European Journal of Cardiovascular Nursing 10 (2011) 44 – 49 www.elsevier.com/locate/ejcnurse

Characteristics, implementation of evidence-based management and outcome in patients with chronic heart failure☆ Results from the Norwegian heart failure registry Morten Grundtviga,⁎, Lars Gullestadb , Torstein Holec , Berit Flønæsd , Arne Westheime a Innlandet Hospital Trust, Division Lillehammer, Department of Medicine, Lillehammer, Norway Department of Cardiology, Oslo University Hospital, Rikshospitalet, and Faculty of Medicine, University of Oslo, Oslo, Norway Sunnmøre Hospital Trust, Ålesund Hospital, Department of Medicine, Ålesund and Norwegian University of Science and Technology (NTNU), Trondheim, Norway d Asker and Bærum Hospital Health Authority, Department of Medicine, Asker, Norway e Oslo University Hospital Trust, Division Ullevål, Department of Cardiology, Oslo, Norway b

c

Received 20 May 2009; received in revised form 8 January 2010; accepted 6 April 2010 Available online 8 May 2010

Abstract Background: Hospitalization rates, morbidity and mortality are undesirably high in heart failure (HF) patients. An organized system of HF specialist outpatient care has been recommended, but the best way to implement such programmes is not clearly established. Aim: To evaluate HF patient characteristics, management and outcome in outpatient HF clinics. Methods: Data from HF patients at 24 hospital outpatient clinics were entered in a common database allowing each centre to monitor its own practice against the rest. Results: A total of 3632 patients were included. At the last registered visit, ACE inhibitors or angiotensin receptor blockers were prescribed for 87%; beta blockers, 83%; spironolactone, 33% and loop diuretics 87% of the patients. The number of hospital admissions and days stayed in hospital for cardiovascular reasons were significantly reduced (p b 0.001). Mortality was high, 11.5 and 22% after one and two years, respectively. Conclusions: The use of evidence-based medication increased over time in HF clinics with the ability of the individual clinics to compare their treatment to other sites. Thus, establishment of specialized HF clinics managed in a registry network might improve the quality of care. © 2010 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. Keywords: Disease management; Drug therapy; Female; Heart failure; Outpatients; Mortality

1. Introduction Hospitalization rates, morbidity and mortality are undesirably high in heart failure (HF) patients [1]. Nearly 50% of patients are readmitted within one year following their first ☆ Presented in part at the World congress of Cardiology September 3, 2006, Barcelona, Spain and published on the web site: http://www.cic. escardio.org/AbstractDetails.aspx?id=46511&eevtid=15. ⁎ Corresponding author. Department of Medicine, Innlandet Hospital Trust, Division Lillehammer, Anders Sandvigsgate 17, 2629 Lillehammer, Norway. Tel.: +47 61272008; fax: +47 61272039. E-mail address: [email protected] (M. Grundtvig).

hospital admission for HF [2]. Medications such as angiotensin converting enzyme inhibitors (ACE inhibitors), beta blockers and aldosterone receptor antagonists have substantially reduced mortality and hospitalizations in HF patients [3], however these medications are generally underused [4]. Results of management strategies used in these programmes have been variable, but recent meta-analyses have shown that HF management programmes reduce overall mortality and hospitalization, improve quality of life, self care ability, survival rates, and reduce health care costs [5,6]. Establishment of an organized system of HF specialist care is therefore a class I recommendation, as detailed by the

1474-5151/$ - see front matter © 2010 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejcnurse.2010.04.001

M. Grundtvig et al. / European Journal of Cardiovascular Nursing 10 (2011) 44–49

European Society of Cardiology [3], but to date, practice has been quite variable, and the best possible way to implement such programmes of care is not clearly established. We established a database for recording of disease management in Norwegian outpatient HF clinics and it was developed so as to allow each participating centre to continuously monitor its own treatment against other participating hospitals. The primary endpoint of this study was to examine the hypothesis that the utilization of evidence-based treatment protocols would improve with time by the participating centres. The secondary endpoint was to describe the characteristics, hospital admissions and mortality of patients in a Norwegian outpatient heart failure population. 2. Methods 2.1. Patients Patients referred to Norwegian HF outpatient clinics were enrolled between October 2000 and February 2006. The number of participating sites gradually increased from 10 to 24 by 2004. Seven of the 8 university hospitals and 10 of the 21 central hospitals were represented and well distributed in all regions of the country. All participating hospitals have specially trained nurses working in close cooperation with cardiologists. Patients of both genders with a diagnosis of HF according to the European Society of Cardiology were enrolled in the registry. The intention was to register consecutive patients. At the first visit (visit 1) all relevant medical history, physical examination data, blood chemistry results and management regimens, including medical treatment, were recorded in the registry database. Similarly, all data from visit 2 and visit 3 (six months after visit 2) were entered for these clinic participants. Registration from visit 2 was entered when all information and optimal titration of drugs had been performed. Thus, the number of follow-up attendances between visits 1 and 2 was decided at each hospital according to the patient's needs. Mortality data were obtained at regular intervals from the National Statistics Bureau, Statistics Norway. No centre was offered incentives to participate except for the interest in being part of the network and the possibility to join a meeting about the registry once a year. The investigation conforms to the principles outlined in the Declaration of Helsinki. All patients gave their written informed consent. The study was approved by the Regional Committees for Medical and Health Research Ethics and the Norwegian Data Inspectorate.

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antagonist, thiazide diuretic, aspirin, warfarin, statin, aldosterone antagonist and angiotensin receptor antagonists by the study subjects. Diagnosis of HF was based on typical symptoms and clinical and radiological signs of pulmonary congestion. Most patients also demonstrated objective evidence of myocardial dysfunction. Underlying diagnosis of coronary artery disease was based on angiograms or a history of myocardial infarction. Serum creatinine was used to calculate the estimated glomerular filtration rate (eGFR) according to the MDRD formula [7]. The daily dose of loop diuretics was expressed in furosemide equivalents (e.g., bumetanide 1 mg = furosemide 40 mg). If the patient was treated with a thiazide, 10 mg was added to express the total daily dose of diuretic. The dose was calculated for each patient from visits 1 to 2. Additionally, the dose at the last visit was calculated for the aggregate database utilizing those registered in the first half of the study compared to those registered in the last half of the study. 2.3. Statistical analysis Continuous variables are expressed as mean ± standard deviation (SD). When comparing NYHA functional class, hospitalization pre and post intervention and rate of prescription of drugs, only paired samples were used. These were assessed by Student's t-test after log transformation of the data for variables not normally distributed. New York Heart Association functional class (NYHA class) was converted to numerical heart failure functional codes from 1 to 5 by splitting functional class III into codes 3 and 4. Patients who were assigned to code 4 were not able to cover 325 m during the 6-min walk test. Each of the following parameters was dichotomised to investigate associations with subsequent mortality: blood haemoglobin at 12 g/100 ml, serum creatinine at 100 µmol/l, coronary artery disease as aetiology for the presence of heart failure, body mass index at the median for men and women separately, eGFR at 60 ml/min and at the median value for serum sodium, potassium and uric acid. The hazard ratio for the risk of death was calculated in univariate analysis using Pearson's chi-square. Variables at the first visit with a p value b 0.10 associated with mortality by univariate analysis were selected for hazard ratio of time to death by Cox regression using the forward Wald method for all the 3632 patients. Variables in the final equation were deemed significant with a p value of less than 0.05. A Kaplan Meyer plot of survival was constructed for all patients. Analyses were performed using SPSS statistical software for Windows (SPSS inc. Chicago, IL, v. 14.0).

2.2. Measurements 3. Results The content of local programmes was decided by each hospital, but in general consisted of patient education, selfmanagement guidelines, and medication adjustments. Data input included the type and amount of ACE inhibitor, beta blocker and diuretic prescribed as well as the use of calcium

Data are reported for the first 3632 patients of whom 30% were female. Baseline characteristics of the patients are reported in Table 1. Note that 1296 patients completed only visit 1, 934 patients completed only through visit 2 while

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M. Grundtvig et al. / European Journal of Cardiovascular Nursing 10 (2011) 44–49

Table 1 Baseline clinical, demographic characteristics and medication prescribed at the last registered visit of patients at participating heart failure outpatient clinics. N = 3632. Data are given as mean ± SD or as percentages. Demographic profile Women (%) Mean age (years) Lives alone (%) Daily smoking (%) NYHA class (%) I/II/IIIA/IIIB/IV Aetiology (%) Coronary artery disease Dilated cardiomyopathy Hypertension Valvular Congenital heart disease Hypertrophic cardiomyopathy Other and unknown Left ventricular ejection fraction (%) Body mass index (kg/m2) Hemodynamics Heart rate (bpm) Systolic blood pressure (mm Hg) Atrial fibrillation (%) Co-morbidity (%) Hypertension Diabetes mellitus Chronic obstructive airway disease History of stroke Intermittent claudication Blood profile Hemoglobin (g/100 ml) Sodium (mmol/l) Potassium (mmol/l) Creatinine (µmol/l) eGFR (ml/min/) Uric acid (mmol/l) Total cholesterol (mmol/l Medication at the last registered visit (%) ACE inhibitor ARB Beta blockers Diuretic* Aldosterone antagonist Statin Aspirin Warfarin

30 70.8 ± 11.8 33 16 5/43/40/12/1 57 14 9 6 0.3 1 12 33 ± 12 26 ± 4.9 73 ± 15 126 ± 23 27 30 19 17 11 6 13.7 ± 1.7 140 ± 3.5 4.4 ± 0.5 110 ± 49 64 ± 23 470 ± 137 4.9 ± 1.3 73 14 83 87 27 50 41 48

Diagnosis of HF was based on objective measurement of myocardial function in 80% of study subjects, whereas diagnosis was based solely on clinical criteria in 15% and on chest X-ray in 5%. Left ventricular function was measured utilizing echocardiography in 95.4%, radionuclide ventriculography in 2.4% and angiography in 2% of the patients. Cardiac MRI was used in only two patients. Of the patients who had their left ventricular ejection fraction (LVEF) measured (N = 3161), 73% had LVEF b 40%; 19%, 40-50%; and 8%, N 50%. The main causes of HF are given in Table 1. Almost 1/3rd of the patients had previously undergone coronary intervention. A number of comorbid conditions were seen: 58% had at least one comorbid condition — 36% had one, 17% had two, 4% had three and 1% had four. The comorbid conditions, distribution of NYHA functional classes and hemodynamics are given in Table 1. During the treatment period, functional status improved by one or two heart failure functional codes in 29%, while 65% remained unchanged and 7% worsened (Fig. 1). The mean time intervals between visits 1 and 2 were 123 ± 138 days and between visits 2 and 3 were 7 ± 4.2 months. Paired data were available for 1169 patients with respect to the number of hospital admissions for cardiovascular reasons when comparing the 6 month periods before visit 1 and after visit 2. The number was markedly reduced from 885 to 179 admissions and the corresponding number of days stayed in hospital was reduced from 8112 to 1613, both p b 0.001). Since one of the clinics' main functions was to adjust medication, the drug treatments at the last registered visit for each individual patient are shown in Table 1. Treatment with an aldosterone antagonist was prescribed for 33% of the patients in NYHA class III to IV. During follow-up, (analysed using paired samples) no significant changes in the proportion of patients using ACE-inhibitors or diuretics were found ,77 and 76% and 88 and 88%, respectively, while

*In this context an aldosterone antagonist is not counted as a diuretic. ACE = angiotensin converting enzyme. ARB = angiotensin II receptor blocker. eGFR = estimated glomerular filtration rate — see Methods, Section 2.2 for calculation of eGFR.

1402 participants completed visit 3 before file closure (see Methods, Section 2.1 above for definition of visits). The mean age was 69.8 ± 12 for men and 73.2 ± 11.2 years for women (p b 0.001), while the median age was about 2 years higher than the mean for both genders. Fifty-two percent of the females and 40% of the male patients were older than 75 years. The majority of patients (91%) were referred from their hospital and 8% from their primary care doctor and 71% had been admitted for cardiovascular reasons in the 6 month period before visit 1.

Fig. 1. Change in heart failure functional code* from visit 1 to visit 2§ for patients attending specialized managed outpatient heart failure clinics (N=2206). * Heart failure functional code: The NYHA classification was converted into numbers 1-5 by splitting NYHA class III into codes 3 and 4 according to performance in the six minute walk test. §See Methods, Section 2.1 for definition of visits.

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Fig. 2. Percentage medications prescribed at visit 1 and visit 2§ for the first half of enrolees attending specialized managed outpatient heart failure clinics as compared to the second half at each site. §See Methods, Section 2.1 for definition of visits.

the use of angiotensin II receptor blockers (ARBs) increased from 12 to 17% (p b 0.05) and beta blockers from 79 to 87% (p b 0.01). The daily dose of ACE inhibors and betablockers did not change (data not shown), while the mean daily dose of diuretics decreased from 58 to 53 mg/day (p b 0.01). However, the use of diuretics was quite variable among individual hospitals ranging from a mean daily dose of 40.7 to 88 mg at the last visit. Patients with obstructive airway disease, diabetes mellitus and intermittent claudication were treated with a beta blocker in 76, 84 and 81% of cases, respectively. This statistic was significantly less for those with obstructive airway disease than those without this comorbidity (p b 0.001). When comparing those entered as part of the first half of the study participants to the patients to the last half in each centre, the use of either ACE inhibitors or ARBs were unchanged while the use of beta blockers increased from 82% to 89% (p b 0.05), (Fig. 2), and the use of aldosterone antagonists increased from 28% to 30% (p b 0.01). The daily doses of the most commonly used ACE inhibitors and betablockers remained unchanged (enalapril 16.4 ± 6.7 and 16.1 ± 7.8 mg (p = 0.650), ramipril 8.7 ± 3.1 and 8.5 ± 2.9 mg (p = 0.330), carvedilol 35.1 ± 21.6 and 34.0 ± 20.7 mg (p = 0.580) and for metoprolol 111.5 ± 62.7 and 110.1 ± 61.1 mg (p = 0.684)). The only exception being for lisinopril which decreased from 15.9 ± 6.6 to 14.3 ± 7.0 mg (p = 0.048). The use of diuretic decreased from a mean daily dose of 56 to 51 mg/day (p b 0.05). Mortality at 12 and 24 months post-enrolment in the study was 11.5% and 22% respectively and was significantly related to the daily dose of diuretic (Fig. 3). Univariate analysis revealed that survival was significantly related to several baseline parameters (Table 2), but was not significantly related to the left ventricular ejection fraction (R = −0.004, p = 0.85), gender, present smoking habits, heart rate, warfarin use, asthma/chronic obstructive airways disease, history of treatment for hypertension nor to treatment with a calcium channel blocker. None of the significant parameters had a strong relation to survival. The strongest correlations noted were R2 = 0.057, 0.053 and 0.04 for age, eGFR and heart failure

Fig. 3. Kaplan Meyer plot of survival in patients with heart failure enrolled in specialized managed outpatient heart failure clinics related to the daily dose furosemide equivalents divided into 25 percentiles. The number of patients at the start in each group from top to bottom: 893, 1102, 924 and 546.

functional code respectively. However, in multivariate analysis, the strongest predictor of death was the daily dose of diuretic at the first visit. The mean age at death was 75 ± 9.9, and 77.4 ± 9.8 years for men and women, respectively. The median age was 2 years higher for both genders. Cox regression analysis demonstrated that 8 parameters were significantly related to mortality (see Table 2).

4. Discussion The patients in The Norwegian HF Registry were relatively old with a mean age of 71 years and had a high prevalence of comorbid conditions. The use of evidencebased medication was high and compares favourably to other registries [8,9]. More than 86% of the patients used an ACE inhibitor or an ARB and 83% a beta blocker. Importantly, the use of beta blockers increased as demonstrated by marked improvement upon comparison of the first half with the second half of the patients registered at each clinic. Old patients, and patients with co morbidities, such as diabetes mellitus, obstructive airways disease and peripheral vascular disease, among which ACE inhibitors/ARBs and beta blockers are underutilized [4], could tolerate such medications in a large proportion of cases. Since both treatments are effective in these subgroups [10], this strongly suggests that these medications should be used and up-titrated in almost all patients with HF. Mortality was high, especially among those using the highest dose of diuretics. The dose of diuretics decreased during the time in the clinics which is in accordance with the view that the use of diuretic is only for symptomatic relief and should be used with caution in elderly patients [11]. Interestingly, the daily dose of diuretics was one of the strongest predictors of

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Table 2 Risk of death according to parameters at the first visit in patients attending specialized outpatient heart failure clinics. Variable

Daily dose diuretic Age HF functional code eGFR Blood Hemoglobin S-Sodium Stroke IHD Systolic BP S-uric acid Diabetes mellitus Lives alone S-potassium Aldosterone antagonist Aspirin Statin Intermittent claudication Coronary intervention No of admissions No of days in hospital ACE inhibitor Beta blockers ACE/ARB BMI

Univariate analysis

Cox regression analysis

HR (95% CI)

p

HR (95% CI)

p

2.38 (2.04-2.79) 2.55 (2.17-2.99) 2.39 (2.03-2.81) 0.34 (0.29-0.40) 0.48 (0.39-0.58) 0.79 (0.68-0.92) 1.82 (1.44-2.30) 1.71 (1.45-2.03) 0.73 (0.63-0.85) 1.67 (1.37-2.03) 1.37 (1.12-1.66) 1.16 (0.99-1.36) 1.17 (1.00-1.36) 1.44 (1.22-1.71) 0.81 (0.70-0.94) 0.67 (0.58-0.79) 2.08 (1.55-2.80) 0.81 (0.68-0.97) 1.21 (1.00-1.45) 1.35 (1.15-1.60) 0.86 (0.72-1.03) 0.65 (0.54-0.78) 0.63 (0.50-0.79) 0.66 (0.56-0.78)

b0.001 b0.001 b0.001 b0.001 b0.001 0.003 b0.001 b0.001 b0.001 b0.001 0.002 0.073 0.049 b0.001 0.007 b0.001 b0.001 0.023 0.045 0.045 0.091 b0.001 b0.001 b0.001

1.83 (1.48-2.27) 1.52 (1.22-1.91) 1.52 (1.20-1.91) 0.63 (0.50-0.79) 0.61 (0.48-0.78) 0.71 (0.58-0.88) 1.40 (1.06-1.86) 1.27 (1.02-1.57) … … … … … … … … … … … … … … … …

b0.001 b0.001 b0.001 0.002 b0.001 0.001 0.016 0.016 … … … … … … … … … … … … … … … …

R = hazard ratio. BP = blood pressure. No. of admissions and No. of days in hospital = in the 6 months before the first visit for cardiovascular reasons. ACE = angiotensin converting enzyme. ARB = angiotensin receptor blocker. BMI = body mass index. eGFR = estimated glomerular filtration rate. IHD = ischemic heart disease. Variables with a univariate value of p b 0.1 were used in the Cox regression analysis.

death. This is in accordance with previous studies among patients with acute HF [12] and chronic stable HF [13]. Although a major reason for using higher doses of diuretic is more severely ill patients with impaired renal function, the diuretic dosing in the present study was quite variable among hospitals, but in multivariate analysis diuretic dose was an independent predictor of death. Thus, until we have more data regarding the dosing of diuretics, the present data suggest that diuretic dose should be kept at the lowest possible level, and a major effort should be to teach the patients how to use these drugs. This should be the focus of a randomized trial. In Norway HF patients have traditionally been taken care of in general practice, while the establishment of outpatient HF clinics has been up to the local clinics to decide. Furthermore, there has been scarcity of data evaluating treatment and the quality of care. We reasoned that a common database with online registration of data and the allowance of each clinic to monitor itself against the rest could be one way to improve the quality of treatment. The present study has demonstrated that while the use of ACE inhibitors/ARBs was high and unchanged the use of beta blockers and aldosterone blockers improved and diuretic dose decreased both during the management in the clinics, and also markedly comparing the first half with the second half of patients entering each clinic. We cannot rule out that this also would have happened without such a database, but we believe that motivation was greatly

enhanced with such a system and contributes to the high use of evidence-based medication. A high proportion of our patients improved in terms of heart failure functional status, while few worsened during followup. This is in agreement with a thorough meta-analysis on the effectiveness of comprehensive disease management programmes in improving clinical outcomes in HF described by Roccaforte et al. [6]. Our patients had a significantly lower rate of admission (16%) and number of hospital days for cardiovascular reasons in the 6 months after entering the HF clinic compared to the 6 months before enrolment in the study, similar to results reported in other studies [14,15]. There are a few limitations to the data presented from our registry. Changes in hospitalization rates from prior to enrolment in the study to post-enrolment may be exaggerated since the majority of patients were recruited after hospitalization for HF. This part of the results therefore does not provide insight into the management of HF by general practitioners as compared to specialist care. Our data were observational with no control group, and it should be noted that although there was significant improvement in heart failure functional status, others have found improvement in placebo treated patients [16]. The lack of a control group does not allow drawing any conclusion about the effectiveness of such programmes in terms of clinical outcomes. As specialized HF clinics have a class I

M. Grundtvig et al. / European Journal of Cardiovascular Nursing 10 (2011) 44–49

indications as delineated by the ESC [3], different programmes could be evaluated by randomization. Although inclusion of BNP or proBNP might have increased the predictiveness of mortality, there was not enough data available to reliably do so. In conclusion, the use of evidence-based medication increased over time in HF clinics with the ability of the individual clinics to compare their treatment to other sites. Thus, the establishment of specialized HF clinics managed in a registry network might improve the quality of care. Acknowledgements The following hospitals participated in the HF registry: Aker universitetssykehus HF, Akershus universitetssykehus HF, Diakonhjemmet sykehus, Haukeland Universitetssykehus, Helse Nord Trøndelag HF, Levanger, Helse Stavanger HF, Helse Sunnmøre HF, Ålesund, Lovisenberg diakonale sykehus, Nordlandssykehuset HF, Bodø, St. Olavs hospital HF, Sykehuset Asker og Bærum HF, Sykehuset Buskerud HF, Drammen, Sykehuset i Telemark HF, Skien, Sykehuset i Vestfold HF Tønsberg, Sykehuset Innlandet HF Gjøvik, Sykehuset Innlandet HF Hamar, Sykehuset Innlandet HF Lillehammer, Sykehuset Østfold HF Moss, Sykehuset Østfold HF Sarpsborg, Stavanger Universitetssjukehus, Stavanger, Sørlandet Sykehus HF Kristiansand, Sørlandet Sykehus HF Lister, Sørlandet Sykehus HF, Arendal, Oslo universitetssykehus HF - Ullevål, Universitetssykehuset Nord-Norge HF. AstraZeneca, Norway AS (who did not have access to the data) provided secretarial assistance and database maintenance by an external IT consultant.

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