Bisoprolol dose–response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II)

T. Simona,*, M. Mary-Krauseb, C. Funck-Brentanoa, Ph. Lechatc and P. Jaillona on behalf of CIBIS II investigators

a Department of Pharmacology, Saint Antoine University Hospital AP-HP, 27, Rue Chaligny, 75012, Paris, France
b INSERM EMI0214, 56 Bvd V. Auriol, 75013, France
c Department of Pharmacology, Pitié-Salpétrière University Hospital AP-HP, 83, Bcd de l’hopital, 75013, France

* Corresponding author. Tel.: +33-1-40-01-14-57; fax: +33-1-40-01-14-04
E-mail address: tabassome.simon{at}chusa.jussieu.fr

Received 17 August 2002; revised 8 October 2002; accepted 9 October 2002


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aims Whether all patients with congestive heart failure (CHF) need to reach the target dose of beta-blocker to obtain a benefit in terms of survival remains uncertain.

Methods and results We classified by tertile the 2647 patients enrolled in CIBIS II according to the last tolerated dose: low dose (LD: 1.25, 2.5 or 3.75mg/day, ), moderate dose (MD: 5 or 7.5mg/day, ) and high dose (HD: 10mg/day, ) of bisoprolol or placebo (LD=234, MD=278 and HD=808). In both groups, patients tolerating only low doses were significantly older with more severe New York Heart Association (NYHA) functional class and higher frequency of co-morbidities. Treatment withdrawal was associated with a significant increase of mortality in the bisoprolol group (relative hazard (RH)=2.13, 95% confidence interval (CI)=1.43–3.17, ). After adjustment, all-cause mortality was significantly reduced in the bisoprolol group compared to placebo regardless of the dose level considered: LD (RH=0.66, 95% CI=0.48–0.92), MD (RH=0.33, 95% CI=0.21–0.51) or HD (RH=0.59, 95% CI=0.40–0.89).

Conclusions Bisoprolol reduces mortality in CHF patients at all tolerated dose levels and its withdrawal increases the risk of mortality. Efforts should be made to maintain bisoprolol therapy based on the individual patient's tolerability.

Key Words: Congestive heart failure • Adrenergic beta-antagonists • Dose–response relationship • Mortality


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The rationale for using ß-adrenoceptor blockers in the treatment of congestive heart failure (CHF) is well described and established.1,2 The degree of sympathetic activation correlates with the severity and clinical outcome of the disease.3 The Cardiac Insufficiency Bisoprolol Study (CIBIS II), a randomized double-blind placebo-controlled trial,4 showed a 34% reduction in all-cause mortality with bisoprolol, a ß1-selective adrenergic antagonist, added to standard treatment with ACE inhibitors and diuretics in class III and IV CHF patients.

Because ß blockade has been shown to produce a dose-dependent improvement in ventricular function5,6 which may result in a dose-related decrease in mortality,6 all effort is made in order to achieve the highest tolerated dosage.1,2 Thus the strategy for administering a ß blocker in each of the major clinical trials has been based on a very slow gradual tolerance-limited up-titration7 over the course of several weeks until the target dose is achieved (10mg daily for bisoprolol,4 200mg/day for metoprolol succinate CR8 and 50mg daily for Carvedilol9–11). Despite this slow dose-titration, some patients do not tolerate the target dose and/or experience various degrees of decompensated CHF which may lead to ß blocker withdrawal. Previous studies have shown the risk of deterioration with the beta-blockade withdrawal in CHF patients.12,13

An important challenge for physicians in charge of the management of beta-blocker therapy in CHF patients is therefore to find the relevant and optimal dose for each individual patient in order to obtain the best benefit/risk ratio for the treatment. The purpose of the current study was to examine whether patient's survival in CIBIS II was related to the tolerated dose of the bisoprolol.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
We analyzed the data in CIBIS II by classifying the patients enrolled into tertile groups according to the last tolerated dose before event or last follow-up visit14: low dose (1.25, 2.5 or 3.75mg/day, (33%)), moderate dose (5 or 7.5mg/day, (25%)) and high dose (10mg/day, (43%)) of bisoprolol or placebo (low dose ( (18%)), moderate ( (21%)) and high dose ( (61%)).

Details on the study design and results of CIBIS II trial have been reported previously.4 Briefly, a total of 2647 patients with New York Heart Association (NYHA) class III and IV heart failure treated by diuretic and ACE inhibitor for at least 2 weeks were randomized in the study. Other vasodilator was allowed in case of intolerance to an ACE inhibitor (4%), whereas the use of digoxin was optional. Additional entry criteria included clinical stability for at least 6 weeks for heart failure (3 months in case of heart failure due to myocardial infarction), a left ventricular ejection fraction (LVEF) of 35% or less obtained either from echocardiography or ventriculography. The titration of the randomized study medication was performed without a run in period. The initial dose of bisoprolol was administered for a week and was increased according to clinical response towards the target dose; patients received the first three dose levels (1.25, 2.5 and 3.75mg) for 1 week, and the higher levels (5 and 7.50mg) for 4 weeks before the final step of 10mg daily. It was recommended to maintain the target dose if possible throughout the study.

2.2. Outcome events
The primary endpoint in CIBIS II was all-cause mortality. Classification of deaths has been reported elsewhere.4 Secondary endpoints were cardiovascular mortality, non-cardiovascular mortality, all-cause hospital admissions, cardiovascular hospital admissions and permanent treatment withdrawal (PTW). Temporary treatment withdrawals were authorized in the trial.

All medical events, including treatment withdrawals, were blindly reviewed and classified by members of an independent Critical Event Committee according to standardized definitions established before inclusions started. Medical events considered in CIBIS II were worsening of heart failure, cardiogenic shock, documented ventricular tachycardia/fibrillation, symptomatic supraventricular tachycardia, symptomatic bradycardia, symptomatic hypotension, myocardial infarction, revascularization, cardiac transplantation, other cardiac surgery, angina pectoris requiring hospital admission, stroke, other cardiovascular hospitalizations and non-cardiovascular events. The reasons for PTW were classified by the Critical Event Committee as personal decision of patient or investigator (i.e. not a medical event considered by the Committee as justifying withdrawal), contraindication to beta-blocker therapy or mandatory indication for beta-blocker therapy (intractable angina, high ventricular rate despite authorized bradycardiac treatments and severe ventricular arrhythmias which did not respond to amiodarone alone).

2.3. Statistical analysis
Statistical analysis was performed by using SAS®computer software version 8.2. Follow-up data for outcome events were available for all patients. Survival curves were estimated by the Kaplan–Meier method and compared by log–rank test.

Chi square and non-parametric tests were used to assess the relationship between baseline characteristics and dose groups. Each significant predictor identified by this analysis was tested for time to death in a multivariate Cox proportional hazards model stratified on PTW. Other variables considered likely to have an important prognostic factor, and variables with a p value up to 0.20, were also forced into the model. Adjustment was performed with the following variables: age, gender, body mass index, NYHA class, duration of heart failure, etiology of CHF, smoking status, history of diabetes, atrial fibrillation, heart rate at inclusion, systolic and diastolic blood pressure, presence of left and right bundle branch block, presence of atrio-ventricular block, abnormal ST segment interval, LVEF, concomitant and randomized treatment, and the last tolerated dose group. Results are expressed as relative hazard (RH) and 95% confidence intervals (CI). Presence of interaction between dose groups and randomized treatment, and between PTW and randomized treatment were also tested by Cox analysis.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
3.1. Baseline patients characteristics
Patients characteristics at baseline in each tolerated dose group of bisoprolol and placebo are shown in Table 1 (a) and (b), respectively. No difference was observed across the three bisoprolol groups of dose with regard to factors such as gender, race, LVEF, abnormal ST segment, diabetes and atrial fibrillation. However, compared with patients treated with moderate and high doses of bisoprolol (25 and 43% of patients), those receiving low doses (33%) were significantly older with more severe NYHA functional class and had a lower systolic and diastolic blood pressure (Table 1 (a)). They were more likely to have a previous history of hypotension, severe arrhythmia and a higher frequency of left bundle branch block and atrio-ventricular block. Patients tolerating low doses of beta-blocker were also those who had a higher prevalence of documented ischemia as the underlying cause of CHF, whereas an undefined etiology was more frequent among moderate and high dose groups (Table 1 (a)). A similar proportion were receiving ACE inhibitors, diuretics, digitalis and aspirin whereas the use of nitrates and amiodarone were significantly more frequent in patients receiving low dose of bisoprolol. In the same way there was a consistent pattern of a more severe disease among patients in whom placebo was maintained at low doses (Table 1 (b)).


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Table 1 Baseline characteristics

 
Patients tolerating low doses of bisoprolol or placebo did not differ regarding their baseline clinical characteristics with the exception of heart rate at rest, lower in the bisoprolol group (77±14bpm vs. 81±14bpm, ). The use of nitrates was the single variable that differed among patients tolerating moderate doses (67 vs. 57% in the placebo and bisoprolol groups, respectively, ). Among patients tolerating high dose, those in the bisoprolol group had a lower frequency of previous history of hypotension (1 vs. 3%,), severe arrythmia (19 vs. 27%, ), concomitant use of amiodarone (10 vs. 14%, ) and diuretics (98 vs. 100%, ) compared to placebo.

3.2. Permanent treatment withdrawal during follow-up
PTW was required in 381 patients, 191 treated with placebo and 190 with bisoprolol groups (14% of patients in each group). No difference was observed in the two treatment groups regarding the main cause of PTW (the patient's or investigator's personal decision in 81% of cases, i.e. not a medical event considered by the Critical Event Committee as justifying withdrawal) or the cause of death after PTW.

The distribution of the PTW was significantly related to the tolerated dose in both placebo and bisoprolol groups: 125 patients (9%) and 87 patients (7%) stopped bisoprolol or placebo at low doses, 45 patients (3%) and 47 patients (4%) at moderate doses, and 20 (2%) and 57 patients (4%) at high doses of bisoprolol and placebo, respectively, . PTW occurred earlier in patients receiving low doses of placebo and bisoprolol. Timebetween the start of the dose in which PTW occurred and PTW was significantly dose-dependent in both bisoprolol (61±114 days, 123±143 and 171±131 days in LD, MD and HD,respectively, ) and placebo groups (76±139 days, 101±120 and 254±176 days in LD, MD and HD, respectively, ).

PTW was associated with an increased risk of mortality (RH=2.13, 95% CI=1.43–3.17, ) in the bisoprolol group. A non-significant increase was also observed in the placebo group (RH=1.44, 95% CI=0.99–2.08) but the impact of PTW on the risk of mortality was significantly more pronounced in the bisoprolol group compared to placebo . Time from withdrawal to death and causes of deaths did not differ significantly in the bisoprolol and the placebo groups.

The deleterious impact of bisoprolol withdrawal on survival was related to the dose. Compared to patients in whom bisoprolol was continued, the mortality risk in patients with PTW was 1.79 (95% CI=1.14–2.82, ), 1.95 (95% CI=0.74–5.16, ) and 10.17 (95% CI=3.85–26.86, ) in LD, MD and HD bisoprolol groups, respectively.

3.3. Mortality and morbidity outcomes
Death occurred in 384 patients, 156 patients in the bisoprolol and 228 in the placebo groups. After adjustment for baseline differences and PTW during follow-up, the probability of all-cause mortality in bisoprolol group was significantly reduced in high dose (RH=0.30, 95% CI=0.19–0.46, ), and moderate dose groups (RH=0.49, 95% CI=0.32–0.75, ) compared to low dose group (Table 2). The risk of cardiovascular deaths, all-cause hospitalizations and cardiovascular hospitalizations were lower in the high and moderate doses of bisoprolol compared to low dose (Table 2).


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Table 2 Risks of outcome events in bisoprolol dose groups

 
Mortality was also reduced with increasing doses of placebo compared to low dose (RH=0.28, 95% CI=0.20–0.40 and RH=0.76, 95% CI=0.54–1.09 for high dose and moderate dose groups, respectively). However, compared to placebo, bisoprolol was associated with a significant reduction of all-cause mortality regardless of the dose level considered (Fig. 1). Compared to placebo, the reduction of mortality with bisoprolol treatment was 34% with low doses (RH=0.66, 95% CI=0.48–0.92), 67% with moderate doses (RH=0.33, 95% CI=0.21–0.51) and 41% with high doses (RH=0.59, 95% CI=0.40–0.89). Bisoprolol also reduced significantly cardiovascular deaths, all-cause and cardiovascular hospitalizations regardless of the tolerated dose as compared to placebo (Table 3).



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Fig. 1 Kaplan–Meier survival curves in patients receiving placebo and bisoprolol at LD, MD and HD. p is given by the multivariate Cox analysis adjusted to baseline differences and PTW.

 

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Table 3 Risks of the outcome events with bisoprolol compared to placebo

 

    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The titration of the beta-blockers in the randomized trials has been performed with a gradual increase in the dosage guided by tolerance until the target dose was achieved. Whether all patients need to reach this target dose in order to obtain a relevant benefit in terms of survival remains uncertain. The major findings of the present additional analysis of CIBIS II data are the reduction of mortality with all tolerated doses of bisoprolol compared to placebo and the confirmation of the deleterious impact of bisoprolol withdrawal13 on the risk of mortality. Therefore for a given patient, bisoprolol should be up-titrated guided by the tolerance. If necessary, physicians should maintain low doses rather than interrupting the beta-blocker treatment.

4.1. Baseline clinical characteristics and tolerated dose
Clearly the tolerated dose in CIBIS II was dependent on the severity of the chronic heart failure in both placebo and bisoprolol groups and was independent of the randomized treatment. In both groups,patients tolerating only low doses were significantly older with more severe NYHA functional class and higher frequency of co-morbidities. Whereas a similar proportion of patients interrupted placebo or bisoprolol during follow-up, the treatment withdrawal was more frequent and occurred earlier in those receiving low doses. At the time CIBIS II trial was performed, the results of the other large-scale trials were unknown. Since the two treatment regimens were given in a double-blinded fashion, it is possible that physicians have been fearful and increased doses more cautiously or interrupted treatments (bisoprolol and placebo) more easily in the patients with more severe forms of heart failure. Therefore the tolerated dose in CIBIS II patients may have been influenced in some extent to the physician's tolerability.

4.2. Permanent treatment withdrawal and risk of death
The discontinuation of bisoprolol was significantly associated with an increase risk of mortality. Interestingly, the deleterious impact of bisoprolol withdrawal on survival was related to the dose, uppermost in the high dose group. This may be due to an increased unopposed upregulation of ß adrenoreceptors at withdrawal. However, because this finding is based on a limited number of deaths , it should be taken with great caution and needs to be confirmed by further trials.

The increased risk of events is consistent with previous findings of the risk of deterioration after beta-blocker withdrawal.12,13 Patients who interrupted bisoprolol were not sicker than those who stopped placebo. Interestingly, the main cause of PTWs was due to the investigator's or patient's personal decision and not due to medical reasons. Moreover, time from withdrawal to death and the causes of death were similar in patients who interrupted treatment, regardless of the dose.

The beneficial effects of bisoprolol on mortality and other outcome events remained significant after adjustment for PTWs and baseline characteristics of patients.

4.3. Tolerated doses and risk of death
As shown in Table 2, a significant reduction of all-cause mortality within the bisoprolol group was observed with the high and moderate tolerated doses of bisoprolol compared to low dose. A dose-related reduction of mortality has been previously observed in the MOCHA trial, a 6-month, dose–response evaluation of carvedilol (6.25, 12.5 and 25mg bid vs. placebo) in 345 patients with mild to moderate stable CHF.6 The study found no beneficial effect from carvedilol on submaximal exercise, the main objective of the trial, but a dose-related reduction in mortality was observed among the 25 patients who died of whom 13 were treated by placebo. Because of the low number of deaths, the likelihood of chance finding is not negligible. However, surprisingly we also observed a similar pattern of reduced mortality with patients tolerating increasing doses of placebo, reinforcing the finding that regardless of the randomized treatment, patients in low doses were more severe than those receiving higher doses.

Interestingly compared to placebo a significant reduction of death and all other outcome events was found with bisoprolol regardless of the tolerated dose (Table 3). The proportion of general patients with CHF in whom the target dose can be reached is lower than those in clinical trials since the patients are older with higher frequency of comorbidities. Compared to placebo, even low doses of bisoprolol conferred benefit in our study. Therefore the therapy should be continued if low doses of bisoprolol are the only doses tolerated. This finding is consistent with the recent analysis of MERIT data.15 Although placebo mortality rate was also higher in the low dose group, a significant reduction of mortality was observed with metoprolol in both low (<100mg daily) and high dose groups (<100mg daily) compared toplacebo.15

Previous studies have shown the link between heart rate reduction and survival in CHF.16,17 In CIBIS II, heart rate reduction was not the single mechanism responsible for bisoprolol-induced benefit in CHF.17 The heart rate reduction with bisoprolol (baseline to 2 months) was similar regardless of the tolerated dose: –9±13, –10±15 and –11±15bpm with LD, MD and HD of bisoprolol, respectively, .

To what extent is it beneficial to reduce the effects of sympathetic stimulation by beta-blockers remains questionable. In the present analysis, a significant 34, 67 and 41% relative risk reduction of mortality was found with low, moderate and high dose of bisoprolol, respectively, compared to placebo. Similarly the relative risk reduction for all other outcomes was also more pronounced with the moderate dose level (Table 3). However, within the bisoprolol group, the highest reduction of mortality was observed in the high dose group (Table 2). Since the present study was not a dose-ranging trial, it is not possible to prove that a particular dose is optimal or that all doses are equivalent. The treating physician should try to take the patient to the high dose group, since a priori there is no wayto determine other than with forced up-titration to the highest tolerated dose.

The present study is limited by the post hoc nature of its analyses. Patients were not randomized to receive different doses of bisoprolol. Up-titration of bisoprolol and placebo were clearly influenced by the patient's status and physician's decision.


    5. Conclusions
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Bisoprolol reduced significantly the risk of mortality in CHF patients for all tolerated dose levels. The withdrawal of bisoprolol increased significantly the risk of mortality. All efforts should be made to maintain bisoprolol therapy based on the individual patient's tolerability and decrease the dose if necessary in case of intolerance. Further randomized dose-ranging studies are needed to establish the benefit/risk ratio at each dose level.


    Footnotes
 
This work was presented at the Annual Scientific Sessions of the American Heart Association, Circulation 2000; 102(18): II-629, 3051.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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