© 2005 European Society of Cardiology
Tolerability of beta-blockers in elderly patients with chronic heart failure: The COLA II study
a NHMRC Centre for Clinical Research Excellence in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University 3rd Floor, Burnet Tower, AMREP Precinct, Commercial Road, Melbourne Vic 3004, Australia
b Roche Pharmaceuticals Pty Ltd NSW, Australia
c Department of Internal Medicine, Division of Cardiology Graz, Austria
d SZTE AOK I Belklinika, Hungary
e Zhong Shan Hospital Shanghai, China
f Sanatorio Parque Rosario, Argentina
g Atrium Medical Centre Heerlen, The Netherlands
* Corresponding author. Tel.: +61399030042; fax: +61399030556. E-mail address: henry.krum{at}med.monash.edu.au (H. Krum).
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Background: Beta-blockers are recommended therapy for patients with chronic heart failure (CHF). However, there remains concern regarding tolerability of these agents in the elderly, which has contributed to the limited uptake of these agents in clinical practice.
Aims: We conducted a multi-national, prospective evaluation of tolerability to carvedilol in 1030 CHF patients aged >70 years selected by their treating physician to receive this agent in everyday practice.
Methods and Results: NYHA Class II–IV CHF patients were assessed at baseline for key demographic parameters that may predict tolerability, then followed for 6 months after starting carvedilol. Tolerability was defined as being on 
6.25 mg bd of carvedilol at 6 months having received a total of 3 months therapy. Tolerability overall was 80% with age 70–75 years 84.3%, 76–80 years 76.8% and >80 years 76.8%. Mean carvedilol dose achieved was 31.2 mg. In multivariate analysis, advanced age, low diastolic BP, LVEF, obstructive airways disease and presence of diabetes were predictors of tolerability.
Conclusions: Carvedilol appears to be well tolerated in this elderly CHF patient cohort. Therefore, elderly CHF patients should not be denied treatment with carvedilol because of concerns regarding tolerability.
Key Words: Beta-blocker • Tolerability • Elderly
Received March 17, 2005; Revised May 31, 2005; Accepted August 17, 2005
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Chronic heart failure (CHF) is a major public health problem with continued high mortality, frequent hospitalisation, reduced quality of life and accompanying burden on patients, their families and the health care system. Neurohormonal blocking strategies, specifically angiotensin converting enzyme inhibitors and beta-adrenergic blocking agents (β-blockers), beneficially impact on mortality and morbidity in patients with systolic CHF. However, there is continued under-utilisation of β-blockers in the management of these patients with systolic CHF in everyday practice [1,2], despite overwhelming data supporting their clinical efficacy [3-6].
Advanced age is a common reason for non-prescribing of β-blockers [7]. This may in part relate to concerns regarding efficacy of these agents in this patient population as the major large-scale β-blocker trials generally enrolled younger patients, with patients >70 years under-represented in these studies.
However, a greater concern than efficacy may be that regarding tolerability in this patient population. Specific evaluation of tolerability of β-blockers in an elderly CHF cohort has not as yet been performed. We therefore undertook the second Carvedilol Open-Label Assessment (COLA II) to perform these evaluations.
The aim of COLA II was to determine tolerability of β-blocker introduction with carvedilol, in patients felt by their clinician to require these agents, in elderly systolic CHF patients in everyday clinical practice. In addition, a further aim was to ascertain whether there were differences in tolerability in elderly heart failure patients sub-grouped according to age.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2.1. Study design
COLA II prospectively studied 1030 CHF patients greater than the age of 70 years in whom their prescribing physician commenced the P-beta-blocker, carvedilol. This was a multinational trial with recruitment extending from May 2002 to August 2003. It was performed in the real-world setting of general physicians, primary care practitioners, non-teaching hospital cardiologists and geriatricians. COLA II was a prospective, six-month, observational assessment of tolerability of carvedilol introduction, evaluated according to ages 70-75, >75-80 and >80 years.
2.2. Criteria for selection
Patients were enrolled into COLA II if they were considered by their treating physician to be clinically appropriate for β-blocker therapy and were aged >70 years. The decision to enroll patients was left entirely up to the treating physician, with the general recommendation to follow that country's approved product information regarding carvedilol. This is usually recommended prescribing for patients with systolic CHF (left ventricular ejection fraction of <40%) and NYHA Class II-IV symptoms.
Tolerability was defined as patients having received carvedilol at a dose of 6.25 mg twice daily at the end of the six-month study period, having received a minimum of three months therapy during this period.
2.3. Statistical considerations
A sample size of 1000 patients provided 84% power to detect a difference in proportions of patients tolerating carvedilol of 80% versus 67% between two pre-defined age groups within the overall cohort (two-group 
2 test with p<0.05, 2-sided significance). Differences in tolerability between the three age ranges (and other variables) were tested by analysis of variance (ANOVA). Associations between baseline patient characteristics and tolerability were tested using survival analysis with time-to-intolerance being the end-point of interest.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1. Baseline demographic parameters
Baseline demographic parameters for the three age groups are listed in Table 1.
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Patients were generally well matched across the three age ranges except for gender, where there was a progressive reduction in percentage of males with advanced age and diabetes mellitus, where there was a progressive reduction in percent of patients with this condition with advanced age. Other parameters were well matched across the three age ranges, including background CHF medications.
3.2. Blood pressure and heart rate
Blood pressure and heart rate at baseline and following up to 6 months carvedilol therapy are summarised in Table 2. Changes for these parameters were significant within the three age groups. Specifically, there were significant reductions in systolic blood pressure, diastolic blood pressure and heart rate with carvedilol within each age group after up to 6 months carvedilol therapy. However, the magnitude of these changes were not significant across the three age ranges between baseline and up to six months therapy.
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3.3. Other measured parameters
Left ventricular ejection fraction (when measured) was significantly increased within all three age groups over up to 6 months of carvedilol therapy, with no difference in response across the three age groups.
NYHA functional class (considered as a continuous variable) was significantly reduced by carvedilol within all three age groups over up to 6 months of carvedilol therapy, with no difference in response across the three age groups.
3.4. Tolerability of carvedilol
Overall, 805 of 1009 patients (80%) enrolled in COLA II tolerated carvedilol according to the definition of tolerability given above. Tolerability was similar independent of gender (male 78.9%, female 80.8%), presence of ischaemic heart disease (77.8%) and hospitalisation within the last six months (76.4%).
There was little variability in tolerability according to use of background CHF medications. Tolerability was 78.6% in patients receiving background ACE-inhibitors, 80.2% in those receiving angiotensin receptor blockers (ARB), 76.5% in those receiving spironolactone, 75.3% in those receiving diuretics and 76.3% in those receiving digoxin.
There was a significant diminution of tolerability with advanced age (Fig. 1). Tolerability still remained high (at 76.8%) even in patients over the age of 80 years. Similarly, there was a progressive reduction in tolerability (which was statistically significant) according to the NYHA Class. Only 62.7% of patients with NYHA Class IV symptoms were able to tolerate carvedilol therapy.
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Tolerability according to relatively contraindicated co-morbid conditions was somewhat variable. Tolerability was 71.8% (87/224) in patients with obstructive airways disease, 67.5% (27/40) in patients with concomitant amiodarone but 84.4% (206/244), significantly greater than for all patients, in those with concomitant diabetes mellitus.
Fig. 2 summarises univariate (left panel) and multivariate (right panel) predictors of tolerability in the COLA II cohort. Most parameters were as expected, with the exception of the presence of diabetes mellitus, which appeared to be both a univariate and multivariate predictor of better tolerability.
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3.5. Reasons for discontinuation by age
Reasons for discontinuation of carvedilol by age are summarised in Fig. 3. There was, as expected, an increase in the percentage of patients in whom death was the reason for discontinuation by age with advanced age. However, for other usual reasons for β-blocker discontinuation (i.e. worsening heart failure, symptomatic hypotension, bradycardia and amiodarone use), there was no significant difference in the percentage of patients with these symptoms with advanced age.
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3.6. Achieved dose
Achieved dose was not significantly different according to age, although there was a progressive diminution in dose with advancing age. Patients aged 70-75 years achieved a mean dose of 33.3 mg per day, 75-79 years at 30.4 mg per day and >80 years at 29.3 mg per day.
3.7. Time to death and discontinuation of study drug
There was a significant reduction in time to discontinuation of study drug in patients receiving doses below the mean (Fig. 4). It was also observed that there was a significant reduction in time to death according to dose, with more mortal events in patients receiving doses below the mean (low dose 12.3%, high dose 2.4%, p<0.0001).
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The present study examines prospectively for the first time tolerability of β-blocker therapy in an elderly CHF patient cohort in a real-world setting removed from clinical trials. The major observation is that of overall good tolerability in patients thought appropriate by their treating clinician for beta-blockade, despite advanced age. There was little diminution in tolerability even in the extreme elderly, i.e. >80 years.
Not surprisingly, advanced age was both a univariate and multivariate predictor of poor tolerability to carvedilol as was low diastolic blood pressure, presence of obstructive airways disease and low ejection fraction. Somewhat surprisingly, the presence of diabetes actually predicted better tolerability. This may represent a chance observation or alternatively may have occurred because less severely ill diabetic patients were selected within the COLA II cohort, even accounting for adjustments made by multivariate analysis. This suggestion is supported by the lower percentage of extreme elderly patients with diabetes receiving carvedilol therapy. The combination of diabetes and CHF may be sufficiently lethal to leave fewer patients over the age of 80 surviving with both conditions.
It is also of interest that the pharmacodynamic and functional effects of carvedilol (including beneficial effects on LV ejection fraction) appeared to be preserved within an elderly systolic CHF cohort of patients, with little change in response to carvedilol therapy across the three age ranges. In addition, the symptomatic response to carvedilol introduction, as assessed by NYHA Class, was unchanged between the three groups, i.e. all patient groups showed an improvement in functional class.
Achieved dose at 29-33 mg per day was somewhat lower than that observed in younger patients in open-label studies such as in COLA I [8] where average age was 58 years and average dose achieved was 38 mg per day. Furthermore, doses in clinical trials, where patients are younger and are force-titrated to target dose, was also higher (COPERNICUS [6] 38 mg/day, COMET [9] 42 mg/day). Nevertheless, the dose achieved in COLA II in everyday clinical practice (in an observational study) demonstrates that therapeutic doses of carvedilol therapy can be achieved even in an elderly CHF patient cohort.
It was also of great interest that low-dose carvedilol was associated with the poorest tolerability and greatest mortality in these patients. These findings are consistent with previous observations that patients who are only able to tolerate lower doses of therapy comprise a sicker cohort [10,11] and this was reflected by poorer tolerability to introduction of β-blocker as well as increased mortality on treatment.
The SENIORS study [12] has recently reported on the efficacy of β-blocker therapy with the β1 selective vasodilator nebivolol in a systolic and diastolic CHF population greater than 70 years of age. The primary end-point of death and cardiovascular hospitalisation was reduced with nebivolol compared to placebo. This agent appeared to be generally well tolerated in that study supporting the present analysis.
There are a number of caveats to this analysis. This was an observational study without a control group. It is therefore not possible to draw definitive conclusions regarding overall efficacy or tolerability of carvedilol introduction without a relevant comparable group. Furthermore, data on patients considered for beta-blocker therapy but not actually commenced (for whatever reason) have not been collected. Therefore, a selection bias, specifically regarding patients entering the trial being those most likely to tolerate carvedilol, is possible and indeed likely. This is supported by the COLA II cohort mostly being NYHA Class II, having relatively preserved ventricular function overall and having relatively low use of diuretics. Nevertheless, the observational nature of this study is, we believe, also one of the study's strengths. This study merely observed practice and found that physicians, outside of the major teaching hospital and clinical trials setting, were able to successfully commence and maintain carvedilol therapy, at clinically efficacious doses, in 4 out of 5 of their elderly CHF patients thought appropriate for this therapy.
In summary, the COLA II study demonstrates for the first time tolerability of β-blocker therapy in an elderly CHF cohort. Notwithstanding issues of selection bias in this analysis, carvedilol appeared to be generally well tolerated in these patients in everyday clinical practice. Moreover, elderly patients with co-morbid conditions in which a β-blocker may be considered relatively contraindicated also appeared to tolerate carvedilol well. Therefore, based on the above observations, elderly systolic CHF patients should not be denied carvedilol therapy because of concerns regarding tolerability.
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References |
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