judgement in each patient. A result showing that bisoprolol-first is superior to enalapril-first will challenge the paradigm of testing compounds for the treatment of CHF against a background of ACE inhibitor therapy.

To date the CIBIS III study has randomised 500 patients. Enrollment is expected to be completed in Q2 of 2004. The last included patient will be followed-up for 1 year, and the study should be completed by Q2 2005. Presentation of the results of CIBIS III is planned in early 2006.

	Appendix A

Top Abstract 1. Introduction 2. Rationale 3. Study design and... 4. Discussion 5. Conclusion and implications Appendix A References

 
A.1. Members of the steering committee
Prof. P. Lechat, Paris, France: Chairman.

Ass. Prof. R. Willenheimer, Malmö, Sweden: Co-chairman, co-ordinating investigator.

Prof. E. Erdmann, Cologne, Germany.

Prof. F. Follath, Zürich, Switzerland.

Prof. H. Krum, Melbourne, Australia.

Dr P. Ponikowski, Wroclaw, Poland.

Dr B. Silke, Dublin, Ireland.

Prof. D.J. van Veldhuisen, Groningen, The Netherlands.

A.2. Members of the DSMB
Prof. P. Jaillon, Paris, France.

Prof. A. Leizorovicz, Lyon, France.

Dr C. Höglund, Stockholm, Sweden.

A.3. Members of the endpoint committee
Prof. C. Funck-Brentano Paris, France.

Prof. E. Vanoli, Pavia, Italy.

Dr S. Hansen, Eksjö, Sweden.

	References

Top Abstract 1. Introduction 2. Rationale 3. Study design and... 4. Discussion 5. Conclusion and implications Appendix A References

 

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