Treatment with beta-blockers in nurse-led heart failure clinics: Titration efficacy and predictors of failure

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1 European Journal of Heart Failure 9 (2007) Treatment with beta-blockers in nurse-led heart failure clinics: Titration efficacy and predictors of failure Finn Gustafsson a,, Morten Schou b, Lars Videbæk c, Tonny Nielsen d, Hans Ulriksen e, John Markenvard f, Tage Lysbo Svendsen g, Henrik Ryde h, Else Vigholt i, Per Hildebrandt j on behalf of the Danish Heart Failure Clinics Network a Departments of Cardiology, Rigshospitalet, Copenhagen, Denmark b Frederiksberg University Hospital, Frederiksberg, Denmark c Odense University Hospital, Odense, Denmark d Departments of Medicine Esbjerg Central Hospital, Esbjerg, Denmark e Skive Hospital, Skive, Denmark f Fredericia Hospital, Fredericia, Denmark g Holbaek Central Hospital, Holbaek, Denmark h Slagelse Central Hospital, Slagelse, Denmark i Horsens Hospital, Horsens, Denmark j Roskilde County Hospital, Roskilde, Denmark Received 5 December 2006; received in revised form 9 March 2007; accepted 14 May 2007 Available online 14 June 2007 Abstract Background: Beta-blockers (BBs) are a cornerstone in the treatment of chronic heart failure (HF), but several surveys have documented that many patients are not offered treatment or are not titrated to target doses. In part to address this problem, specialized, nurse-led HF clinics have been initiated in many countries. However, little information is available to describe if such programs are successful in initiating and uptitrating BBs in daily clinical practice. Aims: To assess the proportion of patients with HF due to left ventricular systolic dysfunction on BB treatment three months after referral to a nurse-led HF clinic, and to identify baseline predictors of treatment failure. Methods: Consecutive records from 14 Danish nurse-led HF clinics were used. Results: 1533 patients met inclusion criteria. Mean age was 68.7 years and 72% were men. Three months after the initial HF clinic visit 63% of the patients were being treated with a BB. Mean dose (relative to target dose) was 63 (±35)% in patients receiving a BB and target dose was reached by 21%. Patients who were not on BBs were more often female, elderly and in NYHA class III IV. In a multivariable model only lower age predicted BB use at three months (Pb0.05). Younger age (Pb0.001) and higher systolic blood pressure (Pb0.001) were associated with higher doses of BB. Conclusion: BB up-titration continues to be a challenge even in specialized clinics dedicated to this task. Elderly patients appear to be less likely to receive treatment European Society of Cardiology. Published by Elsevier B.V. All rights reserved. Keywords: Beta blocker; Ejection fraction; Case management; Heart failure clinic 1. Introduction Corresponding author. Division of Cardiology, Heart Failure and Transplant, Toronto General Hospital, 585 University Ave, 11c-1203, Toronto, Canada ON M5G 2N2. Fax: address: finng@dadlnet.dk (F. Gustafsson). Beta blockers (BBs) markedly reduce mortality and morbidity in patients with heart failure (HF) due to left ventricular systolic dysfunction and BBs are now a cornerstone in HF management [1 3]. BBs were well tolerated in the /$ - see front matter 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. doi: /j.ejheart

2 F. Gustafsson et al. / European Journal of Heart Failure 9 (2007) landmark clinical trials where approximately 85% of the patients remained on BB during the trials. In contrast, physicians have found it difficult and time consuming to uptitrate these drugs in daily clinical practice, resulting in inadequate prescription rates. The recent Euro Heart Survey documented that the rate of BB usage in patients discharged after admission for heart failure was less than 40% [4], and data showing low rates in HF outpatients have been published as well [5,6]. Moreover, in HF patients who are on BB treatment, doses are often substantially lower than the doses proven effective in randomised clinical trials [5 7]. Thishasledtoa search for effective strategies to increase BB usage in HF patients. Specialized, nurse-led, HF clinics devoted to the care and medical optimization of HF patients have been proposed as one solution to the difficulties related to management of HF patients, including BB up-titration. Such programs are effective in preventing readmission of HF patients [8] and most studies have shown that HF clinics effectively increase the use of ACE inhibitors compared with usual care [9]. Indeed, referral of HF patients to specialized management programs is clearly recommended in current guidelines [10]. However, limited data are available on the rate of success of BB up-titration in nurse-led HF clinics [9]. Information on the efficacy of nurse-led HF programs to improve BB treatment rates is of interest, since nurse-led HF clinics are becoming widely employed in several countries [11 14], If, indeed, the treatment rates in the programs were not acceptable new measures should be considered. In Denmark nurse-led HF clinics have been launched in most hospitals during the last 10 years. In daily practice these clinics are run by nurses with special training in HF management. The nurses are authorized to initiate and change doses of medications within pre-specified guidelines. Several HF clinics in Denmark have joined a national network to promote HF education and quality assurance. Using data from this network of HF clinics, the aim of the present study was to evaluate the rate of success of BB uptitration after three months in nurse-led HF outpatient clinics and to determine baseline predictors of treatment failure. 2. Methods 2.1. Setting and intervention Data for the current study were obtained from the Danish Heart Failure Clinics Network in December The Network was established in April 2002, and initially comprised 8 HF clinics [12]. The Network has expanded and at the time of data collection 14 clinics in Denmark were contributing to the Network database. Small county hospitals as well as urban, university hospitals participate in the Network. Although differences exist in the management of the individual clinics in the Network, fundamental elements in the participating clinics are homogenous. All participating centres are nurse-led physician supervised, hospital based out patient clinics. Referral pattern and staff resources do not differ significantly between the clinics [12]. Generally, an HF physician completes an initial clinical evaluation of the patient and orders a treatment plan. The up-titration of ACE inhibitors and BBs as well as adjustment of diuretics guided by clinical and laboratory monitoring is subsequently carried out by a specialized HF nurse. The physician is consulted in case of doubt or clinical deterioration of the patient. Clinic appointments are scheduled at variable intervals depending on individual needs, but on average patients are seen every two weeks for the first three months. Easy telephone access during the daytime is also offered in many clinics. An Internet based manual, which describes patient evaluation and drug up-titration has been developed, and strategies for BB therapy are discussed at meetings between nurses and physicians. Generally, initiation and up-titration of BB in a fashion similar to that used in the major clinical trials is encouraged. Details of the design and some intermediate results of BB up-titration success in two individual clinics participating in the Network have been reported [15,16] Data collection Participating clinics use a dedicated, HF specific, electronic patient file system (Hjerterplus) developed specifically for the Network. The system serves as a combined patient file system and a research database (Microsoft Access). The file system contains all patient baseline information such as medical history, cause of HF, co-morbidities, left ventricular ejection fraction, blood work analyses and medication. It also includes prospective data such as clinical status and medication at each subsequent clinic visit. At each visit to the clinic, a drug dispensing sheet is printed from the system and given to the patient, to ensure accordance between the medication data in the system and the drugs and doses the patient is actually taking (or supposed to take) until the next clinic visit. Generally, clinics participating in the Network base their daily clinical practice on the use of the program and all patients followed in the clinics are entered into the database. For the current study, data were collected electronically from the participating centres in December 2005 and merged into a Network database Inclusion criteria Since the aim of the study was to evaluate the success of BB up-titration after three months, we only included patients who had 1) at least three months follow-up in the heart failure clinic at the time of data harvesting or 2) had died within three months after the first visit or 3) had been discharged from the clinic to a family doctor within three months after the first visit, implying that no further uptitration would take place. We chose to include the patients who died before the end of three month follow-up, to avoid bias towards higher BB treatment rates by limiting the study to the surviving and likely the least sick patients.

3 912 F. Gustafsson et al. / European Journal of Heart Failure 9 (2007) was performed using linear regression analysis. Models as described for logistic regression analysis were created. All calculations were made using SPSS 11.5 (SPSS, Chicago, IL). A P value b 0.05 was considered significant Ethics Fig. 1. Patient selection for the study. HFC: Heart failure clinic. GP: General practitioner. LVEF: Left ventricular ejection fraction. At the time of data collection a total of 1852 patients fulfilled the inclusion criteria (Fig. 1). However, since we were only interested in analyzing BB usage in patients who had a definite indication for HF, we excluded 319 patients who did not have documented left ventricular ejection fraction (LVEF) in the database or who had a LVEFN0.45, leaving 1533 patients for the analyses Measures of titration efficacy For the group of patients with a follow-up visit more than three months after the initial visit to a HF clinic, the BB dose at the visit preceding the three-month mark was used. For patients who died or were discharged from the clinic at a time point earlier than three months after the first visit to the HF clinic, the dose at the last visit before recorded death or discharge from the clinic was used. BB doses were expressed relative to the daily target doses used in the major clinical trials: carvedilol 50 mg [17], bisoprolol 10 mg [1], and metoprolol XR 200 mg [18]. Hence, for a patient treated with 5 mg bisoprolol the relative dose would be 50%. The decision to measure BB doses three months after the first visit to the HF clinic was based on the fact that several observational studies have shown that a stable level of BB dose is reached after three months in most patients [19 21] Statistics Comparison of baseline characteristics between the groups of patients who were taking BBs after three months to those who were not, was performed using Student t-tests and Chi-square tests as appropriate. Logistic regression analysis was used to identify baseline predictors of patients being on versus off treatment at three months. Initially a model containing only age and sex was constructed, followed by a model containing age, sex, NYHA III IV (yes/no), diabetes (yes/no), LVEF, systolic BP, heart rate, serum creatinine. These parameters were chosen because they were a priori believed to have potential impact on BB up-titration success. Association between baseline parameters and BB dose at three months in the patients who were treated with BB The electronic file record system, Hjerterplus, is used in daily clinical practice to help monitor and treat patients, and patients were not asked for consent to have their data entered into the system. The local databases as well as the merged database have been approved by the Danish Data Protection Agency. 3. Results 3.1. Baseline characteristics Clinical characteristics of the 1533 patients at the initial visit to the HF clinic are shown in Table 1. Patients were elderly, most often male, and two thirds had a history of ischaemic heart disease. Most patients had mild or moderate HF symptoms. Comorbidity such as atrial fibrillation and diabetes was common. The prevalence of chronic obstructive pulmonary disease was low, raising some concern about underreporting specifically for this disease. Before entering the HF clinics 320 (21%) patients had already started treatment with BBs BB use at three months Medications recorded at three months are presented in Table 2. The vast majority of patients were treated with an angiotensin-blocking drug. A fairly large proportion of patients (33%) did not require loop diuretics at this time, implying that they were either not taking a diuretic or were managed with thiazides alone. This is compatible with the fact that almost three quarters of the patients were in NYHA class I or II at baseline. A total of 1285 (84%) patients were treated with BBs at some time within the first three months, but at Table 1 Clinical characteristics of the study population (n=1533) Age (years) 68.7±11.7 Female (%) 28 Ischaemic heart disease (%) 64 Duration of HF (months) 20±49 NYHA III IV (%) 26 Atrial fibrillation (%) 23 Diabetes (%) 19 COPD (%) 5 Body weight (kg) 79.6±17.0 Systolic blood pressure (mmhg) 126±23 Heart rate (bpm) 72±15 S-creatinine (μmol/l) 111±53 S-sodium (mmol/l) 139±4 LVEF 0.31±0.8 LVEFb0.25 (%) 32 Values are means±sd, unless otherwise indicated.

4 F. Gustafsson et al. / European Journal of Heart Failure 9 (2007) Table 2 Medications 3 months after the first clinic visit Beta-blockers (%) 63 ACE-I/ARB (%) 86 Loop-diuretics (%) 67 Spironolactone (%) 37 Digoxin (%) 22 Amiodarone (%) 6 three months only 63% tolerated BBs. The BBs used were metoprolol XR (33%), bisoprolol (7%) and carvedilol (60%). Among the female patients 57% were treated with BBs at three months, the corresponding number for men being 65%. Table 3 shows the differences between patients who were treated with BBs at three months versus patients who were not. Patients who were not on BBs were more often female, elderly and in NYHA class III IV. In a multivariate logistic regression model containing age and sex, both low age (HR 0.99 ( ), Pb0.05) and being male (HR 1.35 ( ), Pb0.05) predicted use of BBs at three months. In a multivariable model containing several variables, only lower age predicted BB use at three months (HR per year 0.99 ( ), Pb0.05, Table 4). There were considerable differences in BB use at three months between the participating clinics, which varied from 52 to 81% (ANOVA, P b 0.001). However, when the effect of different clinics (each clinic was randomly assigned a number)was added to the regression model containing age and sex or the model including all variables, no significant association was found between clinic number and treatment with beta-blockers (P values for the effect of clinics were and 0.71, respectively). Adding the clinics to the models did not change the effect of age and sex BB doses at three months Table 3 Patient's characteristics according to BB treatment after three months On beta-blocker at three months (n=968) Not on beta-blocker at three months (n=565) Age 68.1± ±11.7 Women (%) NYHA III/IV (%) Ischaemic heart disease (%) Diabetes (%) Atrial fibrillation (%) Heart rate (bpm) 72±14 73±15 Systolic BP 126±23 126±23 (mmhg) Creatinine 111 ± ± 40 (μmol/l) LVEF 0.31±8 0.31±8 Values are means±sd, unless otherwise indicated. Pb0.05, Pb0.01. Table 4 Multivariate logistic regression analysis of predictors of BB treatment at three months Variable P HR Female NS 1.33 Systolic BP NS 1.00 Heart rate NS.993 No diabetes NS 1.41 P-creatinine NS 1.00 Age (per year) Ejection fraction NS 1.00 Distribution of the relative BB doses is shown in Fig. 2. Some patients received doses higher than the doses recommended in randomised clinical trials. The drug used in patients treated with higher than recommended doses was almost exclusively carvedilol. This is presumably an indication that some caregivers were applying the results of older trials, such as the US carvedilol trial, in which 100 mg carvedilol was the target dose in some patients [22]. In patients receiving BB at three months the mean relative dose was 63±35% of target dose. Among patients on BBs, the mean relative dose was higher in men than in women (65±34% versus 60±35%, P b 0.05). In patients younger than the median age of 69.5 years, the mean relative dose was 69±34% versus 57± 34% in those older than the median age (Pb0.001). In a linear regression analysis containing age and sex, age was a significant predictor of dose (beta 0.21, P b 0.001), whereas sex did not significantly predict dose. In a multivariate linear regression analysis containing several clinical variables, age (beta 0.19, Pb0.001) and systolic BP (beta 0.17, Pb0.001) predicted BB dose. In patients with systolic BP above the median of 121 mmhg, the mean BB dose was 66±34% versus 60±35% in those with lower BP (Pb0.01). Altogether 21% of the 1533 patients were on target doses at three months. In a logistic regression analysis both age (P N 0.001) and sex (Pb0.01) predicted up-titration to target dose. In a model containing all variables from Table 4, low age(p b 0.001) and Fig. 2. Beta-blocker dose (relative to target dose) three months after the first visit to the HF clinic.

5 914 F. Gustafsson et al. / European Journal of Heart Failure 9 (2007) being male (P b 0.05) were the only significant predictors of reaching target dose. 4. Discussion The main findings of the present study are that even in dedicated HF programs focusing on optimization of medical therapy, the rate of BB use remains moderate and doses reached are considerably lower than the guideline targets. Furthermore it is shown that younger male patients are the most likely to be on treatment. The patients included in the current study were selected from a population of consecutive patients referred for HF management in specialized, nurse-led clinics. The patients are therefore not necessarily representative of HF patients in the community. Indeed, the proportion of females in the current study was relatively low and the mean age (69 years) was lower than in most epidemiological studies. The mean age in the current study is, however, comparable to [23,24] or significantly higher than [20,25] that seen in previous studies of beta-blocker utilization. Furthermore, the patients included in the current study are representative of the patients referred to the participating heart failure clinics with respect to age and sex. Several studies have reported on BB use in HF populations, but results are difficult to compare because of differences in study populations and in the methods by which BB use was analyzed and reported. If, for instance, any BB use during a period is considered as BB treatment for that patient, the resulting BB rates are likely to be high. When analyzed in this way, the rate of BB use in the current study was 84%. This figure, however, does not provide insight into the proportion of patients taking BB for a longer time. Furthermore, some reports on BB use in HF populations are based on results from trials designed specifically to increase BB use in a selected HF population over a well-defined period of time [21,23,26,27], and as such these results are likely to differ from registry data from everyday practice as recorded in our study. Finally, some studies only report data for patients in whom starting a BB was a criterion for enrollment into the study, again increasing the likelihood of reaching higher treatment rates when compared to the design of our study. Few studies have assessed BB use in unselected HF outpatients followed in specialized HF clinics. These studies have generally been smaller than the present registry, since they were usually based on only one clinic [5,25,28,29]. Indeed, there are few data available to compare directly with the findings of the current study. Butler et al. reported that only 19% of patients starting BBs in an HF program discontinued treatment, but the mean age in this study was approximately 10 years lower than the cohort of the Danish HF Clinics Network [25]. Others have reported results from HF clinics similar to those from our study [28,30,31], but lower rates (46%) [6] as well as higher rates (88%) [20] have also been reported. In intervention studies specifically aimed at increasing BB use, higher rates, than those seen in the Danish Network have been reported. In the IMPACT-HF study, treatment rates of 91% in the intervention group versus 73% in the control group were reported [27]. However, lower (50%) and similar (59%) rates were reported from the recent BRING-UP 1 and 2 trials, respectively [21,26]. Results of the current study were also comparable to those obtained after launching a multifaceted program to promote BB use in the practices registered in the Duke Databank for Cardiovascular Disease [23]. Hence, it appears that the BB use in the Danish HF clinics, although clearly not optimal, is generally at the level of most reported results from other HF programs dedicated to medical optimization and even at the level of the results of some intervention studies, specifically aimed at increasing BB usage. In the current study, patients who were treated with a BB three months after the initial visit to the HF clinic were receiving a little over half the recommended target dose. We do not have specific information about reasons why some patients were treated with doses lower than the target dose in the current study, but based on the multivariate model it appears that older patients as well as patients with low systolic blood pressure (at the initial visit to the HF clinic) were treated with the lowest doses. In comparison, patients in the COPERNICUS study were treated with carvedilol at 74% of the target dose of 50 mg daily and in the MERIT-HF study the corresponding figure was 64% at the end of the study [2,3]. The BB doses reached in the current study are comparable to those reached in the cardiologist arm of the COHERE registry [19] and those recently reported from a heart failure clinic in Canada, in which 18% of patients were treated at target doses of metoprolol and carvedilol [6]. The results are also in keeping with the results of the intervention arm of a recently published study of nurse facilitated BB titration versus usual care [24]. Some studies have reported even lower proportions of patients reaching target doses [5]. A few small studies have reported that their patients were able to reach higher doses (N70% of target), but in these studies initiation of BB treatment was an entry criterion, implying that patients known to be intolerant to BB were not included [30,32]. In the current study it appeared that the elderly and women were less likely to receive a BB and further that patients with low systolic blood pressure were likely to be treated with lower doses. It should be noted, however, that the differences between these groups (e.g. elderly versus younger, low blood pressure versus high blood pressure) were small, implying that the impact of these factors on the success of BB up-titration was not marked. These results have not been reproduced in other similar studies, but this could be due lack of power [6,25]. The finding that the elderly are treated with lower doses of BBs are, however, supported by results from an analysis from the MERIT HF trial [33]. Reassuringly this study showed that the elderly patients had similar benefit from the treatment despite the fact that their doses were lower. The observation that patients

6 F. Gustafsson et al. / European Journal of Heart Failure 9 (2007) with a low systolic blood pressure were treated with lower doses than those with higher pressures seems intuitively logical. A similar trend was seen in the COPERNICUS study, which nevertheless documented safety and a solid benefit from treatment even in the patients with the lowest blood pressure [34]. Hence, every effort should be made to ensure that patients with low systolic blood pressure are initiated and up-titrated to the highest tolerated BB dose. The results of the current study taken together with those of most previous studies of BB titration success performed in heart failure clinics, indicate that although results in these clinics are better than results observed in populations not served by a heart failure clinic, the success rate of BB treatment is moderate, reaching only approximately 2/3 of the levels reached in the landmark clinical trials. There may be several factors to explain this. Generally patients recruited for randomised clinical trials are younger and have less comorbidity. Furthermore, such patients are carefully selected to avoid patients with contraindications to BB, and presumably patients with less well-defined fragility were excluded as well. Hence, one cannot expect treatment rates comparable to those obtained in the drug trials. On the other hand, the clinics in this large network did not perform equally well. Data from dedicated trials to improve BB use in other settings (IMPROVE HF) as well as previously published results from a single clinic in the Danish Network have documented that very high rates of treatment success are indeed possible in this setting [15]. Although differences in success rates may very well relate to differences in local demographics and patient referral pattern, it cannot be excluded that outcome will also depend on local expertise and involvement in the titration process. These data emphasize the need for continuous monitoring of clinic performance and ongoing training of nurses and physicians involved in the care for heart failure patients [8]. Given the very positive results of the recently published IMPACT HF trial, one strategy to improve BB use may be to start an intensive program to ensure BB treatment and titration during hospital admission (IMPACT HF) [27]. Possibly, the intensity of the heart failure clinic program needs to be increased, as is currently under investigation in the COACH trial conducted in the Netherlands [35]. In the current study, clear differences between clinics with respect to the proportions of patients treated with BB were demonstrated. This does not necessarily reflect differences in the efficacy of the nurses and doctors employed in those clinics, but to some extent reflects differences in patient selection. It is not really enough to just start an HF clinic and ask the staff to follow a protocol, success requires dedicated staff and continuous education primarily in communication and patient centred approaches [36].We have taken action within the Danish Network based on these results. We have arranged meetings where the nurses and doctors from the best performing clinic have outlined their protocols and methods for the other participants in the Network. Nurses from other clinics have visited the best performing clinics to join patient sessions in order to obtain practical experience. We have yet to see if these initiatives will translate into better achievements across the Network. This can be easily monitored through the use of the Network database. In conclusion, this large study from the Danish Network of Heart Failure Clinics has demonstrated that BB up-titration continues to be a challenge even in specialized clinics dedicated to this task. 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