© 2001 European Society of Cardiology
Results from post-hoc analyses of the CIBIS II trial: effect of bisoprolol in high-risk patient groups with chronic heart failure
a University of Cologne Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany
b Hôpital Pitié Salpétrière 47, Boulevard de l'Hôpital, F-75651 Paris Cedex 13, France
c Merck KGaA Frankfurter Str. 250, D-64271 Darmstradt, Germany
* Corresponding author. Tel.: +49-2214-78-45-03; fax: +49-2214-78-62-75. E-mail address: erland.erdmann{at}uni-koeln.de (E. Erdmann).
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Abstract |
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 TopNotes Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Background: The beneficial effects of the β-blocker bisoprolol on mortality and rate of hospitalisation as well as its safety in patients with chronic heart failure has been proven. However, its efficacy in patients in whom β-blockers have traditionally been contraindicated or caution has been advised has not been clearly determined. Therefore, analyses in high-risk subgroups of patients taking part in CIBIS II have been performed to investigate the effect of bisoprolol in elderly patients, in patients with type 2 diabetes, with renal failure, NYHA functional class IV or concomitantly treated with digitalis, aldosterone antagonists or amiodarone.
Methods: High-risk subgroups of patients with chronic heart failure taking part in the CIBIS II study were retrospectively analysed with respect to mortality, hospitalisation, combined endpoint of cardiovascular mortality or hospitalisation for cardiovascular reasons and treatment withdrawal as well as cause of death and hospitalisation. Analysis is based on intention-to-treat.
Results: It was demonstrated that in spite of the expected increase in the overall risk of death and hospitalisation, patients who are diabetic, have renal impairment, NYHA class IV symptoms, are elderly, are taking either digitalis, amiodarone or aldosterone antagonists as co-medication benefit equally from β-blockade with bisoprolol as patients without these complications or drugs. Benefit was shown for the primary endpoint all cause mortality, as well as for the secondary endpoints.
Conclusions: Contrary to the hitherto prevailing doctrine of not using beta-blockers in high risk patient groups with chronic heart failure, retrospective analyses of the CIBIS II study justify the use of this drug class in patients regardless of age, NYHA functional class, the presence of diabetes, renal impairment or concomitant treatment with digitalis, amiodarone or aldosterone antagonists.
Key Words: Beta-blocker • Heart failure • Concomitant diseases • Concomitant therapy • Elderly • NYHA class IV • Bisoprolol
Received February 6, 2001; Revised April 24, 2001; Accepted May 10, 2001
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1. Introduction |
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TopNotesAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Contrary to the traditional approach of discouraging the use of β-adrenergic receptor blockers in the treatment of chronic heart failure (CHF) because of their negative inotropic effect, a paradigm shift has taken place, largely emerging from the realisation that sympathetic activation is a key factor in disease progression [1]. As a consequence, therapeutic strategies have been developed to counteract the deleterious effects resulting from excessive stimulation of this neurohormonal system. Both clinical and experimental evidence lend strong support for the use of beta-blockers in heart failure, with the aim of reducing both morbidity and mortality [2–4].
The beneficial long-term effects of β-blockade in this indication have been demonstrated in various studies, including CIBIS II with bisoprolol [5], MERIT-HF with metoprolol [6] and the US Carvedilol Program [7]. In the CIBIS II and MERIT-HF trials, the β-1 selective β-blockers bisoprolol and metoprolol showed a significant reduction of 34% in total mortality, the primary endpoint in both studies. In the US Carvedilol Program, a pooled analysis showed a 65% reduction in total mortality; however, this was only a secondary endpoint and the majority of patients included had less severe heart failure than those taking part in CIBIS II and MERIT-HF. Recently, the data from the COPERNICUS study with Carvedilol in patients with severe heart failure have been orally communicated and very recently published [27]. According to this oral communication (American Heart Association, 2000), a comparison of the main features of the CIBIS II and COPERNICUS studies is shown in Table 1. A mortality reduction of 35% was found in the COPERNICUS study. Nevertheless, current data from prospective randomised studies justifying the use of beta-blockers in high risk patients with CHF are still scarce. Therefore, a retrospective subgroup analysis of patients taking part in the CIBIS II study was done in order to investigate whether high-risk groups of patients, in particular, those with type 2 diabetes mellitus, advanced age, NYHA functional class IV, renal impairment or patients taking either digitalis, amiodarone or aldosterone antagonists, who have so far commonly been deprived of beta-blocker therapy [8], may obtain equal benefit from these agents as the overall patient population with heart failure.
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2. Methods |
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TopNotesAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Symptomatic ambulatory patients (2647) in NYHA class III or IV (with an ejection fraction of
35%), stable on standard treatment with ACE-inhibitors and diuretics were included in the double-blind, placebo-controlled randomised CIBIS II trial. The study design, methods and results have been published [5].
Ambulatory patients with symptomatic heart failure, NYHA class III–IV, EF35% were randomly allocated to either bisoprolol (n=1327), starting dose of 1.25 mg, progressively increasing to a maximum of 10 mg per day, or to a placebo (n=1320). The primary endpoint was all-cause mortality. The secondary endpoints were all-cause hospital admissions, cardiovascular mortality, combined endpoint of cardiovascular mortality or cardiovascular hospital admissions, and permanent premature treatment withdrawals. The study was stopped early, after the second interim analysis, because bisoprolol showed a significant mortality benefit. The mean follow-up period was 1.3 years. Bisoprolol reduced the primary endpoint, all-cause mortality, by 34%. Significant reductions also occurred in sudden death (44%, P-value=0.0011) and the combined endpoint of cardiovascular mortality or cardiovascular hospital admissions (21%, P-value=0.0004).
Retrospective subgroup analyses of all study endpoints were conducted for patients who were either elderly (
71 years), had type 2 diabetes mellitus, renal impairment, severe heart failure (NYHA IV) or were taking either amiodarone, aldosterone antagonists or digitalis as concomitant medication.
Renal function was evaluated by estimating the glomerular filtration rate (GFR) as standard indicator. Under steady-state conditions, GFR is estimated from serum creatinine using a formula that accounts for the influence of age and body weight on creatinine production (Cockroft Gault equation: GFRc=[(140–age in years)x(body weight in kg)]/(72xserum creatinine in mg/dl) [9]. In women, the value is multiplied by 0.85. This formula has been validated in several studies of CHF and renal dysfunction, and it showed a correlation >0.9, with accurately measured GFR. Patients receiving either amiodarone (the only permitted anti-arrhythmic agent in this study), digitalis (which was optional), or aldosterone antagonists were examined to investigate whether the concomitant use of bisoprolol and these drugs has an impact on the study endpoints.
Analysis of subgroups was performed on an intention-to-treat basis. Relative risks were calculated with 95% confidence limits.
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3. Results |
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TopNotesAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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As in the overall patient population taking part in the CIBIS II study, baseline characteristics in the different subgroups were comparable (Table 2).
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As expected, the overall rates of death, hospitalisation, combined endpoint and permanent treatment withdrawal were more elevated in the high-risk groups of patients (Figs. 1–7) and in patients taking digitalis, aldosterone antagonists or amiodarone, compared to patients without these risk factors and not taking these concomitant medications. The same holds true for the rates of ‘sudden death’, ‘death due to pump failure’ and ‘hospitalisation due to worsening of heart failure’ in these subgroups. This may be indicative of a higher co-morbidity in the high-risk subgroups and a more severe baseline disease in those patients who need to take these concomitant drugs.
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3.1. Patients with type 2 diabetes mellitus
One hundred and fifty-five patients in the placebo group (12%) and 157 patients in the bisoprolol group (12%) had type 2 diabetes mellitus. As in non-diabetic patients, a clear benefit of bisoprolol treatment was seen in this subgroup with respect to all mortality/morbidity endpoints (Figs. 1–5). For example, the relative risk (bisoprolol vs. placebo) for mortality was 0.81 (95% CI 0.51–1.28) in patients with diabetes and 0.66 (95% CI 0.54–0.81) in non-diabetic patients; a heterogeneity test for interaction was not statistically significant (P=0.48). Regarding the effects on different causes of death, bisoprolol reduced sudden death in non-diabetic patients, whereas it did not have an effect on this parameter in diabetic patients. Regarding pump failure, the reduction in diabetic patients achieved with bisoprolol was comparable to non-diabetic patients. However, the number of diabetic patients with sudden death or pump failure is not sufficient to draw any reliable conclusions. Hospital admission ‘due to heart failure worsening’ was reduced to a similar extent in both patient groups with and without diabetes mellitus. In diabetic patients, the number of permanent treatment withdrawals was slightly lower in the bisoprolol group compared with placebo, whereas in non-diabetic patients, the figures in the bisoprolol group and the placebo group were similar.
3.2. Elderly patients
Two hundred and seventy-five patients in the placebo group (21%) and 264 patients in the bisoprolol group (20%) were aged 71 years. With respect to the reduction in mortality, bisoprolol was equally effective in patients 71 years and in those <71 years (Figs. 1 and 6). The relative mortality risk (bisoprolol vs. placebo) was similar in the two age groups (0.68 for 71 years, 95% CI 0.48–0.97; and 0.69 for <71 years, 95% CI 0.55–0.86); the heterogeneity test for interaction was not statistically significant (P=0.86). Regarding the secondary endpoints, no notable differences between the age groups could be detected either (Figs. 2–5 and 7). Bisoprolol did not reduce sudden death in patients 71 years, whereas this cause of death was markedly reduced in patients <71 years. Pump failure was only reduced in older patients, with this reduction exceeding 50%. Old age did not have any influence on the number of hospital admissions due to ‘worsening of heart failure’, which was reduced to a similar extent in both age groups with bisoprolol. Regarding permanent treatment withdrawal, no noteworthy differences could be detected.
3.3. Patients with renal impairment
Four hundred and fifteen patients in the placebo group (32%) and 434 patients in the bisoprolol group (33%) had a creatinine clearance of <60 ml/min. Patients with a creatinine clearance of <60 ml/min were more likely to die (Fig. 1) or to be hospitalised (Fig. 2) than those with a creatinine clearance of 60 ml/min, but both categories of patients showed a similar benefit of bisoprolol treatment (Figs. 6 and 7). For example, in patients with a creatinine clearance of <60 ml/min, the relative mortality risk was 0.66 (95% CI 0.50–0.88) and in those with a creatinine clearance of 60 ml/min, the relative mortality risk was 0.69 (95% CI 0.54–0.89); the heterogeneity test for interaction was not statistically significant (P=0.69). There was no evidence that sudden death, pump failure and worsening of heart failure as a cause of hospitalisation were substantially influenced by the presence of renal impairment. The rate of permanent treatment withdrawals was significantly higher in renally compromised patients receiving bisoprolol than in those taking placebo (Fig. 5). This also holds true when the 63 patients with more severe renal impairment (creatinine clearance <30 ml/min) are compared to the 2584 patients with creatinine clearance 30 ml/min. There were again more permanent treatment withdrawals among patients with severely impaired renal function receiving bisoprolol. The large majority of these permanent treatment withdrawals were due to personal decision. The relative mortality risk for these patients was 0.59 (95% CI 0.30–1.18) compared to 0.68 (95% CI 0.56–0.83) in those with creatinine clearance 30 ml/min (Table 3).
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3.4. Patients with NYHA IV
Two hundred and twenty-four patients in the placebo group (17%) and 221 patients in the bisoprolol group (17%) were classified to NYHA class IV. Bisoprolol reduced mortality to the same extent both in NYHA III and in NYHA IV patients (RR 0.66 for NYHA III, 95% CI 0.53–0.83 and RR 0.74 for NYHA IV, 95% CI 0.51–1.06) (Figs. 1 and 6); the heterogeneity test for interaction was not statistically significant (P=0.75). With respect to hospital admissions, the relative risk for NYHA IV patients was 0.95 (95% CI 0.78–1.17), compared to 0.83 for NYHA III patients (95% CI 0.74–0.93) (Figs. 2 and 7); the heterogeneity test for interaction was not statistically significant (P=0.34). Regarding the causes of death, there was a more pronounced effect of bisoprolol on sudden death in NYHA III patients, whereas the effect on death due to pump failure was more pronounced in NYHA class IV patients. Hospitalisations due to worsening of heart failure were slightly more reduced by bisoprolol in NYHA class III patients (Fig. 3). A similar proportion of patients prematurely discontinued the study in both treatment groups regardless of NYHA functional class (Fig. 5).
3.5. Patients with concomitant cardiovascular medications
3.5.1. Digitalis
Six hundred and seventy patients in the placebo group (51%) and 697 patients in the bisoprolol group (53%) received digitalis. The mortality risk in patients taking digitalis vs. those not receiving digitalis was lowered to a similar extent under bisoprolol [relative risk 0.66 (95% CI 0.52–0.83) vs. 0.71 (95% CI 0.52–0.96), respectively; test for interaction not statistically significant, P=0.61]. This also applied to the other secondary endpoints, hospital admission and combined endpoint. Effects of bisoprolol on deaths due to pump failure were negligible, regardless of whether the patients received digitalis or not. Bisoprolol reduced the causes of sudden death more markedly when digitalis was co-administered. The same holds true for the reduction of hospital admissions due to the worsening of heart failure. Bisoprolol was even more effective in these patients receiving digitalis. A similar proportion of patients prematurely discontinued the study in both subgroups.
3.5.2. Amiodarone
Two hundred and six patients in the placebo group (16%) and 185 patients in the bisoprolol group (14%) received amiodarone. With respect to both the primary and secondary endpoints, patients taking amiodarone equally benefited from bisoprolol compared with those patients not taking this concomitant medication (P=0.88 for interaction). Bisoprolol reduced the number of hospitalisations for heart failure worsening to a similar extent in both subgroups (P=0.57 for interaction). More patients in the bisoprolol group taking amiodarone prematurely stopped treatment.
3.5.3. Aldosterone antagonist
One hundred and thirty-seven patients in the placebo group (10%) and 139 patients in the bisoprolol group (10%) received aldosterone antagonists. The reduction of mortality achieved in the bisoprolol group was not influenced by the administration of an aldosterone antagonist as co-medication (P=0.81 for interaction). Also not statistically significant (P=0.54 for interaction), there was a more pronounced effect of bisoprolol on the reduction of hospital admissions in patients treated with an aldosterone antagonist. The effect of bisoprolol on the reduction of sudden death as well as pump failure was somewhat more pronounced in patients taking aldosterone antagonists. However, the figures are too small to draw any reliable conclusions. It has to be noted that the difference between placebo and bisoprolol regarding hospitalisation for heart failure worsening was considerably higher in patients concomitantly receiving an aldosterone antagonist (placebo, 27.7%; bisoprolol, 10.1%) compared with patients not taking an aldosterone antagonist (placebo, 16.4%; bisoprolol, 12.2%). In patients taking an aldosterone antagonist, premature treatment withdrawal in the bisoprolol group was lower compared with placebo, whereas this endpoint was comparable between bisoprolol and placebo in patients not taking this concomitant medication.
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4. Discussion |
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TopNotesAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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It has been established that long-term administration of beta-blockers to patients with heart failure may substantially improve their left ventricular function, clinical condition and — most important — prognosis. The substantial beneficial effect of beta-blocker therapy on mortality and morbidity endpoints, clearly demonstrated with bisoprolol, metoprolol, and carvedilol, has led to the recommendation that beta-blocker therapy should be routinely administered to clinically stable patients with symptomatic left ventricular systolic dysfunction who are on standard therapy, which typically includes ACE-inhibitors, diuretics as needed to control fluid retention, and optionally digitalis glycosides [10]. Our knowledge of the efficacy of beta-blockers in special risk populations in whom beta-blockade has traditionally been contra-indicated is limited.
4.1. Patients with type 2 diabetes mellitus
Framingham study data have shown a four-fold increase in heart failure in diabetic men and an eight-fold increase in diabetic women. Patients with diabetes who develop heart failure have a particularly poor prognosis. Both SOLVD and RESOLVD studies [11,12] identified diabetes as an independent risk factor for death. In fact, diabetic patients accounted for approximately 25% of the total population in the MERIT-HF and the US Carvedilol Program [6,7]. Although this proportion was somewhat lower in the CIBIS II study, a clear benefit for bisoprolol treatment could be demonstrated, which justifies the future use of this drug in diabetic patients with systolic dysfunction. Experience of beta-blockade treatment in diabetic patients with heart failure has mainly been collected in the US Carvedilol Heart Failure Trials [7], which showed that diabetic patients receiving standard treatment for CHF who were randomised to placebo have an increased risk of mortality compared with the group receiving Carvedilol, and that survival was improved with carvedilol in both diabetic and non-diabetic patients. The MERIT-HF study did not show a similar benefit for the subgroup of diabetic patients; however, a systematic evaluation of the results has not been described.
4.2. Elderly patients
The results of this subgroup obtained in the CIBIS II study have provided further evidence that there is no justification for withholding beta-blockers in heart failure simply on the grounds of age. Patients aged 71 years benefited just as much from bisoprolol treatment as those <71 years. Bisoprolol reduced sudden death only in the population aged <71 years, which is in contrast to the findings for death due to pump failure, which was reduced by bisoprolol mainly in the older population and not in the younger patients. Thus, bisoprolol appeared to be effective in reducing progressive deterioration of heart failure in the older population. This is of particular interest, because it is well known that the prevalence of chronic heart failure rises with increasing age, this disease affecting 10–16% of older people over 75 years of age [13]. CHF patients >75 years have a higher mortality and morbidity than younger patients with CHF [14] and require 10–50 times more bed days for the management of CHF than do younger patients [15]. The reluctance of many physicians to use beta-blockers may be explained by the fact that few studies of older patients are available and analyses were mainly limited to patients less than 69 or 75 years of age [16]. Extrapolating from the myocardial infarction literature, however, it can be argued that the elderly will benefit equally, if not more, from beta-blocker therapy for CHF compared with their younger counterparts, because their absolute risk of events is higher [17,18].
4.3. Patients with impaired renal function
Fluid retention is a major characteristic of symptomatic, progressive heart failure. Despite considerable success of heart failure therapy, progressive renal dysfunction is a major concern in patients with CHF. It has been known for a long time that a low renal plasma flow is one of the characteristics of this disorder, ultimately resulting in a decrease in the glomerular filtration rate in more advanced stages [19]. In a recent study, it could be demonstrated that renal function is strongly associated with mortality in patients with advanced CHF [20] and seems to be more powerful than cardiac parameters (e.g. LVEF) in discriminating patients at risk. Patients with renal dysfunction had a significantly poorer prognosis compared to patients with a relatively preserved renal function, despite a similar NYHA functional class and LVEF. In CIBIS II, patients with renal impairment defined as GFRc<60 ml/min and GRFc<30 ml/min for those with severely reduced renal function, had a markedly higher crude mortality rate than patients with a less compromised renal function; however, they benefited to the same extent from bisoprolol treatment. The much higher difference in permanent treatment withdrawal between bisoprolol and placebo in renally compromised patients compared with the difference between these groups in patients with normal renal function was mainly caused by the higher frequency of personal patient decisions to stop treatment.
4.4. Patients with NYHA functional class IV
Previous clinical trials provided little information regarding the efficacy or safety of beta-blockers in patients with severe heart failure. Only 3–5% of patients enrolled in the large multicentre trials with metoprolol and carvedilol had class IV symptoms at the time of entry into the study. Therefore, in the US Carvedilol Program, and in MERIT-HF, only a trend to a beneficial effect of the respective beta-blockers was noted. Two recently completed large scale studies targeted advanced heart failure. In the BEST study [21], there was a negative trend in the subgroup of NYHA IV patients treated with bucindolol. This study was stopped because bucindolol produced only a 10% non-significant reduction in mortality in the total population included.
Meanwhile, the results of the CIBIS II study with 17% of patients classified to NYHA IV and the COPERNICUS study [27] with carvedilol have considerably contributed to increasing the evidence regarding the use of beta blockers in NYHA IV patients with chronic heart failure. In the latter study, a total of 2289 patients with stable, chronic CHF receiving standard treatment, with LVEF25% and classified as NYHA class IV were included. All-cause mortality was 18.5% in the placebo arm and 11.4% in the carvedilol arm, constituting a 35% relative risk reduction. This result is remarkably in line with the 34% mortality reduction found in CIBIS II and MERIT HF, although the mean LVEF in COPERNICUS was lower.
4.5. Patients with concomitant cardiovascular medications
Most patients with heart failure remain symptomatic despite treatment, thus requiring the administration of additional drugs, which can improve clinical status as long as they do not adversely affect long-term outcome. Consensus Guidelines recommend the concomitant use of digoxin [10] which will continue to play an important role in the symptomatic management of chronic heart failure patients whilst having neutral effects on mortality endpoints. This recommendation is mainly based on recent analyses of the data from the DIG trial and the combined PROVED and RADIANCE databases [22,23]. Prescribing habits concerning digoxin clearly differ between the US and Europe. The concomitant use of digoxin was 91% in the US carvedilol program, in contrast to 64% in the MERIT-HF and 52% in CIBIS II.
Digoxin treatment was not associated with any change of mortality rate but with a marked increased frequency of hospital admissions for worsening of heart failure (63%) in the CIBIS II population. The result provided by the multivariate analysis indicates that digoxin per se increased hospitalisation rate after adjustment for the other prognostic factors [24]. Bisoprolol showed a clear benefit with regard to all morbidity and mortality endpoints in patients taking digoxin in addition to the baseline treatment. The beneficial effect on reducing sudden death and hospital admission due to worsening of heart failure in patients taking bisoprolol and digoxin compared to digoxin alone favour its concomitant use when clinically indicated.
Since patients with heart failure have frequent and complex ventricular arrhythmias and are at high risk of sudden death, there has been considerable interest in the use of concomitant anti-arrhythmic drugs, e.g. the class III agent amiodarone. Of the patients enrolled in CIBIS II, 15% were taking amiodarone concomitantly and this population had an increased probability of deaths and rehospitalisations [24]. Patients taking amiodarone and bisoprolol benefited to the same extent as those not taking amiodarone. In a recent pooled analysis of the EMIAT and CAMIAT data [25], it could be demonstrated that patients receiving beta-blockers and amiodarone have lower relative risks for all cause mortality, cardiac death, arrhythmic cardiac death, non-arrhythmic cardiac death or resuscitated cardiac arrest than patients without beta-blockers, with or without amiodarone. The interaction was statistically significant for cardiac death and arrhythmic death or resuscitated cardiac arrest. In conclusion, when indicated, beta-blocker therapy should be continued in patients concomitantly using amiodarone.
New data on aldosterone and its association with increased morbidity and mortality in heart failure place an increased emphasis on the importance of its role in the pathophysiologic cycle of progressive disease. Conventional therapies for heart failure including ACE inhibitors, loop diuretics and digoxin do not effectively block aldosterone synthesis. The RALES study [26] showed a significant survival benefit of low-dose spironolactone added to standard diuretic and ACE inhibitor treatment in NYHA class III and IV patients (30% relative risk reduction in all-cause mortality). The greatest reduction in mortality (60%) was seen in patients who were also receiving a beta-blocker. In CIBIS II, only 10% of the patients took an aldosterone antagonist but the findings of this study show a similar trend. A clear benefit could be demonstrated for the combined endpoint and hospitalisation due to worsening of heart failure.
In conclusion, there is strong justification for prescribing beta-blockers in heart failure patients regardless of age, the presence of diabetes, renal impairment, concomitant use of digitalis, amiodarone or aldosterone antagonists. Beta-blocker therapy is also indicated in patients with more advanced stages of heart failure.
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Acknowledgements |
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We thank Dr Ralf Wulkow and Ms Susanne Müller-Wessling for their support with preparation of the paper.
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1 On behalf of the CIBIS II Investigators.
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