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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Rationale and design of CIBIS III

Piotr Ponikowski*

Cardiology Department, Centre for Heart Disease, Clinical Military Hospital, Weigla 5, 50-891 Wroclaw, Poland

* Corresponding author. Tel: +48 71 7660237; fax: +48 71 7660228. E-mail address: piotrponikowski{at}4wsk.pl


   Abstract
Top
 Abstract
Introduction
 Arguments supporting a beta...
 Preliminary evidence that a...
 CIBIS III: study design
 References
 
Although European guidelines indicate that treatment for chronic heart failure (CHF) should be started with an angiotensin-converting enzyme (ACE) inhibitor, followed by a beta-blocker, this order is not evidence-based. The order of initiation may be important because patients often cannot tolerate optimum doses of both an ACE-inhibitor and a beta-blocker. The first-prescribed agent is likely to be titrated to a higher dose, and the second agent may not be prescribed at all. There are arguments for starting a beta-blocker first, as the sympathetic nervous system is activated earlier in CHF than the renin–angiotensin–aldosterone system. Beta-blockers have a more pronounced effect on early left ventricular (LV) remodelling than ACE-inhibitors. Moreover, sudden cardiac death (the most prevalent mode of death in early and mild CHF) is markedly reduced by beta-blockers but not by ACE-inhibitors. The third Cardiac Insufficiency Bisoprolol Study was designed to determine whether a beta-blocker could be safely and effectively initiated first in CHF. It was a controlled open-label non-inferiority trial, including 1010 patients aged ≥65 years, in stable New York Heart Association class II or III, and with LV ejection fraction ≤35%. Patients received 6 months of monotherapy with either bisoprolol (target dose 10 mg od, n=505) or enalapril (target dose 10 mg bid, n=505), followed by their combination for 6–24 months. The combined primary endpoint was all-cause mortality or hospitalization.

Key Words: Beta-blockers • Chronic heart failure


   Introduction
Top
 Abstract
 Introduction
Arguments supporting a beta...
 Preliminary evidence that a...
 CIBIS III: study design
 References
 
The recently published European Society of Cardiology (ESC) guidelines1 recommend that unless contraindicated, beta-blockers should be considered for all patients with stable mild, moderate, or severe chronic heart failure (CHF) in New York Heart Association (NYHA) classes II–IV, with reduced left ventricular (LV) ejection fraction (EF), who are on standard treatment with angiotensin-converting enzyme (ACE) inhibitors and diuretics. In addition, they state that beta-blockers should be used in patients with LV systolic dysfunction, following an acute myocardial infarction, regardless of whether symptomatic CHF is present, in addition to ACE-inhibitors. Similarly, the American College of Cardiology/American Heart Association guidelines2 also recommend beta-blockers for all stable patients with current or prior symptoms of CHF and reduced LVEF.

Although both the European and US guidelines1,2 state that beta-blockers should be initiated in patients already receiving ACE inhibitors, this order of initiation is not evidence-based. On the contrary, it is determined only by the protocols used in previous clinical trials. The major mortality and morbidity trials with ACE-inhibitors3–7 preceded those with beta-blockers. Thus, in all the major beta-blocker trials [the Cardiac Insufficiency Bisoprolol Study II (CIBIS II),8,9 the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF),10 and the Carvedilol Prospective Randomized Cumulative Survival Trial],11 the beta-blocker was given on top of an ACE-inhibitor. There is no evidence that this order is superior to the alternative order (i.e. a beta-blocker given before an ACE-inhibitor).

Guidelines issued by national and international medical societies play a critical role in shaping evidence-based practice. Unpublished data from the Study of Heart Failure Awareness and Perception in Europe show that approximately one-third of cardiologists and general practitioners consider that their practice to be primarily influenced by guidelines, and a further one-third by expert opinion. The Medical Management of Chronic Heart Failure in Europe (MAHLER) study recently showed that adherence of physicians to treatment guidelines is a strong predictor of fewer cardiovascular hospitalizations in real-life clinical practice.12 Yet, guidelines committees sometimes have to make recommendations on the basis of inadequate evidence. It is important to challenge the guidelines and fill in gaps in the evidence, especially with regard to issues of everyday clinical relevance.

The third Cardiac Insufficiency Bisoprolol Study (CIBIS III)13,14 challenged commonly accepted practice by investigating whether a beta-blocker-first strategy was non-inferior to an ACE-inhibitor-first strategy in the initiation of CHF treatment in patients in NYHA classes II and III. Although the combination of an ACE-inhibitor and a beta-blocker is most likely to be more effective than monotherapy with either agent, the order of initiation of treatment is important in clinical practice. CHF patients often cannot tolerate optimum doses of both an ACE-inhibitor and a beta-blocker. This is particularly common among the elderly, who constitute the majority of CHF patients. In everyday clinical practice, once a CHF patient is already stabilized on ACE-inhibitor (usually together with a diuretic), a physician may be concerned whether a beta-blocker (which may exert some side effects) should be added at all. Moreover, dosing considerations are relevant, as it may be predicted that the first treatment (i.e. the ACE-inhibitor) has a better chance of being up-titrated to the target dose.15,16 The second agent (i.e. the beta-blocker) will be given in addition as tolerated. It is therefore more likely to be given at lower, inadequate doses, or may be given initially but then withdrawn if clinical deterioration occurs. Evidence from CIBIS II shows that the withdrawal of the beta-blocker in patients receiving combination treatment increases the risk of mortality.17

In real clinical practice, ACE-inhibitor monotherapy and underdosing of beta-blockers are both common. The EURO-HF,15 IMPROVEMENT,16 and MAHLER12 studies show that, at present, fewer CHF patients receive beta-blockers than ACE-inhibitors. Furthermore, when given, beta-blockers are often prescribed at suboptimal doses. Thus, to ensure that patients receive the greatest possible benefit from treatment, it is important to know which therapy should be started first. There are a number of putative arguments for initiating treatment of CHF with a beta-blocker, which are explored subsequently in detail.


   Arguments supporting a beta-blocker-first strategy in CHF
Top
 Abstract
 Introduction
 Arguments supporting a beta...
Preliminary evidence that a...
 CIBIS III: study design
 References
 
Early activation of the sympathetic nervous system in CHF
In the natural course of CHF, the sympathetic nervous system (SNS) is activated early and prior to the renin–angiotensin–aldosterone system (RAAS) (Figure 1).18,19 Sympathetic activation is already present in patients with mild CHF20 and precedes the development of symptoms in those with asymptomatic LV dysfunction.21 Moreover, plasma norepinephrine (a neurohumoral transmitter in the SNS) is one of the most powerful predictors of mortality in early CHF.18,22,23 As beta-blockers have a more pronounced protective effect against elevations in norepinephrine than ACE-inhibitors, this suggests that a beta-blocker should be initiated prior to an ACE-inhibitor, following the diagnosis of CHF or LV dysfunction.


Figure 0121
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  		Figure 1 Sequential activation of the SNS and RAAS in CHF. ANF, atrial natriuretic factor. Figure reproduced with permission from Anker.19

 
Dual inhibitory effect of beta-blockers
Beta-blockers inhibit the activation of the SNS, and by blocking beta1-receptors in the juxtaglomerular cells of the kidneys, they reduce renin release and also block the RAAS. In contrast, ACE-inhibitors predominantly affect the RAAS and have only a slight effect on the SNS [diminished enhancement of sympathetic activity due to decreased angiotensin II (AT II) levels]. Complete suppression of these two overactive neurohormonal systems exerting unfavourable biological effects in CHF is desirable and may be achieved more effectively with beta-blockade. In one study, 50% of patients with CHF had raised plasma AT II concentrations, despite chronic ACE-inhibitor therapy. These patients were more likely to die or suffer exacerbations of heart failure.24 The suppression of AT II by an ACE-inhibitor is more effective in patients who are treated with a beta-blocker, and the escape of AT II from ACE inhibition is attenuated in patients treated with a beta-blocker.25,26 Thus, giving ACE-inhibitors against a background of beta-blockade may lead to more complete suppression of AT II.

Protective effect of beta-blockers against sudden cardiac death
Sudden cardiac death (SCD) is the most prevalent mode of death in early and mildly symptomatic CHF.10,27,28 The protective effect of beta-blockers against SCD in CHF is well established.8,10,11,28–33 For example, when compared with standard treatment with ACE-inhibitors and diuretics, the addition of a beta-blocker reduced sudden death by 44% in CIBIS II,8 by 41% in MERIT-HF,10 and by 54% in the US Carvedilol Program.34 The overall risk reduction based on six large heart failure trials has been estimated at 38%.35

Various studies in post-MI patients have also shown that beta-blockers reduce the risk of sudden death by 28–47% (compared with 3–26% for ACE-inhibitors). A meta-analysis of 31 secondary prevention trials of beta-blockade found that beta-blockers reduced the risk of re-infarction (a potential cause of increased risk of SCD) by 28%.36 In contrast to beta-blockers, ACE-inhibitors appear to protect mainly against death due to pump failure.33,37 Thus, it may be wise to initiate a beta-blocker early in CHF to guard against the risk of SCD.

Renoprotective effect of beta-blockade in CHF
Protection of renal function is an often-overlooked aim of therapy in CHF. In theory, therapies that improve renal function may have additional benefits in reducing progression of CHF and vice versa. Impaired renal function is an independent risk factor for poor outcome in CHF, and the risk of death rises with increasing serum creatinine.38,39 The risk of developing CHF is nearly doubled in subjects with serum creatinine ≥1.7 mg/dL, compared with those with serum creatinine <1.1 mg/dL.40 Between 20 and 50% of patients in CHF trials have been reported to have mild-to-moderate renal insufficiency.

It is therefore important to monitor and manage renal function in CHF. Therapies targeting the RAAS [ACE-inhibitors and angiotensin receptor blockers (ARBs)] are beneficial in combating renal insufficiency in many patients with CHF. However, in 10–20% of CHF patients, particularly elderly individuals and those with severe CHF, the maintenance of already compromised renal function is critically dependent on AT II. In such cases, therapy with ACE-inhibitors or ARBs may significantly worsen renal function with potentially serious clinical consequences.41 Additionally, among patients with severe CHF, there is a group who develop intolerance to ACE-inhibitors because of renal limitations (progressive renal dysfunction and hyperkalaemia).42 They have an extremely poor prognosis and beta-blockers seem to be the only available life-saving therapy.

Data from the Studies on Left Ventricular Dysfunction (SOLVD) trial show that enalapril increased the risk of deteriorating renal function in patients with CHF by 33%.43 Diuretic use, diabetes, and advanced age exacerbated this effect. Beta-blocker therapy and higher EF were renoprotective in all patients regardless of other therapies.43 Thus, there is an argument for instituting beta-blockade early to protect the kidney. It might be argued that in some patients with advanced CHF, beta-blockade should be used in the absence of ACE inhibition to avoid further deterioration in renal function. It is well established that beta-blockers can be used safely in CHF patients with renal impairment; subgroup analysis of CIBIS II showed that the beta-blocker bisoprolol reduced mortality regardless of patients' creatinine clearance.9

Early and substantial mortality benefit of beta-blockers
ACE-inhibitors have been shown to reduce mortality in CHF by 20–25%.37 However, the addition of a beta-blocker leads to a further reduction of ~35% and this effect is seen relatively early after the introduction of beta-blocker therapy.8,10,11,29–32 This suggests that beta-blockers are at least as effective as ACE-inhibitors in improving survival, which would support the argument that they could reasonably be given priority in the initiation of treatment.44 It should also be remembered that the first favourable clinical effects of beta-blockers in CHF were demonstrated in patients not treated with ACE-inhibitors.45,46

Beneficial peripheral effects of beta-blockers
It is becoming increasingly apparent that peripheral changes in CHF, including abnormalities in the skeletal musculature, augmented ventilation, impaired cardiorespiratory reflex regulation, or abnormal immune function, can also be partially corrected by beta-blockers.47 Ventilatory inefficiency in CHF is related to exercise intolerance and high mortality,47 and therapy with beta-blockers may decrease augmented ventilatory response to exercise.48 Weight loss constitutes an ominous sign in CHF49 and strategies to prevent it are desirable. Analysis of CIBIS II data reveals that bisoprolol increases body weight and reduces the incidence of new undesirable weight loss (cardiac cachexia) in patients with moderate-severe CHF.50 Immunomodulatory properties of carvedilol have been shown in experimental studies,51 and in humans, carvedilol therapy reduces levels of circulating pro-inflammatory cytokines.52

Reverse remodelling with beta-blockade
There is evidence from the recent Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure Evaluation (CARMEN)53 that beta-blockade may be more effective than ACE inhibition in reversing LV remodelling in patients with mild-to-moderate CHF. CARMEN was a double-blind, parallel-group, three-arm, 18-month study in which 572 patients with mild CHF were randomly assigned to carvedilol, enalapril, or their combination. Importantly, in the combination group, carvedilol was up-titrated before enalapril. LV remodelling was assessed by transthoracic echocardiography at baseline and after 6, 12, and 18 months of maintenance therapy.

The main outcome measure, LV end-systolic volume index (LVESVI), was reduced significantly more by combination therapy than by enalapril (Figure 2). Patients receiving carvedilol as monotherapy or in combination with enalapril showed a reversal of LV remodelling, an effect not observed with enalapril monotherapy. According to the investigators, ‘the results of the CARMEN study support a therapeutic strategy in which the institution of beta-blockade should not be delayed.’53


Figure 0122
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  		Figure 2 Effect of carvedilol, enalapril, and the combination on LVESVI, in the CARMEN study. The study suggests that LV remodelling is reduced significantly more by combination therapy with carvedilol plus enalapril than by enalapril monotherapy. Mean change from baseline in LVESVI. *P-values for within-group comparison. Adapted with permission from Remme et al. with kind permission from Springer Science and Business Media.53

 
Reverse remodelling with carvedilol has also been reported in an echocardiographic substudy of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial.54 The CAPRICORN55 study showed that carvedilol improved outcome in patients with LV dysfunction and in patients with acute MI treated with ACE-inhibitors. The substudy aimed at determining the effects of carvedilol on LV remodelling and included 127 patients. In this subgroup, quantitative 2D echocardiography was performed before randomization and after 1, 3, and 6 months of treatment with carvedilol or placebo. At 6 months, LVESV was significantly lower in the carvedilol plus ACE-inhibitor group than in the placebo plus ACE-inhibitor group, and LVEF was significantly higher (Figure 3). Thus, reverse remodelling may contribute to the beneficial effect of beta-blockade on LV function in post-MI patients.


Figure 0123
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  		Figure 3 Changes in LVESV and LVEF in post-MI patients receiving carvedilol or placebo against a background of ACE inhibition in the CAPRICORN study. Data are presented as mean±SE. P-values comparing carvedilol and placebo are MANOVA over 6 months of treatment. Adapted with permission from Doughty et al. Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy. Circulation 2004;109:201–206.

 
Reverse remodelling has also been demonstrated with bisoprolol in a study including 201 CHF patients receiving ACE-inhibitors.56 Bisoprolol therapy resulted in an increase in LVEF of nearly 30%, with a significant decrease in end-diastolic and end-systolic left ventricle diameters and volumes.


   Preliminary evidence that a beta-blocker-first strategy can be effective
Top
 Abstract
 Introduction
 Arguments supporting a beta...
 Preliminary evidence that a...
CIBIS III: study design
 References
 
Although CIBIS III was the first large randomized study to compare initiation of treatment with a beta-blocker or an ACE-inhibitor by measuring ‘hard’ endpoints, its publication shortly followed that of a South African study using surrogate endpoints.57 This prospective, randomized, open-label study by Sliwa et al. showed that a beta-blocker-first strategy improved NYHA class and LVEF more than an ACE-inhibitor-first strategy. It was conducted in newly diagnosed patients with idiopathic dilated cardiomyopathy (NYHA classes II–III). Patients were required to be aged 18–70 and in NYHA II or III with LVEF <40% and receiving treatment with diuretics and digoxin. The study design was rather similar to CIBIS III (discussed subsequently), although the follow-up period was shorter and mortality/morbidity endpoints were not examined.

Patients were randomized to ACE inhibition with perindopril first (target dose 8 mg od, n=40) or beta-blockade with carvedilol first (target dose 25 mg bid, n=38). Both drugs were titrated to maximum tolerable doses. After 6 months of monotherapy, the other agent was added in both groups and combination treatment was continued for a further 6 months. The main outcome measures were changes in NYHA class and LV function (assessed by echocardiography and radionuclide ventriculography). A physician who was unaware of the treatment assigned assessed the NYHA class of all patients during baseline and follow-up visits.

At 12 months, the carvedilol-first group achieved a higher tolerable dose of carvedilol and a lower dose of furosemide than the perindopril-first group. They also had greater improvement in NYHA functional class, LVEF, and plasma N-terminal pro-BNP concentrations (Figure 4).


Figure 0124
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  		Figure 4 Effect of initiating carvedilol or perindopril therapy before combination therapy (beta-blocker-first vs. ACE-inhibitor-first) on NYHA functional class, LVEF and NT-proBNP in newly diagnosed patients with idiopathic dilated cardiomyopathy (NYHA classes II–III). Adapted and reprinted with permission from The American College of Cardiology Foundation.57

 
It may be speculated that the differences in symptomatic and haemodynamic improvements were due to the higher beta-blocker dose achieved in the group who received the beta-blocker first. Alternatively or additionally, it may be that beta-blocker therapy is more effective than ACE-inhibitor therapy in newly diagnosed patients with CHF. Sliwa et al. stated that ‘these results are encouraging and suggest an alternative therapeutic approach in patients with newly diagnosed HF, data that require confirmation in larger trials with mortality as one of the outcome measures.’ CIBIS III provided this confirmation.


   CIBIS III: study design
Top
 Abstract
 Introduction
 Arguments supporting a beta...
 Preliminary evidence that a...
 CIBIS III: study design
References
 
The study design of CIBIS III has been previously reported in detail,13,14 and a brief overview is given subsequently.

Objectives
The hypothesis underlying CIBIS III was that initiation of treatment of patients with CHF with the beta1-selective beta-blocker bisoprolol (to which the ACE-inhibitor enalapril is subsequently added) is as effective and safe as a regimen beginning with enalapril (to which bisoprolol is subsequently added).

The primary objective of CIBIS III was to demonstrate that a bisoprolol-first strategy is comparable (non-inferior) to an enalapril-first strategy with reference to the primary combined endpoint of all-cause mortality or all-cause hospitalization. Secondary objectives were to compare the efficacy and safety of bisoprolol and enalapril with regard to all-cause mortality or all-cause hospitalization (separately), cardiovascular death, and cardiovascular hospitalization.

Patient selection
To maximize the external validity of the results, eligibility criteria for patients in CIBIS III were chosen to be as close as possible to the profile of patients encountered in everyday practice, especially with regard to age. Key inclusion criteria were established diagnosis of CHF; LVEF ≤35%; NYHA class II or III; age ≥65; clinically stable, without fluid retention for at least the previous 7 days before randomization; concomitant therapy with diuretics, if any, unchanged for at least 7 days before randomization; no treatment with ACE-inhibitors, AT II antagonists, or beta-blockers within the previous 3 months (treatment for a period not exceeding 7 days within the previous 3 months was allowed). Patients were excluded if they had uncontrolled hypertension, acute coronary syndromes within 3 months before randomization, planned PTCA or CABG, or stroke within 1 month before randomization.

Study design
CIBIS III was a randomized, parallel-group, open, blinded endpoint evaluation, multinational study at 128 centres in 18 countries in Europe, Tunisia, and Australia. Treatment in CIBIS III was open, as it was not practical to blind the treating physicians to the different drug titration regimens required. An open design made it possible for physicians to make separate adjustments of the doses of two different agents during the combined study phase—they would need to know which drug was which in order to adjust the dose according to side effects. To minimize any possible bias inherent in the open design, the trial followed the Prospective Randomized Open, Blinded Endpoint format,58 in which endpoints are evaluated by a blinded endpoint committee. This limits investigator bias and allows for a valid non-inferiority analysis, despite the open design.

There were two phases of treatment (Figure 5). The study started with a monotherapy phase of 6 months, in which patients were randomized to receive either the beta-blocker bisoprolol or the ACE-inhibitor enalapril. This was followed by a combination therapy phase, which varied in length according to the date of randomization, from 6 months (last included patient) to 24 months (all patients completed the study on the same day). As the recruitment period lasted over 1.5 years, the total study duration was between 1 and 2.5 years. The target doses for each drug were bisoprolol 10 mg od or enalapril 10 mg bid. This rather prolonged period of monotherapy was necessary in CIBIS III to allow an effective statistical comparison of the two treatment strategies. It also allowed for the fact that the patients in the trial were relatively elderly; a small proportion might require a long period of stabilization on the first agent before the addition of the second.


Figure 0125
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  		Figure 5 Design and up-titration schedule for bisoprolol and enalapril in CIBIS III.

 
Endpoints
Primary and secondary endpoints in CIBIS III are listed in Table 1. The choice of the combined primary endpoint of the combination of all-cause mortality and all-cause hospitalization at study end (time to first event) reflects the fact that improving survival and decreasing hospitalization are equally important objectives in CHF. Among the elderly, decreasing hospitalization may even be considered a primary target, as ESC guidelines state that improved quality of life in addition to improved survival is an important treatment goal.1


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  		Table 1 Primary and secondary endpoints in CIBIS III13,14

 
Conflict of interest: P.P. has received honoraria for lectures from Merck.


   References
Top
 Abstract
 Introduction
 Arguments supporting a beta...
 Preliminary evidence that a...
 CIBIS III: study design
 References
 

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