Archives of Cardiovascular Disease (2014) 107, 21—32
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CLINICAL RESEARCH
Prescription of cardiovascular drugs in the French ODIN cohort of heart failure patients according to age and type of chronic heart failure Prescription des médicaments à visée cardiovasculaire selon l’âge et le type d’insuffisance cardiaque chronique dans la cohorte franc ¸aise ODIN Yves Juillière a,∗, Christine Suty-Selton a, Elisabeth Riant a, Jean-Pierre Darracq b, Arnaud Dellinger c, Jean-Philippe Labarre d, Justine Druelle e, Geneviève Mulak f, Nicolas Danchin g, Patrick Jourdain h , for the ODIN cohort participants a
Cardiology Department, institut Lorrain du coeur et des vaisseaux, allée du Morvan, 54500 Vandœuvre-lès-Nancy, France b Cardiology, CHG Samuel-Pozzi, Bergerac, France c Cardiology, CHG William-Morey, Chalon-sur-Saône, France d Cardiology, clinique Château-de-Vernhes, Bondigoux, France e URC-Est, CHU Saint-Antoine, Paris, France f French Society of Cardiology, Paris, France g Cardiology, European Hospital Georges Pompidou, Paris, France h Cardiology, CHG René-Dubos, Pontoise, France Received 22 April 2013; received in revised form 21 November 2013; accepted 25 November 2013 Available online 30 December 2013
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; CHF, chronic heart failure; HF-BEF, heart failure with borderline ejection fraction; HF-PEF, heart failure with preserved ejection fraction; HF-REF, heart failure with reduced ejection fraction; I-CARE, insuffisance cardiaque : éducation thérapeutique; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid-receptor antagonist; ODIN, observatoire de l’insuffisance cardiaque. ∗ Corresponding author. E-mail address: [email protected] (Y. Juillière). 1875-2136/$ — see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.acvd.2013.11.001
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KEYWORDS Age; Cardiovascular drugs; Systolic heart failure; Heart failure with preserved ejection fraction; Left ventricular ejection fraction
MOTS CLÉS Âge ; Médicaments cardiovasculaires ; Insuffisance cardiaque systolique ; Insuffisance cardiaque avec fraction d’éjection préservée ; Fraction d’éjection ventriculaire gauche
Summary Background. — Chronic heart failure (CHF) is a frequent severe disease. Disease-management programmes, which contain a therapeutic patient education component, will play a central role in improving delivery of care and reducing mortality and hospitalizations for CHF. Aims. — In order to have an up-to-date overview of medical treatment of CHF in France implemented by hospital and clinic cardiologists especially interested in CHF and therapeutic patient education, we described the prescription of cardiovascular drugs in the large ODIN cohort of CHF patients, according to age and type of CHF. Methods. — From 2007 to 2010 (median follow-up 27.2 months), CHF patients were prospectively enrolled in a multicentre ‘real-world’ French cohort by centres previously trained in therapeutic patient education. Patients were grouped according to age (< 60 years, 60 to < 70 years, 70 to < 80 years and ≥ 80 years) and type of CHF (characterized by level of LVEF: reduced, borderline or preserved). Medical prescription was described and mortality was assessed at long-term follow-up. Results. — The cohort consisted of 3237 patients (67.6 years; 69.4% men). The oldest age group had the highest LVEF. Blockers of the angiotensin-aldosterone system were prescribed progressively and significantly less frequently as the population advanced in age or as LVEF was more preserved. The mean dosages of the main prescribed CHF drugs remained ≥ 50% lower than those recommended for most drugs in all age and LVEF groups. Drug prescriptions were related to aetiology of reduced or preserved CHF. A global decrease in CHF drug prescription was observed for all medication classes except calcium blockers, according to maintenance of relatively or totally preserved LVEF. Survival was related to age but not to type of CHF. Conclusion. — In CHF, and despite management by cardiologists particularly interested in CHF and specifically trained to deliver therapeutic patient education, medical prescription differed substantially from guidelines. Age and type of CHF (reduced versus preserved) appeared to be important factors in lack of adherence to guidelines. However, only age influenced mortality; the type of CHF did not affect survival. © 2013 Elsevier Masson SAS. All rights reserved.
Résumé Contexte. — L’insuffisance cardiaque (IC) est une maladie fréquente et sévère. Les programmes de prise en charge de la maladie, qui contiennent une composante d’éducation thérapeutique du patient, jouent un rôle central dans l’amélioration des soins et la réduction de la mortalité et des hospitalisations liées à l’IC. Objectif. — Afin d’avoir un aperc ¸u récent du traitement médical de l’IC en France, mis en place par des cardiologues d’hôpitaux ou de cliniques spécialement intéressés par l’IC et l’éducation thérapeutique du patient, nous avons décrit la prescription des médicaments cardiovasculaires au sein de la grande cohorte ODIN de patients IC selon l’âge et le type d’IC déterminé par le niveau de fraction d’éjection ventriculaire gauche (FEVG). Méthodes. — De 2007 à 2010 (suivi médian 27,2 mois), les patients IC étaient prospectivement inclus dans une cohorte franc ¸aise multicentrique sur la base de la pratique réelle, par des centres ayant été formés à l’éducation thérapeutique du patient. Les patients étaient regroupés selon leur âge (< 60 ans ; 60 à < 70 ans ; 70 à < 80 ans ; et ≥ 80 ans) et le type d’IC caractérisé par le niveau de FEVG (réduite, borderline ou préservée). La prescription médicale était décrite et la mortalité était évaluée à long terme. Résultats. — La cohorte comprenait 3237 patients (67,5 ans ; 69,5% d’hommes). Le groupe d’âge le plus âgé avait la FEVG la plus haute. Les bloqueurs du système angiotensine-aldostérone étaient progressivement et significativement moins prescrits alors que la population avanc ¸ait en âge ou que la FEVG était plus préservée. Le dosage moyen des drogues principalement prescrites dans l’IC restait au moins 50 % plus bas que celui recommandé pour la majorité des substances dans tous les groupes d’âge ou de FEVG. La prescription des médicaments était liée à l’étiologie de l’IC avec FEVG réduite ou préservée. Une diminution globale de la prescription des médicaments de l’IC était observée en fonction du maintien d’une FEVG relativement ou totalement préservée, pour toutes les classes de médicaments à l’exception des inhibiteurs calciques. La survie était liée à l’âge mais pas au type d’IC.
Prescription of cardiovascular drugs in the French ODIN cohort
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Conclusions. — Dans l’IC et malgré une prise en charge par des cardiologues particulièrement intéressés à l’IC et spécifiquement formés pour pratiquer une éducation thérapeutique du patient, la prescription médicale différait sensiblement des recommandations. L’âge et le type d’IC (systolique vs à fonction systolique préservée) étaient d’importants facteurs d’inadéquation à la prescription médicale recommandée. Cependant, seul l’âge influenc ¸ait la mortalité; le type d’IC défini par le niveau de FEVG ne jouait aucun rôle dans la survie. © 2013 Elsevier Masson SAS. Tous droits réservés.
Introduction Chronic heart failure (CHF) is a frequent severe disease that has become a major public health problem in industrialized countries [1,2]. In this context, disease management programmes appear geared up to play a central role in improving delivery of care [3,4] and reducing mortality and CHF hospitalizations, as established by meta-analyses [5,6]. As an integral part of disease management programmes, therapeutic patient education [7] has been recognized in most industrialized countries [4,8—10] and is recommended in European guidelines [11]. Following this format, the insuffisance cardiaque : éducation thérapeutique (I-CARE) programme was developed in France to promote the establishment of therapeutic patient education units in all types of cardiology centres, based on a voluntary approach by the medical team [12]. A large prospective multicentre French cohort of CHF patients (ODIN: observatoire de l’insuffisance cardiaque) enrolled in I-CARE centres trained in therapeutic patient education for CHF was constituted from 2007 to 2010 to assess the role of therapeutic patient education applied in routine practice; therapeutic patient education by trained health professionals appeared to be associated with a decrease in all-cause mortality [13]. Among multivariable independent prognostic factors of survival, younger age and prescription of recommended neurohormonal blockers appeared to play an important role. In order to have an up-to-date overview of medical treatment of CHF in France implemented by hospital and clinic cardiologists especially interested by CHF and trained in therapeutic patient education, we decided to describe the prescription of cardiovascular drugs in the large ODIN cohort of CHF patients, according to age and type of CHF.
Methods Patient population Selection of centres has been described in detail previously [13]. Briefly, centres had to have fulfilled the requirements for participation in the I-CARE programme [14], thereby validating their specialization in CHF management. Training was completed for 110 centres in 2007 and for more than 220 in 2010. Among the first 110 trained centres throughout France, 61 (55.5%) volunteered to contribute patients to the ODIN cohort. Patients were enrolled prospectively between 2007 and 2010; during this period the therapeutic guidelines for CHF remained largely stable [11]. Enrolment in the study was
consecutive. To increase the external validity, exclusion criteria were deliberately kept to a minimum: patients were excluded only if they attended sites not participating in the I-CARE programme or if they declined to participate. All patients received usual care, which consisted of care management according to European guidelines [11]. Medical therapy was adjusted as judged necessary by the investigator. Patients completed a full education programme [13,14] in addition to receiving usual care. Four patient groups were defined according to age: < 60 years (Age 1); 60 to < 70 years (Age 2); 70 to < 80 years (Age 3); and ≥ 80 years (Age 4). The initial clinical questionnaire did not take into account the pathophysiological type of CHF (i.e. systolic or diastolic CHF); however, left ventricular ejection fraction (LVEF) was available in 92.3% of the patients, with a mean value of 39.8 ± 14.2% (range 6—88%). The threshold for defining LVEF groups has been discussed in European and American heart failure guidelines [15,16]. We chose the usual 45% threshold for defining reduced LVEF and the 50% threshold for defining preserved LVEF. In accordance with the American guidelines [16], we preferred to create a borderline group to see if patients with an LVEF between 45 and 50% presented a similar profile to one of the other usual LVEF groups. It was therefore decided to create three groups according to LVEF: < 45% (heart failure with reduced ejection fraction, HF-REF); 45—50% (heart failure with borderline ejection fraction, HF-BEF); and > 50% (heart failure with preserved ejection fraction, HF-PEF).
Data collection The investigation conformed to the principles outlined in the Declaration of Helsinki. The study was approved by the Commission nationale informatique et liberté — as required by French law for any patient cohort study in France — and the institutional independent ethical committee of the French Society of Cardiology. All patients gave informed consent before their inclusion in the cohort. Declarations of inclusion were made by centres on both nominative 1page and medical 2-page record forms for each patient after being given an anonymous number by the centre; these were mailed separately to the French Society of Cardiology. Data were then recorded on two types of computerized case record forms according to the procedure requested and approved by the Commission nationale informatique et liberté. Data were collected on the main cardiovascular classes of drugs administered by the oral route: all recommended CHF classes (angiotensin-converting enzyme inhibitors [ACEIs],
24 beta-blockers, angiotensin-receptor blockers [ARBs], diuretics, mineralocorticoid-receptor antagonists [MRAs], digoxin and nitrates) and all other main non-CHF cardiovascular classes usually prescribed for the treatment of CHF causes or complications (amiodarone, antiplatelet therapies [aspirin and clopidogrel], anticoagulant drugs [antivitamin K therapies only], calcium blockers and statins). Furthermore, for all main CHF classes, the types of drugs used most frequently were listed with their daily dosage (perindopril and ramipril for ACEIs; bisoprolol, carvedilol, metoprolol and nebivolol for beta-blockers; candesartan and valsartan for ARBs; furosemide for loop diuretics; and eplerenone and spironolactone for MRAs) [13]. Follow-up data were collected through contact with the attending physicians, the patients or their families. If missing, vital status was assessed from the registries of the patients’ birthplaces. Only 4.9% (n = 158) of patients were lost to follow-up.
Statistical analysis All continuous variables are described as means ± standard deviations, except for time variables, which are expressed as medians [interquartile ranges]. All categorical variables are described with absolute and relative frequency distributions. Comparisons between groups used one-way analysis of variance and unpaired t tests for continuous variables and 2 tests for discrete variables. The Bonferroni test was used for comparisons between LVEF groups. Survival curves were generated by the Kaplan-Meier method and compared with log-rank tests. Prognostic factors for mortality, including age-defined groups, LVEF-defined groups, risk factors, heart failure aetiology, biological variables and main CHF drug treatments, were analysed with bivariate and multivariable Cox models. Biological variables were categorized into quartiles for serum creatinine (< 9.5 mg/L; 9.5—11.5 mg/L; > 11.5—15.0 mg/L; > 15 mg/L) or divided according to their median value for serum glucose (≤ and > 0.99 g/L) and serum haemoglobin (≤ and > 13.0 g/L). Serum natriuretic peptides were organized as non-decompensated (defined as B-type natriuretic peptide ≤ 400 pg/mL and/or N-terminal pro-B-type natriuretic peptide ≤ 450 pg/mL if the patient was aged < 50 years, ≤ 900 pg/mL if aged between 50 and 75 years and ≤ 1800 pg/mL if aged > 75 years) or decompensated levels. For multivariable models, a stepwise variable selection with sle = 0.1 and sls = 0.05 was applied. Results are expressed as hazard ratios with a 95% confidence interval. All statistical analyses were performed using SPSS version PASW 18.0 software. For all tests, P < 0.05 was considered significant.
Results Cardiovascular medications in the whole population The ODIN population has been detailed previously [13]. In summary, a total of 3248 patients were included in the ODIN cohort, 11 of whom were declared twice (i.e. by two different centres). For these patients, the first declaration
Y. Juillière et al. was considered as the inclusion in the cohort and the second declaration was considered as a follow-up visit. The ODIN cohort therefore comprised 3237 patients with a mean age of 67.6 ± 14.2 years (range 16—97 years); 69.4% were men. Baseline clinical and biological main variables according to age-defined and LVEF-defined groups are reported in Table 1. For CHF-dedicated medications, the large majority of patients received blockers of the renin-angiotensin system (69.9% received ACEIs and 20.3% received ARBs, which were always prescribed for ACEI intolerance), beta-blockers (80.6%), and loop diuretics (80.1%). Fewer patients were treated with MRAs (32.7%), digoxin (12.6%) and nitrates (8.7%). Regarding other cardiovascular medications, 20.4% of the population received amiodarone, 40.8% received aspirin, 18.0% received clopidogrel, 43.3% received oral anticoagulants, 8.8% received calcium blockers and 50.0% received statins [13]. Mean duration of follow-up was 25.9 ± 11.7 months. Death was the only event collected during follow-up; 682 deaths were recorded. Multivariable Cox analysis found the usual predictors of survival (Table 2).
Age and prescription of cardiovascular medications Regarding the four age-defined groups, there were 985 (30.4%) patients in Age 1, 669 (20.7%) in Age 2, 869 (26.8%) in Age 3 and 714 (22.1%) in Age 4. The percentage of men decreased according to age group (74.1% in Age 1, 75.9% in Age 2, 70.2% in Age 3 and 56.0% in Age 4; P < 0.001). Mean LVEF was significantly different according to age group: the older the age group, the higher the mean LVEF (36.0 ± 12.3% for Age 1, 38.3 ± 13.9% for Age 2, 41.2 ± 14.7% for Age 3 and 44.8 ± 14.7% for Age 4; P < 0.001) (Fig. 1). Cumulative survival curves showed the effect of age on survival (Fig. 2). The three major CHF medications (ACEIs + ARBs, betablockers and MRAs) were prescribed progressively and significantly less frequently as the population advanced in age (Fig. 3). By comparison, loop diuretics, digoxin and nitrates were prescribed more frequently with advancing age. For the other drugs, prescriptions were probably related to aetiology (antiplatelet therapies, statins or calcium blockers) or the presence of atrial arrhythmias (amiodarone and anticoagulants) (Fig. 3) [13]. The mean dosages of the main prescribed CHF drugs remained ≥ 50% lower than those recommended for the majority of the drugs (Table 3). The older the age, the lower the mean dosage (Table 3).
Type of CHF and prescription of cardiovascular medications Regarding the three LVEF-defined groups, there were 1934 (59.7%) patients in HF-REF, 460 (14.2%) patients in HF-BEF and 595 (18.4%) patients in HF-PEF. The LVEF value was unknown in 248 patients (7.7%) out of the whole ODIN population. The percentage of men was higher in case of reduced LVEF (75.8% in HF-REF, 65.2% in HF-BEF and 55.1% in HF-PEF; P < 0.001). Mean age was higher in case of preserved LVEF
Prescription of cardiovascular drugs in the French ODIN cohort Table 1
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Main patient characteristics according to age-defined and LVEF-defined groups.
Women Age (years) Ischaemic heart disease DCM Hypertension Diabetes Hypercholesterolaemia Smoking NYHA III/IV class LVEF (%) Atrial fibrillation LBBB Biventricular pacemaker ICD BMI (%) Serum glucose (g/L) Serum creatinine (mg/L) Serum haemoglobin (g/L) BNP (pg/mL) NT-BNP (pg/mL) Follow-up deaths
Age 1
Age 2
Age 3
Age 4
P
HF-REF
HF-BEF
HF-PEF
P
26 50.2 ± 8.1 38
24 64.9 ± 3.0 48
30 75.3 ± 2.9 53
44 84.7 ± 3.3 50
< 0.001 < 0.001 < 0.001
24 65.6 ± 13.9 52
35 68.6 ± 14.2 45
45 72.3 ± 12.9 34
< 0.001 < 0.001 < 0.001
37 36 25 46
28 56 39 58
19 65 43 58
12 67 27 43
< 0.001 < 0.001 < 0.001 < 0.001
32 49 31 53
20 57 35 52
11 71 38 47
< 0.001 < 0.001 0.006 ns
55 13.5 36.0 ± 12.3 9.3 21.8 5.7
44 17.0 38.3 ± 13.9 20.5 27.4 11.7
34 22.7 41.2 ± 14.7 36.6 26.6 11.2
22 36.5 44.8 ± 14.7 48.9 23.7 5.2
< 0.001 < 0.001 < 0.001 < 0.001 ns < 0.001
45 22.5 31.1 ± 7.4 22.5 29.9 11.5
39 19.1 47.2 ± 2.3 30.3 17.8 5.4
31 17.2 62.0 ± 7.0 40.7 13.8 1.7
< 0.001 0.010 < 0.001 < 0.001 < 0.001 < 0.001
16.8 27.8 ± 6.2 1.07 ± 0.43
19.1 28.1 ± 5.8 1.13 ± 0.42
11.7 27.6 ± 5.5 1.13 ± 0.38
1.7 25.3 ± 4.2 1.09 ± 0.42
< 0.001 < 0.001 0.028
18.9 26.8 ± 5.4 1.07 ± 0.38
3.9 27.8 ± 5.9 1.09 ± 0.38
1.3 28.7 ± 6.3 1.16 ± 0.44
< 0.001 < 0.001 0.002
11.2 ± 5.3
13.1 ± 6.2
13.9 ± 5.8
14.4 ± 6.2
< 0.001
12.8 ±5.7
13.3 ± 7.2
13.3 ± 5.8
ns
13.5 ± 1.9
13.1 ± 1.9
12.6 ± 1.8
12.4 ± 1.8
< 0.001
13.1 ± 1.9
12.7 ± 1.9
12.7 ± 1.9
< 0.001
415 ± 582 2370 ± 3831 9.4
574 ± 874 2875 ± 5149 14.5
816 ± 1374 4115 ± 5420 25.9
1158 ± 1404 6047 ± 7003 37.4
< 0.001 < 0.001 < 0.001
764 ± 1259 4323 ± 6058 20.3
565 ± 735 3803 ± 5697 22.8
550 ± 708 2504 ± 3986 20.5
0.003 0.003 ns
Data are % or mean ± standard deviation. BMI: body mass index; BNP: B-type natriuretic peptide; DCM: idiopathic dilated cardiomyopathy; ICD: implantable cardiac defibrillator; LBBB: left bundle branch block; LVEF: left ventricular ejection fraction; ns: not significant; NT-BNP: NT-pro-type B natriuretic peptide; NYHA: New York Heart Association.
(65.5 ± 13.9 years in HF-REF, 68.6 ± 14.2 years in HF-BEF and 72.3 ± 12.9 years in HF-PEF; P < 0.001). The proportion of older patients (≥ 70 years, Age 3 and Age 4) was higher in case of borderline and preserved LVEF (Fig. 1). Cumulative survival curves showed that type of CHF did not affect survival (Fig. 2).
Regarding aging, the three major CHF medications (ACEIs + ARBs, beta-blockers and MRAs) were prescribed progressively and significantly less frequently as LVEF was more preserved (Fig. 4). However, the use of loop diuretics, nitrates, amiodarone and anticoagulants was influenced poorly or not at all by LVEF. The prescription of the other
Table 2 Multivariable Cox analysis according to age-defined groups, LVEF-defined groups, risk factors and main drug treatments. Variable
Hazard ratio
95% CI
P
Age-defined group LVEF-defined group Valvular heart disease Idiopathic dilated cardiomyopathy Beta-blockers ACEIs or ARBs Loop diuretics Atrial fibrillation Serum haemoglobin Serum natriuretic peptides
1.46 0.80 1.33 0.72 0.76 0.60 2.09 1.40 1.00 1.00
1.33—1.60 0.71—0.89 1.08—1.64 0.57—0.91 0.62—0.92 0.48—0.75 1.51—2.89 1.17—1.67 1.00—1.00 1.00—1.00
< 0.001 < 0.001 0.007 0.006 0.006 < 0.001 < 0.001 < 0.001 0.009 < 0.001
ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; CI: confidence interval; LVEF: left ventricular ejection fraction.
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Figure 1. A. Distribution of types of chronic heart failure (left ventricular ejection fraction < 45% [heart failure with reduced ejection fraction, HF-REF], 45—50% [heart failure with borderline ejection fraction, HF-BEF] and > 50% [heart failure with preserved ejection fraction, HF-PEF]), according to age group (< 60 years [Age 1], 60 to < 70 years [Age 2], 70 to < 80 years [Age 3], and ≥ 80 years [Age 4]). B. Distribution of age groups according to type of chronic heart failure.
drugs was related to aetiology, depending on the presence of reduced or preserved CHF; this was as expected, given that there is less frequent ischaemic heart disease when systolic cardiac function is preserved, resulting in less frequency of prescription of statins and antiplatelet therapies; in addition, systemic hypertension is more frequently associated with preserved ejection fraction, resulting in a higher rate of prescription of calcium blockers (Fig. 4). The mean dosages of the main prescribed CHF drugs also remained ≥ 50% lower than those recommended for the majority of the drugs (Table 4). However, only two drugs had a mean dosage that was significantly different according to the type of CHF: perindopril titrated lower and spironolactone higher in HF-PEF than in HF-REF or HF-BEF (Table 4).
Figure 2. Kaplan-Meier cumulative 2-year survival curve of allcause mortality according to (A) age and (B) type of chronic heart failure. HF-REF: heart failure with reduced ejection fraction; HFBEF: heart failure with borderline ejection fraction; HF-PEF: heart failure with preserved ejection fraction; ns: not significant.
showing a global decrease in CHF drug prescription according to maintenance of relatively or totally preserved LVEF for all classes of medications, except for calcium blockers (which were prescribed increasingly when LVEF was more preserved) and loop diuretics (which were little influenced by the type of CHF).
Interaction between age and type of CHF
Discussion
When comparing prescription of medications in each age group according to type of CHF (Figs. 5—7), differences in drug prescription appeared to persist between age groups,
We assessed the effect of age and type of CHF (defined by the level of LVEF) on prescription of cardiovascular medications in CHF in a large French cohort of CHF patients. In routine
Prescription of cardiovascular drugs in the French ODIN cohort
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Figure 3. Distribution of cardiovascular classes according to age groups. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; MRA: mineralocorticoid-receptor antagonist.
Table 3 groups.
Comparison of mean dosages (mg/day) for the main prescribed chronic heart failure drugs according to age Age 1
Ramipril Perindopril Bisoprolol Carvedilol Nebivolol Candesartan Spironolactone Furosemide
7.1 5.6 5.8 40.0 5.6 15.4 27.4 85
± ± ± ± ± ± ± ±
Age 2 3.3 2.5 3.2 25.0 2.8 9.8 13.1 132
7.0 5.2 5.4 36.1 5.3 14.1 25.8 101
± ± ± ± ± ± ± ±
Age 3 3.1 2.4 3.3 22.6 3.2 9.2 11.1 154
6.3 4.9 4.8 30.1 4.3 14.7 24.2 109
± ± ± ± ± ± ± ±
Age 4 3.2 2.6 3.1 17.3 2.5 9.3 11.5 165
4.9 4.4 3.8 22.8 3.9 11.6 23.7 102
± ± ± ± ± ± ± ±
P 3.2 2.3 2.7 16.7 2.7 7.3 10.4 133
< 0.001 < 0.001 < 0.001 < 0.001 0.003 0.024 0.004 0.021
Data are mean ± standard deviation.
Table 4 groups.
Comparison of mean dosages (mg/day) for the main chronic heart failure drugs prescribed according to LVEF
Ramipril Perindopril Bisoprolol Carvedilol Nebivolol Candesartan Spironolactone Furosemide
HF-REF
HF-BEF
6.6 ± 3.3 5.4 ± 2.5 5.2 ± 3.2 34.6 ± 22.3 4.8 ± 3.0 14.8 ± 9.7 25.0 ± 10.9 100 ± 150
6.3 5.2 5.0 33.2 4.0 13.2 25.5 93
± ± ± ± ± ± ± ±
HF-PEF 3.5 2.5 3.1 24.5 2.5 7.6 13.9 134
6.9 4.4 5.2 36.6 4.5 13.5 28.2 100
± ± ± ± ± ± ± ±
3.2 2.2 3.4 21.6 2.8 8.8 13.5 145
P
Pa
ns (0.274) 0.001 ns (0.691) ns (0.845) ns (0.318) ns (0.310) 0.021 ns (0.735)
ns (1.000) < 0.001 ns (1.000) ns (1.000) ns (1.000) ns (0.754) 0.017 ns (1.000)
Data are mean ± standard deviation. HF-REF: heart failure with reduced ejection fraction; HF-BEF: heart failure with borderline ejection fraction; HF-PEF: heart failure with preserved ejection fraction; LVEF: left ventricular ejection fraction; ns: not significant. a For the comparison between HF-REF and HR-PEF.
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Y. Juillière et al.
Figure 4. Distribution of cardiovascular classes according to types of chronic heart failure. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; LVEF: left ventricular ejection fraction; MRA: mineralocorticoid-receptor antagonist; ns: not significant.
clinical practice, both older age and preserved LVEF were associated with a decrease in the rate of prescription of all major recommended CHF drugs. A decrease in CHF drug prescription according to age persisted, regardless of the type of CHF (represented by the level of LVEF). Long-term survival was influenced by age but not by the type of CHF (defined by the level of LVEF).
As already shown by the OFICA registry [17], patients hospitalized for CHF in France are often old and a large proportion has preserved LVEF. As previously published [13], the baseline characteristics of the patients in the ODIN cohort appear similar to those in previous French and Western European cohorts [18—21]. The percentage of prescribed cardiovascular medications was in accordance with
Figure 5. Distribution of cardiovascular classes according to age groups in patients with heart failure with reduced ejection fraction (HFREF). ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; MRA: mineralocorticoid-receptor antagonist; ns: not significant.
Prescription of cardiovascular drugs in the French ODIN cohort
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Figure 6. Distribution of cardiovascular classes according to age groups in patients with heart failure with borderline ejection fraction (HFBEF). ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; MRA: mineralocorticoid-receptor antagonist; ns: not significant.
European guidelines for the relevant period [11]. Changes in therapeutic recommendations appeared in 2012, after the end of inclusion [15]. However, dosages of the recommended drugs remained lower than recommended, as previously reported [19—21]. While the role of high dosage of ACEIs might be under discussion following the ATLAS results [22], large cohorts have shown that higher is better, even in
the elderly [23]. Many gaps exist between the population characteristics of randomized controlled trials (younger age, fewer co-morbid conditions) and real-life CHF populations, as in registries. Applying the results of randomized trials to the general population can lead to an increase in adverse effects, as shown by the epidemic of hyperkalaemia described after publication of the RALES study [24].
Figure 7. Distribution of cardiovascular classes according to age groups in patients with heart failure with preserved ejection fraction (HFPEF). ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; MRA: mineralocorticoid-receptor antagonist; ns: not significant.
30 Our study has confirmed the improvement in the percentage of major CHF drugs prescribed that was seen in previous international publications [21,25] from national French registries [20,21,26]; this is probably related to a better knowledge of international guidelines and the results of large therapeutic trials. Nevertheless, we found a marked increase in the rate of prescription of beta-blockers compared with the results of the IMPACT-RECO survey (65 to 81%) [20], while prescription rates for blockers of the renin-angiotensin system (ACEIs, ARBs or MRAs) remained unchanged. These findings show that the cardiologists in charge of CHF well understand the major role of betablockade in CHF, even if, in 2013, ivabradine might be initiated too often prior to optimization of beta-blockade titration, based on the results of the SHIFT trial [27]. Although prescription rates of recommended CHF drugs increased, mean doses of the major recommended drugs remained dramatically low, as is always found in the majority of registries [28—30]. As already shown by the IMPACT-RECO survey [20,21], age is a most important limiting factor for the prescription of CHF therapy. Older patients received fewer ACEIs/ARBs, beta-blockers and MRAs, but more diuretics. These results are in agreement with previous reports [31]. However, age is too often a poor justification for not introducing recommended CHF treatments, even if the presence of renal failure or a history of asthma or chronic obstructive pulmonary disease remain prognostic factors for lower prescription rates, particularly in relation to age [20]. Despite the heterogeneity of HF-PEF, prescription rates remained similar to those for HF-REF, with age having a similar effect, even if the rates were significantly lower for the major recommended drugs in general. These data have been already shown in European registries [32] and in France [28] with drugs having a similar impact. As guidelines regarding HF-PEF are scarce, the only efficient treatment applied in practice was the use of the lowest diuretic dose necessary to relieve fluid overload, salt restriction and blood pressure control. However, in HF-PEF, the absence of impact of medical treatment on survival curves over the last three decades [33], as well as the negativity of all randomized trials [34,35], could suggest that applying recommendations for HF-REF to HF-PEF is not justified. Our study showed that cardiologists did not know which strategy to use in case of CHF due to HF-PEF.
Study limitations This study is subject to the usual limitations of observational studies. The most important potential bias was the lack of randomization. We chose an observational registry performed in routine clinical practice by centres particularly interested in CHF management and trained in therapeutic patient education. Therefore, it did not provide an insight into the management of CHF by general practitioners. National I-CARE centre participation was around 60%. Some centres were unable to develop therapeutic patient education for the usual financial, human and material reasons [14] and decided not to participate in the study. Only 12 (19.7%) institutions (rehabilitation centres and CHF networks) used multidisciplinary teams, permitting more frequent and prolonged contact between patients and healthcare providers.
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Conclusion In CHF, and despite management by cardiologists particularly interested by CHF and specifically trained to deliver therapeutic patient education, medical prescription substantially differed from guidelines. Age and type of CHF (reduced versus preserved) appeared to be important factors in lack of adherence to guidelines. However, only age influenced mortality; the type of CHF (defined by the level of LVEF) did not have any effect on survival.
Disclosure of interest YJ and PJ have received research funding from AstraZeneca, initiated before the ODIN study for the completion of the ICARE project. YJ, JPD, AD, JPL and PJ have received grants from AstraZeneca for developing training of health professionals in therapeutic patient education in their centers. YJ has also participated to a national board on patient education sponsored by Bayer. ND has received research grants from Astra-Zeneca, Eli-Lilly, GSK, Merck, Novartis, Pfizer, Sanofi-Aventis, Servier, and The Medicines Company. The other authors report no conflicts of interest.
Acknowledgements This work was supported by a grant from the French Health Ministry (Direction générale de la santé); the French Society of Cardiology offered an administrative and technical support to the general management of the ODIN cohort. The authors thank Professor Tabassome Simon, Director of the Clinical Research Unit (URC-Est) of the Assistance publique des hôpitaux de Paris and University Paris 6, for directing clinical research technicians. The authors gratefully acknowledge the ODIN patients for their participation and cooperation throughout the study. The French ODIN cohort participants are as follows: F. Rodriguez, MD, C. Brunie, RN, C. Drege, RN, (CHG SaintEsprit, Agen); Ph. Fromage, MD, C. Bastard, RN, N. Coudurier, RN (CHG Annemasse-Bonneville); A. RacineMorel, MD, V. Robert, RN (CHG Autun); J.P. Darracq, MD, S. Egron, RN (CHG Samuel Pozzi, Bergerac); J. Ph. Labarre, MD, C. Valmary, RN (clinique Château de Vernhes, Bondigoux); P. Dominguez-Dos Santos, MD, F. Picard, MD, M.J. Betato, RN, A. Gard, RN, M. Lartigue, RN, F. Lacotte, RN (CHU hôpital du Haut-Lévêque, Bordeaux-Pessac); P. Coulon, MD, M. Lucbert, RN, F. Mendy, RN, C. Bacle, RN (CHU hôpital SaintAndré, Bordeaux); F. Bire, MD, N. Caminade, RN (HIA Robert Piqué, Bordeaux-Villenave d’Ornon); C. Labarrere, MD, M.H. Jaureguiberry, RN (réadaptation cardiaque, CHG CyranoGrancher, Cambo-les-Bains); Ph. Cantie, MD, I. Albert, RN, I. Grand, RN, E. Heral, RN, M. Nouret, RN (CHG CastresMazamet); A. Dellinger, MD, C. Duc, RN, D. Guitton, RN (CHG William Morey, Chalon-sur-Saône); L. Mankoubi, MD, M. Collard, RN, C. Ipcar, RN, C. Soreau, RN (CHG Louis Pasteur, Chartres-Le Coudray); A. Tuambilangana, MD, S. Nogues, RN (CHG Louis Pasteur, Cherbourg-Octeville); M. Fauvel, MD, M.J. Taudou-Martinel, MD, C. Bareille, RN, F. Moles, RN (Clinique des Cèdres, Cornebarrieu-Blagnac); J.C. Eicher, MD, O. Brenot, RN, M. Guerot, RN, F. Moreau, RN (CHU du Bocage,
Prescription of cardiovascular drugs in the French ODIN cohort Dijon); J.M. Gbonon, MD, Y. Fix, RN (clinique médicale de cardio-pneumologie, Durtol); N. Ghanem, MD, M. Quirin, RN (CHG Simone Veil, Eaubonne); S. Hackenberger, MD, S. Giga, RN, I. Lebreton, RN (CHG Evreux); A. Gabriel, MD, C. Geisler, RN, S. Velt (CHG Freyming-Merlebach); M. Gabrovescu, MD, C. Assulin, RN, M. Desenclos, RN (CHG Emmanuel Rain, Gonesse); M. Noirclerc, MD, C. Sicken, RN (réadaptation cardiaque, hôpital Sud, Grenoble-Echirolles); S. Marliere, MD, M. Salvat, MD, N. Hailley, RN (CHU, hôpital Albert Michalon, Grenoble-La Tronche); C. Weber-Stenger, MD, N. Griette, RN, M. Peterle, RN (hôpital Alpha Santé, Hayange); C. Gerard, MD, C. Bonnin, RN, S. Deroche, RN (CHG Hôtel-Dieu, Le Creusot); J.P. Favier, MD, N. Festy, RN (CHG Montivilliers, Le Havre-Montivilliers); S. Tondeux-Lefebvre, MD, S. Mucklisch, RN (CHG Léon Schwartzenberg, Le Quesnoy); F. Mouquet, MD, V. Hazebrouck, RN, A.M. Lebleu, RN, A. Willens, RN (CHU, Lille); F. Dany, MD, M. Faye, RN (ICARLIM Heart Failure Network, Limoges); S. Baleynaud, MD, G. Malarce, RN, M.P. Treguier, RN (KALONIC Heart Failure Network, CHG Bretagne Sud, Lorient); O. Ferry, MD, N. Arend, RN (CHG, Lunéville); B. Maitre, MD, N. Gelin, RN, A.M. Lanctuit, RN (ERIC Heart Failure Network, CHG des Chanaux, Mâcon); N. Baille, MD, N. Kremer, RN (hôpital Sainte-Blandine, Metz); M.F. Deforet, MD, C. Gaiffe, RN, A. Part, RN, E. Simon-Adig, RN (CHG Belfort-Montbéliard); G. Rebuffat, MD, C. Amoros, RN, C. Hebrard, RN, C. Perret, RN (CHG Montélimar); D. Kenizou, MD, M. Bindler, RN, A. Robo, RN (CHG Emile Muller, Mulhouse); Y. Juilliere, MD, G. Bosser, MD, N. Genchi, RN, N. Gouriou, RN, S. Weitkunat, RN, C. Wendling, RN (institut Lorrain du coeur et des vaisseaux, CHU Brabois, Nancy); J.N. Trochu, MD, V. Hossler, MD, A.L. Laprerie, MD, G. Lacaze, RN, H. Lambert, RN, C. Mariaux, RN (RESPECTICOEUR Heart Failure Network, CHU G. et R. Laennec, Nantes); C. AchePapillon, MD, C. Gonzales, RN (CHG Oloron-Sainte-Marie); M.C. Aumont, MD, G. Jondeau, MD, J. Charles, RN (CHU Bichat, Paris); F. Ledru, MD, M. Girault, RN (CHU hôpital européen Georges Pompidou, Paris); F. Beauvais, MD, D. Combres, RN (CHU Lariboisière, Paris); F. Pousset, MD, F. Allab, RN, M. Geoffrain, RN, M. Marlay, RN (CHU PitiéSalpétrière, Paris); B. Lequeux, MD, C. Bobier, RN (RADIC Heart Failure Network, CHU La Milétrie, Poitiers); P. Jourdain, MD, A. Boireau, RN, H. Lebras, RN (CHG René Dubos, Pontoise); C. Leclercq, MD, M.A. Foret, RN, S. Le Maitre, RN, C. Marquer, RN, N. Pellen, RN, I. Timonier, RN (centre cardiopneumologique, CHU Pontchaillou, Rennes); V. Berder, MD, P. Guillo, MD, S. Bertrand, RN, N. Tallec, RN (réadaptation cardiovasculaire, clinique Saint-Yves, Rennes); F. Bauer, MD, S. Cordier-Pouchin, RN, E. Benmokhtar, RN (CHU Charles Nicolle, Rouen); P. Webert, MD, M. Schweitzer, RN (CHG Lemire, Saint-Avold); F. Cadi, MD, S. Lassere-Remy, MD, V. Dolbeau, RN (réadaptation cardiaque, CRF Val Rosay, SaintDidier au Mont d’Or); M. Diallo, MD, S. Martin, RN (Mémorial France-Etats-Unis, Saint-Lo); B. Ouattara, MD, M.F. Aubry, RN, C. Cadieu, RN (hôpital Broussais, Saint-Malo); P. Coulon, MD, I. Flaus, RN (CHG Saint-Nicolas, Sarrebourg); A. Pinzani, MD, J.P. Bazanau, RN, B. Celka, RN, CHG Sète; J.M. Taupin, MD, B. Amaury, RN (pôle prévention et éducation du patient, Soissons); Th. Beard, MD, R. Dos Santos, RN (clinique de l’Ormeau, Tarbes); M. Galinier, MD, A. Pathak, MD, J. Roncalli, MD, S. Mazzon, RN, L. Spinazze-Fournier, RN (CHU Rangueil, Toulouse); A. Belin, MD, C. Dossetto, MD, L. More, RN, M. Pougheul, RN (centre de réadaptation,
31 Trouville-sur-Mer); L. Desprets, MD, M. Linne, RN, CHG Valenciennes; S. Allam, MD, S. Laurent, RN (CHG SaintNicolas, Verdun); A. Atallah, MD, V. Marcel, RN, J. Plantier, RN, N. Saminadin, RN (CHG Basse Terre, Guadeloupe); C. Mimran, MD, Th. Hoarau, RN (CHG Sud-Réunion, SaintPierre, La Réunion).
References [1] Bonneux L, Barendregt JJ, Meeter K, et al. Estimating clinical morbidity due to ischemic heart disease and congestive heart failure: the future rise of heart failure. Am J Public Health 1994;84:20—8. [2] Eriksson H. Heart failure: a growing public health problem. J Intern Med 1995;237:135—41. [3] Cooper H, Booth K, Fear S, et al. Chronic disease patient education: lessons from meta-analyses. Patient Educ Couns 2001;44:107—17. [4] Groves T, Wagner EH. High quality care for people with chronic diseases. BMJ 2005;330:609—10. [5] McAlister FA, Stewart S, Ferrua S, et al. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol 2004;44:810—9. [6] Roccaforte R, Demers C, Baldassarre F, et al. Effectiveness of comprehensive disease management programmes in improving clinical outcomes in heart failure patients. A meta-analysis. Eur J Heart Fail 2005;7:1133—44. [7] Report of a WHO Working Group. Therapeutic patient education: continuing education programmes for health care providers in the field of prevention of chronic diseases. Available at: http://www.euro.who.int/ data/assets/pdf file/ 0007/145294/E63674.pdf [8] Gask L. Role of specialists in common chronic diseases. BMJ 2005;330:651—3. [9] Glasziou P, Irwig L, Mant D. Monitoring in chronic disease: a rational approach. BMJ 2005;330:644—8. [10] Phillips CO, Singa RM, Rubin HR, et al. Complexity of program and clinical outcomes of heart failure disease management incorporating specialist nurse-led heart failure clinics. A metaregression analysis. Eur J Heart Fail 2005;7:333—41. [11] Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29:2388—442. [12] Juilliere Y, Jourdain P, Roncalli J, et al. Therapeutic education for cardiac failure patients: the I-care programme. Arch Mal Coeur Vaiss 2005;98:300—7. [13] Juilliere Y, Jourdain P, Suty-Selton C, et al. Therapeutic patient education and all-cause mortality in patients with chronic heart failure: a propensity analysis. Int J Cardiol 2013;168:388—95. [14] Juilliere Y, Jourdain P, Roncalli J, et al. Therapeutic education unit for heart failure: setting-up and difficulties. Initial evaluation of the I-CARE programme. Arch Cardiovasc Dis 2009;102:19—27. [15] McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803—69.
32 [16] Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810—52. [17] Logeart D, Isnard R, Resche-Rigon M, et al. Current aspects of the spectrum of acute heart failure syndromes in a real-life setting: the OFICA study. Eur J Heart Fail 2013;15:465—76. [18] Cleland JG, Cohen-Solal A, Aguilar JC, et al. Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey. Lancet 2002;360:1631—9. [19] Cleland JG, Daubert JC, Erdmann E, et al. Baseline characteristics of patients recruited into the CARE-HF study. Eur J Heart Fail 2005;7:205—14. [20] de Groote P, Isnard R, Assyag P, et al. Is the gap between guidelines and clinical practice in heart failure treatment being filled? Insights from the IMPACT RECO survey. Eur J Heart Fail 2007;9:1205—11. [21] de Groote P, Isnard R, Clerson P, et al. Improvement in the management of chronic heart failure since the publication of the updated guidelines of the European Society of Cardiology. The Impact-Reco Programme. Eur J Heart Fail 2009;11: 85—91. [22] Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999;100:2312—8. [23] Sin DD, McAlister FA. The effects of beta-blockers on morbidity and mortality in a population-based cohort of 11 942 elderly patients with heart failure. Am J Med 2002;113:650—6. [24] Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 2004;351:543—51. [25] Komajda M, Follath F, Swedberg K, et al. The EuroHeart Failure Survey programme — a survey on the quality of care among
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CLINICAL RESEARCH
Prescription of cardiovascular drugs in the French ODIN cohort of heart failure patients according to age and type of chronic heart failure Prescription des médicaments à visée cardiovasculaire selon l’âge et le type d’insuffisance cardiaque chronique dans la cohorte franc ¸aise ODIN Yves Juillière a,∗, Christine Suty-Selton a, Elisabeth Riant a, Jean-Pierre Darracq b, Arnaud Dellinger c, Jean-Philippe Labarre d, Justine Druelle e, Geneviève Mulak f, Nicolas Danchin g, Patrick Jourdain h , for the ODIN cohort participants a
Cardiology Department, institut Lorrain du coeur et des vaisseaux, allée du Morvan, 54500 Vandœuvre-lès-Nancy, France b Cardiology, CHG Samuel-Pozzi, Bergerac, France c Cardiology, CHG William-Morey, Chalon-sur-Saône, France d Cardiology, clinique Château-de-Vernhes, Bondigoux, France e URC-Est, CHU Saint-Antoine, Paris, France f French Society of Cardiology, Paris, France g Cardiology, European Hospital Georges Pompidou, Paris, France h Cardiology, CHG René-Dubos, Pontoise, France Received 22 April 2013; received in revised form 21 November 2013; accepted 25 November 2013 Available online 30 December 2013
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; CHF, chronic heart failure; HF-BEF, heart failure with borderline ejection fraction; HF-PEF, heart failure with preserved ejection fraction; HF-REF, heart failure with reduced ejection fraction; I-CARE, insuffisance cardiaque : éducation thérapeutique; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid-receptor antagonist; ODIN, observatoire de l’insuffisance cardiaque. ∗ Corresponding author. E-mail address: [email protected] (Y. Juillière). 1875-2136/$ — see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.acvd.2013.11.001
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KEYWORDS Age; Cardiovascular drugs; Systolic heart failure; Heart failure with preserved ejection fraction; Left ventricular ejection fraction
MOTS CLÉS Âge ; Médicaments cardiovasculaires ; Insuffisance cardiaque systolique ; Insuffisance cardiaque avec fraction d’éjection préservée ; Fraction d’éjection ventriculaire gauche
Summary Background. — Chronic heart failure (CHF) is a frequent severe disease. Disease-management programmes, which contain a therapeutic patient education component, will play a central role in improving delivery of care and reducing mortality and hospitalizations for CHF. Aims. — In order to have an up-to-date overview of medical treatment of CHF in France implemented by hospital and clinic cardiologists especially interested in CHF and therapeutic patient education, we described the prescription of cardiovascular drugs in the large ODIN cohort of CHF patients, according to age and type of CHF. Methods. — From 2007 to 2010 (median follow-up 27.2 months), CHF patients were prospectively enrolled in a multicentre ‘real-world’ French cohort by centres previously trained in therapeutic patient education. Patients were grouped according to age (< 60 years, 60 to < 70 years, 70 to < 80 years and ≥ 80 years) and type of CHF (characterized by level of LVEF: reduced, borderline or preserved). Medical prescription was described and mortality was assessed at long-term follow-up. Results. — The cohort consisted of 3237 patients (67.6 years; 69.4% men). The oldest age group had the highest LVEF. Blockers of the angiotensin-aldosterone system were prescribed progressively and significantly less frequently as the population advanced in age or as LVEF was more preserved. The mean dosages of the main prescribed CHF drugs remained ≥ 50% lower than those recommended for most drugs in all age and LVEF groups. Drug prescriptions were related to aetiology of reduced or preserved CHF. A global decrease in CHF drug prescription was observed for all medication classes except calcium blockers, according to maintenance of relatively or totally preserved LVEF. Survival was related to age but not to type of CHF. Conclusion. — In CHF, and despite management by cardiologists particularly interested in CHF and specifically trained to deliver therapeutic patient education, medical prescription differed substantially from guidelines. Age and type of CHF (reduced versus preserved) appeared to be important factors in lack of adherence to guidelines. However, only age influenced mortality; the type of CHF did not affect survival. © 2013 Elsevier Masson SAS. All rights reserved.
Résumé Contexte. — L’insuffisance cardiaque (IC) est une maladie fréquente et sévère. Les programmes de prise en charge de la maladie, qui contiennent une composante d’éducation thérapeutique du patient, jouent un rôle central dans l’amélioration des soins et la réduction de la mortalité et des hospitalisations liées à l’IC. Objectif. — Afin d’avoir un aperc ¸u récent du traitement médical de l’IC en France, mis en place par des cardiologues d’hôpitaux ou de cliniques spécialement intéressés par l’IC et l’éducation thérapeutique du patient, nous avons décrit la prescription des médicaments cardiovasculaires au sein de la grande cohorte ODIN de patients IC selon l’âge et le type d’IC déterminé par le niveau de fraction d’éjection ventriculaire gauche (FEVG). Méthodes. — De 2007 à 2010 (suivi médian 27,2 mois), les patients IC étaient prospectivement inclus dans une cohorte franc ¸aise multicentrique sur la base de la pratique réelle, par des centres ayant été formés à l’éducation thérapeutique du patient. Les patients étaient regroupés selon leur âge (< 60 ans ; 60 à < 70 ans ; 70 à < 80 ans ; et ≥ 80 ans) et le type d’IC caractérisé par le niveau de FEVG (réduite, borderline ou préservée). La prescription médicale était décrite et la mortalité était évaluée à long terme. Résultats. — La cohorte comprenait 3237 patients (67,5 ans ; 69,5% d’hommes). Le groupe d’âge le plus âgé avait la FEVG la plus haute. Les bloqueurs du système angiotensine-aldostérone étaient progressivement et significativement moins prescrits alors que la population avanc ¸ait en âge ou que la FEVG était plus préservée. Le dosage moyen des drogues principalement prescrites dans l’IC restait au moins 50 % plus bas que celui recommandé pour la majorité des substances dans tous les groupes d’âge ou de FEVG. La prescription des médicaments était liée à l’étiologie de l’IC avec FEVG réduite ou préservée. Une diminution globale de la prescription des médicaments de l’IC était observée en fonction du maintien d’une FEVG relativement ou totalement préservée, pour toutes les classes de médicaments à l’exception des inhibiteurs calciques. La survie était liée à l’âge mais pas au type d’IC.
Prescription of cardiovascular drugs in the French ODIN cohort
23
Conclusions. — Dans l’IC et malgré une prise en charge par des cardiologues particulièrement intéressés à l’IC et spécifiquement formés pour pratiquer une éducation thérapeutique du patient, la prescription médicale différait sensiblement des recommandations. L’âge et le type d’IC (systolique vs à fonction systolique préservée) étaient d’importants facteurs d’inadéquation à la prescription médicale recommandée. Cependant, seul l’âge influenc ¸ait la mortalité; le type d’IC défini par le niveau de FEVG ne jouait aucun rôle dans la survie. © 2013 Elsevier Masson SAS. Tous droits réservés.
Introduction Chronic heart failure (CHF) is a frequent severe disease that has become a major public health problem in industrialized countries [1,2]. In this context, disease management programmes appear geared up to play a central role in improving delivery of care [3,4] and reducing mortality and CHF hospitalizations, as established by meta-analyses [5,6]. As an integral part of disease management programmes, therapeutic patient education [7] has been recognized in most industrialized countries [4,8—10] and is recommended in European guidelines [11]. Following this format, the insuffisance cardiaque : éducation thérapeutique (I-CARE) programme was developed in France to promote the establishment of therapeutic patient education units in all types of cardiology centres, based on a voluntary approach by the medical team [12]. A large prospective multicentre French cohort of CHF patients (ODIN: observatoire de l’insuffisance cardiaque) enrolled in I-CARE centres trained in therapeutic patient education for CHF was constituted from 2007 to 2010 to assess the role of therapeutic patient education applied in routine practice; therapeutic patient education by trained health professionals appeared to be associated with a decrease in all-cause mortality [13]. Among multivariable independent prognostic factors of survival, younger age and prescription of recommended neurohormonal blockers appeared to play an important role. In order to have an up-to-date overview of medical treatment of CHF in France implemented by hospital and clinic cardiologists especially interested by CHF and trained in therapeutic patient education, we decided to describe the prescription of cardiovascular drugs in the large ODIN cohort of CHF patients, according to age and type of CHF.
Methods Patient population Selection of centres has been described in detail previously [13]. Briefly, centres had to have fulfilled the requirements for participation in the I-CARE programme [14], thereby validating their specialization in CHF management. Training was completed for 110 centres in 2007 and for more than 220 in 2010. Among the first 110 trained centres throughout France, 61 (55.5%) volunteered to contribute patients to the ODIN cohort. Patients were enrolled prospectively between 2007 and 2010; during this period the therapeutic guidelines for CHF remained largely stable [11]. Enrolment in the study was
consecutive. To increase the external validity, exclusion criteria were deliberately kept to a minimum: patients were excluded only if they attended sites not participating in the I-CARE programme or if they declined to participate. All patients received usual care, which consisted of care management according to European guidelines [11]. Medical therapy was adjusted as judged necessary by the investigator. Patients completed a full education programme [13,14] in addition to receiving usual care. Four patient groups were defined according to age: < 60 years (Age 1); 60 to < 70 years (Age 2); 70 to < 80 years (Age 3); and ≥ 80 years (Age 4). The initial clinical questionnaire did not take into account the pathophysiological type of CHF (i.e. systolic or diastolic CHF); however, left ventricular ejection fraction (LVEF) was available in 92.3% of the patients, with a mean value of 39.8 ± 14.2% (range 6—88%). The threshold for defining LVEF groups has been discussed in European and American heart failure guidelines [15,16]. We chose the usual 45% threshold for defining reduced LVEF and the 50% threshold for defining preserved LVEF. In accordance with the American guidelines [16], we preferred to create a borderline group to see if patients with an LVEF between 45 and 50% presented a similar profile to one of the other usual LVEF groups. It was therefore decided to create three groups according to LVEF: < 45% (heart failure with reduced ejection fraction, HF-REF); 45—50% (heart failure with borderline ejection fraction, HF-BEF); and > 50% (heart failure with preserved ejection fraction, HF-PEF).
Data collection The investigation conformed to the principles outlined in the Declaration of Helsinki. The study was approved by the Commission nationale informatique et liberté — as required by French law for any patient cohort study in France — and the institutional independent ethical committee of the French Society of Cardiology. All patients gave informed consent before their inclusion in the cohort. Declarations of inclusion were made by centres on both nominative 1page and medical 2-page record forms for each patient after being given an anonymous number by the centre; these were mailed separately to the French Society of Cardiology. Data were then recorded on two types of computerized case record forms according to the procedure requested and approved by the Commission nationale informatique et liberté. Data were collected on the main cardiovascular classes of drugs administered by the oral route: all recommended CHF classes (angiotensin-converting enzyme inhibitors [ACEIs],
24 beta-blockers, angiotensin-receptor blockers [ARBs], diuretics, mineralocorticoid-receptor antagonists [MRAs], digoxin and nitrates) and all other main non-CHF cardiovascular classes usually prescribed for the treatment of CHF causes or complications (amiodarone, antiplatelet therapies [aspirin and clopidogrel], anticoagulant drugs [antivitamin K therapies only], calcium blockers and statins). Furthermore, for all main CHF classes, the types of drugs used most frequently were listed with their daily dosage (perindopril and ramipril for ACEIs; bisoprolol, carvedilol, metoprolol and nebivolol for beta-blockers; candesartan and valsartan for ARBs; furosemide for loop diuretics; and eplerenone and spironolactone for MRAs) [13]. Follow-up data were collected through contact with the attending physicians, the patients or their families. If missing, vital status was assessed from the registries of the patients’ birthplaces. Only 4.9% (n = 158) of patients were lost to follow-up.
Statistical analysis All continuous variables are described as means ± standard deviations, except for time variables, which are expressed as medians [interquartile ranges]. All categorical variables are described with absolute and relative frequency distributions. Comparisons between groups used one-way analysis of variance and unpaired t tests for continuous variables and 2 tests for discrete variables. The Bonferroni test was used for comparisons between LVEF groups. Survival curves were generated by the Kaplan-Meier method and compared with log-rank tests. Prognostic factors for mortality, including age-defined groups, LVEF-defined groups, risk factors, heart failure aetiology, biological variables and main CHF drug treatments, were analysed with bivariate and multivariable Cox models. Biological variables were categorized into quartiles for serum creatinine (< 9.5 mg/L; 9.5—11.5 mg/L; > 11.5—15.0 mg/L; > 15 mg/L) or divided according to their median value for serum glucose (≤ and > 0.99 g/L) and serum haemoglobin (≤ and > 13.0 g/L). Serum natriuretic peptides were organized as non-decompensated (defined as B-type natriuretic peptide ≤ 400 pg/mL and/or N-terminal pro-B-type natriuretic peptide ≤ 450 pg/mL if the patient was aged < 50 years, ≤ 900 pg/mL if aged between 50 and 75 years and ≤ 1800 pg/mL if aged > 75 years) or decompensated levels. For multivariable models, a stepwise variable selection with sle = 0.1 and sls = 0.05 was applied. Results are expressed as hazard ratios with a 95% confidence interval. All statistical analyses were performed using SPSS version PASW 18.0 software. For all tests, P < 0.05 was considered significant.
Results Cardiovascular medications in the whole population The ODIN population has been detailed previously [13]. In summary, a total of 3248 patients were included in the ODIN cohort, 11 of whom were declared twice (i.e. by two different centres). For these patients, the first declaration
Y. Juillière et al. was considered as the inclusion in the cohort and the second declaration was considered as a follow-up visit. The ODIN cohort therefore comprised 3237 patients with a mean age of 67.6 ± 14.2 years (range 16—97 years); 69.4% were men. Baseline clinical and biological main variables according to age-defined and LVEF-defined groups are reported in Table 1. For CHF-dedicated medications, the large majority of patients received blockers of the renin-angiotensin system (69.9% received ACEIs and 20.3% received ARBs, which were always prescribed for ACEI intolerance), beta-blockers (80.6%), and loop diuretics (80.1%). Fewer patients were treated with MRAs (32.7%), digoxin (12.6%) and nitrates (8.7%). Regarding other cardiovascular medications, 20.4% of the population received amiodarone, 40.8% received aspirin, 18.0% received clopidogrel, 43.3% received oral anticoagulants, 8.8% received calcium blockers and 50.0% received statins [13]. Mean duration of follow-up was 25.9 ± 11.7 months. Death was the only event collected during follow-up; 682 deaths were recorded. Multivariable Cox analysis found the usual predictors of survival (Table 2).
Age and prescription of cardiovascular medications Regarding the four age-defined groups, there were 985 (30.4%) patients in Age 1, 669 (20.7%) in Age 2, 869 (26.8%) in Age 3 and 714 (22.1%) in Age 4. The percentage of men decreased according to age group (74.1% in Age 1, 75.9% in Age 2, 70.2% in Age 3 and 56.0% in Age 4; P < 0.001). Mean LVEF was significantly different according to age group: the older the age group, the higher the mean LVEF (36.0 ± 12.3% for Age 1, 38.3 ± 13.9% for Age 2, 41.2 ± 14.7% for Age 3 and 44.8 ± 14.7% for Age 4; P < 0.001) (Fig. 1). Cumulative survival curves showed the effect of age on survival (Fig. 2). The three major CHF medications (ACEIs + ARBs, betablockers and MRAs) were prescribed progressively and significantly less frequently as the population advanced in age (Fig. 3). By comparison, loop diuretics, digoxin and nitrates were prescribed more frequently with advancing age. For the other drugs, prescriptions were probably related to aetiology (antiplatelet therapies, statins or calcium blockers) or the presence of atrial arrhythmias (amiodarone and anticoagulants) (Fig. 3) [13]. The mean dosages of the main prescribed CHF drugs remained ≥ 50% lower than those recommended for the majority of the drugs (Table 3). The older the age, the lower the mean dosage (Table 3).
Type of CHF and prescription of cardiovascular medications Regarding the three LVEF-defined groups, there were 1934 (59.7%) patients in HF-REF, 460 (14.2%) patients in HF-BEF and 595 (18.4%) patients in HF-PEF. The LVEF value was unknown in 248 patients (7.7%) out of the whole ODIN population. The percentage of men was higher in case of reduced LVEF (75.8% in HF-REF, 65.2% in HF-BEF and 55.1% in HF-PEF; P < 0.001). Mean age was higher in case of preserved LVEF
Prescription of cardiovascular drugs in the French ODIN cohort Table 1
25
Main patient characteristics according to age-defined and LVEF-defined groups.
Women Age (years) Ischaemic heart disease DCM Hypertension Diabetes Hypercholesterolaemia Smoking NYHA III/IV class LVEF (%) Atrial fibrillation LBBB Biventricular pacemaker ICD BMI (%) Serum glucose (g/L) Serum creatinine (mg/L) Serum haemoglobin (g/L) BNP (pg/mL) NT-BNP (pg/mL) Follow-up deaths
Age 1
Age 2
Age 3
Age 4
P
HF-REF
HF-BEF
HF-PEF
P
26 50.2 ± 8.1 38
24 64.9 ± 3.0 48
30 75.3 ± 2.9 53
44 84.7 ± 3.3 50
< 0.001 < 0.001 < 0.001
24 65.6 ± 13.9 52
35 68.6 ± 14.2 45
45 72.3 ± 12.9 34
< 0.001 < 0.001 < 0.001
37 36 25 46
28 56 39 58
19 65 43 58
12 67 27 43
< 0.001 < 0.001 < 0.001 < 0.001
32 49 31 53
20 57 35 52
11 71 38 47
< 0.001 < 0.001 0.006 ns
55 13.5 36.0 ± 12.3 9.3 21.8 5.7
44 17.0 38.3 ± 13.9 20.5 27.4 11.7
34 22.7 41.2 ± 14.7 36.6 26.6 11.2
22 36.5 44.8 ± 14.7 48.9 23.7 5.2
< 0.001 < 0.001 < 0.001 < 0.001 ns < 0.001
45 22.5 31.1 ± 7.4 22.5 29.9 11.5
39 19.1 47.2 ± 2.3 30.3 17.8 5.4
31 17.2 62.0 ± 7.0 40.7 13.8 1.7
< 0.001 0.010 < 0.001 < 0.001 < 0.001 < 0.001
16.8 27.8 ± 6.2 1.07 ± 0.43
19.1 28.1 ± 5.8 1.13 ± 0.42
11.7 27.6 ± 5.5 1.13 ± 0.38
1.7 25.3 ± 4.2 1.09 ± 0.42
< 0.001 < 0.001 0.028
18.9 26.8 ± 5.4 1.07 ± 0.38
3.9 27.8 ± 5.9 1.09 ± 0.38
1.3 28.7 ± 6.3 1.16 ± 0.44
< 0.001 < 0.001 0.002
11.2 ± 5.3
13.1 ± 6.2
13.9 ± 5.8
14.4 ± 6.2
< 0.001
12.8 ±5.7
13.3 ± 7.2
13.3 ± 5.8
ns
13.5 ± 1.9
13.1 ± 1.9
12.6 ± 1.8
12.4 ± 1.8
< 0.001
13.1 ± 1.9
12.7 ± 1.9
12.7 ± 1.9
< 0.001
415 ± 582 2370 ± 3831 9.4
574 ± 874 2875 ± 5149 14.5
816 ± 1374 4115 ± 5420 25.9
1158 ± 1404 6047 ± 7003 37.4
< 0.001 < 0.001 < 0.001
764 ± 1259 4323 ± 6058 20.3
565 ± 735 3803 ± 5697 22.8
550 ± 708 2504 ± 3986 20.5
0.003 0.003 ns
Data are % or mean ± standard deviation. BMI: body mass index; BNP: B-type natriuretic peptide; DCM: idiopathic dilated cardiomyopathy; ICD: implantable cardiac defibrillator; LBBB: left bundle branch block; LVEF: left ventricular ejection fraction; ns: not significant; NT-BNP: NT-pro-type B natriuretic peptide; NYHA: New York Heart Association.
(65.5 ± 13.9 years in HF-REF, 68.6 ± 14.2 years in HF-BEF and 72.3 ± 12.9 years in HF-PEF; P < 0.001). The proportion of older patients (≥ 70 years, Age 3 and Age 4) was higher in case of borderline and preserved LVEF (Fig. 1). Cumulative survival curves showed that type of CHF did not affect survival (Fig. 2).
Regarding aging, the three major CHF medications (ACEIs + ARBs, beta-blockers and MRAs) were prescribed progressively and significantly less frequently as LVEF was more preserved (Fig. 4). However, the use of loop diuretics, nitrates, amiodarone and anticoagulants was influenced poorly or not at all by LVEF. The prescription of the other
Table 2 Multivariable Cox analysis according to age-defined groups, LVEF-defined groups, risk factors and main drug treatments. Variable
Hazard ratio
95% CI
P
Age-defined group LVEF-defined group Valvular heart disease Idiopathic dilated cardiomyopathy Beta-blockers ACEIs or ARBs Loop diuretics Atrial fibrillation Serum haemoglobin Serum natriuretic peptides
1.46 0.80 1.33 0.72 0.76 0.60 2.09 1.40 1.00 1.00
1.33—1.60 0.71—0.89 1.08—1.64 0.57—0.91 0.62—0.92 0.48—0.75 1.51—2.89 1.17—1.67 1.00—1.00 1.00—1.00
< 0.001 < 0.001 0.007 0.006 0.006 < 0.001 < 0.001 < 0.001 0.009 < 0.001
ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; CI: confidence interval; LVEF: left ventricular ejection fraction.
26
Y. Juillière et al.
Figure 1. A. Distribution of types of chronic heart failure (left ventricular ejection fraction < 45% [heart failure with reduced ejection fraction, HF-REF], 45—50% [heart failure with borderline ejection fraction, HF-BEF] and > 50% [heart failure with preserved ejection fraction, HF-PEF]), according to age group (< 60 years [Age 1], 60 to < 70 years [Age 2], 70 to < 80 years [Age 3], and ≥ 80 years [Age 4]). B. Distribution of age groups according to type of chronic heart failure.
drugs was related to aetiology, depending on the presence of reduced or preserved CHF; this was as expected, given that there is less frequent ischaemic heart disease when systolic cardiac function is preserved, resulting in less frequency of prescription of statins and antiplatelet therapies; in addition, systemic hypertension is more frequently associated with preserved ejection fraction, resulting in a higher rate of prescription of calcium blockers (Fig. 4). The mean dosages of the main prescribed CHF drugs also remained ≥ 50% lower than those recommended for the majority of the drugs (Table 4). However, only two drugs had a mean dosage that was significantly different according to the type of CHF: perindopril titrated lower and spironolactone higher in HF-PEF than in HF-REF or HF-BEF (Table 4).
Figure 2. Kaplan-Meier cumulative 2-year survival curve of allcause mortality according to (A) age and (B) type of chronic heart failure. HF-REF: heart failure with reduced ejection fraction; HFBEF: heart failure with borderline ejection fraction; HF-PEF: heart failure with preserved ejection fraction; ns: not significant.
showing a global decrease in CHF drug prescription according to maintenance of relatively or totally preserved LVEF for all classes of medications, except for calcium blockers (which were prescribed increasingly when LVEF was more preserved) and loop diuretics (which were little influenced by the type of CHF).
Interaction between age and type of CHF
Discussion
When comparing prescription of medications in each age group according to type of CHF (Figs. 5—7), differences in drug prescription appeared to persist between age groups,
We assessed the effect of age and type of CHF (defined by the level of LVEF) on prescription of cardiovascular medications in CHF in a large French cohort of CHF patients. In routine
Prescription of cardiovascular drugs in the French ODIN cohort
27
Figure 3. Distribution of cardiovascular classes according to age groups. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; MRA: mineralocorticoid-receptor antagonist.
Table 3 groups.
Comparison of mean dosages (mg/day) for the main prescribed chronic heart failure drugs according to age Age 1
Ramipril Perindopril Bisoprolol Carvedilol Nebivolol Candesartan Spironolactone Furosemide
7.1 5.6 5.8 40.0 5.6 15.4 27.4 85
± ± ± ± ± ± ± ±
Age 2 3.3 2.5 3.2 25.0 2.8 9.8 13.1 132
7.0 5.2 5.4 36.1 5.3 14.1 25.8 101
± ± ± ± ± ± ± ±
Age 3 3.1 2.4 3.3 22.6 3.2 9.2 11.1 154
6.3 4.9 4.8 30.1 4.3 14.7 24.2 109
± ± ± ± ± ± ± ±
Age 4 3.2 2.6 3.1 17.3 2.5 9.3 11.5 165
4.9 4.4 3.8 22.8 3.9 11.6 23.7 102
± ± ± ± ± ± ± ±
P 3.2 2.3 2.7 16.7 2.7 7.3 10.4 133
< 0.001 < 0.001 < 0.001 < 0.001 0.003 0.024 0.004 0.021
Data are mean ± standard deviation.
Table 4 groups.
Comparison of mean dosages (mg/day) for the main chronic heart failure drugs prescribed according to LVEF
Ramipril Perindopril Bisoprolol Carvedilol Nebivolol Candesartan Spironolactone Furosemide
HF-REF
HF-BEF
6.6 ± 3.3 5.4 ± 2.5 5.2 ± 3.2 34.6 ± 22.3 4.8 ± 3.0 14.8 ± 9.7 25.0 ± 10.9 100 ± 150
6.3 5.2 5.0 33.2 4.0 13.2 25.5 93
± ± ± ± ± ± ± ±
HF-PEF 3.5 2.5 3.1 24.5 2.5 7.6 13.9 134
6.9 4.4 5.2 36.6 4.5 13.5 28.2 100
± ± ± ± ± ± ± ±
3.2 2.2 3.4 21.6 2.8 8.8 13.5 145
P
Pa
ns (0.274) 0.001 ns (0.691) ns (0.845) ns (0.318) ns (0.310) 0.021 ns (0.735)
ns (1.000) < 0.001 ns (1.000) ns (1.000) ns (1.000) ns (0.754) 0.017 ns (1.000)
Data are mean ± standard deviation. HF-REF: heart failure with reduced ejection fraction; HF-BEF: heart failure with borderline ejection fraction; HF-PEF: heart failure with preserved ejection fraction; LVEF: left ventricular ejection fraction; ns: not significant. a For the comparison between HF-REF and HR-PEF.
28
Y. Juillière et al.
Figure 4. Distribution of cardiovascular classes according to types of chronic heart failure. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; LVEF: left ventricular ejection fraction; MRA: mineralocorticoid-receptor antagonist; ns: not significant.
clinical practice, both older age and preserved LVEF were associated with a decrease in the rate of prescription of all major recommended CHF drugs. A decrease in CHF drug prescription according to age persisted, regardless of the type of CHF (represented by the level of LVEF). Long-term survival was influenced by age but not by the type of CHF (defined by the level of LVEF).
As already shown by the OFICA registry [17], patients hospitalized for CHF in France are often old and a large proportion has preserved LVEF. As previously published [13], the baseline characteristics of the patients in the ODIN cohort appear similar to those in previous French and Western European cohorts [18—21]. The percentage of prescribed cardiovascular medications was in accordance with
Figure 5. Distribution of cardiovascular classes according to age groups in patients with heart failure with reduced ejection fraction (HFREF). ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; MRA: mineralocorticoid-receptor antagonist; ns: not significant.
Prescription of cardiovascular drugs in the French ODIN cohort
29
Figure 6. Distribution of cardiovascular classes according to age groups in patients with heart failure with borderline ejection fraction (HFBEF). ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; MRA: mineralocorticoid-receptor antagonist; ns: not significant.
European guidelines for the relevant period [11]. Changes in therapeutic recommendations appeared in 2012, after the end of inclusion [15]. However, dosages of the recommended drugs remained lower than recommended, as previously reported [19—21]. While the role of high dosage of ACEIs might be under discussion following the ATLAS results [22], large cohorts have shown that higher is better, even in
the elderly [23]. Many gaps exist between the population characteristics of randomized controlled trials (younger age, fewer co-morbid conditions) and real-life CHF populations, as in registries. Applying the results of randomized trials to the general population can lead to an increase in adverse effects, as shown by the epidemic of hyperkalaemia described after publication of the RALES study [24].
Figure 7. Distribution of cardiovascular classes according to age groups in patients with heart failure with preserved ejection fraction (HFPEF). ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blockers; MRA: mineralocorticoid-receptor antagonist; ns: not significant.
30 Our study has confirmed the improvement in the percentage of major CHF drugs prescribed that was seen in previous international publications [21,25] from national French registries [20,21,26]; this is probably related to a better knowledge of international guidelines and the results of large therapeutic trials. Nevertheless, we found a marked increase in the rate of prescription of beta-blockers compared with the results of the IMPACT-RECO survey (65 to 81%) [20], while prescription rates for blockers of the renin-angiotensin system (ACEIs, ARBs or MRAs) remained unchanged. These findings show that the cardiologists in charge of CHF well understand the major role of betablockade in CHF, even if, in 2013, ivabradine might be initiated too often prior to optimization of beta-blockade titration, based on the results of the SHIFT trial [27]. Although prescription rates of recommended CHF drugs increased, mean doses of the major recommended drugs remained dramatically low, as is always found in the majority of registries [28—30]. As already shown by the IMPACT-RECO survey [20,21], age is a most important limiting factor for the prescription of CHF therapy. Older patients received fewer ACEIs/ARBs, beta-blockers and MRAs, but more diuretics. These results are in agreement with previous reports [31]. However, age is too often a poor justification for not introducing recommended CHF treatments, even if the presence of renal failure or a history of asthma or chronic obstructive pulmonary disease remain prognostic factors for lower prescription rates, particularly in relation to age [20]. Despite the heterogeneity of HF-PEF, prescription rates remained similar to those for HF-REF, with age having a similar effect, even if the rates were significantly lower for the major recommended drugs in general. These data have been already shown in European registries [32] and in France [28] with drugs having a similar impact. As guidelines regarding HF-PEF are scarce, the only efficient treatment applied in practice was the use of the lowest diuretic dose necessary to relieve fluid overload, salt restriction and blood pressure control. However, in HF-PEF, the absence of impact of medical treatment on survival curves over the last three decades [33], as well as the negativity of all randomized trials [34,35], could suggest that applying recommendations for HF-REF to HF-PEF is not justified. Our study showed that cardiologists did not know which strategy to use in case of CHF due to HF-PEF.
Study limitations This study is subject to the usual limitations of observational studies. The most important potential bias was the lack of randomization. We chose an observational registry performed in routine clinical practice by centres particularly interested in CHF management and trained in therapeutic patient education. Therefore, it did not provide an insight into the management of CHF by general practitioners. National I-CARE centre participation was around 60%. Some centres were unable to develop therapeutic patient education for the usual financial, human and material reasons [14] and decided not to participate in the study. Only 12 (19.7%) institutions (rehabilitation centres and CHF networks) used multidisciplinary teams, permitting more frequent and prolonged contact between patients and healthcare providers.
Y. Juillière et al.
Conclusion In CHF, and despite management by cardiologists particularly interested by CHF and specifically trained to deliver therapeutic patient education, medical prescription substantially differed from guidelines. Age and type of CHF (reduced versus preserved) appeared to be important factors in lack of adherence to guidelines. However, only age influenced mortality; the type of CHF (defined by the level of LVEF) did not have any effect on survival.
Disclosure of interest YJ and PJ have received research funding from AstraZeneca, initiated before the ODIN study for the completion of the ICARE project. YJ, JPD, AD, JPL and PJ have received grants from AstraZeneca for developing training of health professionals in therapeutic patient education in their centers. YJ has also participated to a national board on patient education sponsored by Bayer. ND has received research grants from Astra-Zeneca, Eli-Lilly, GSK, Merck, Novartis, Pfizer, Sanofi-Aventis, Servier, and The Medicines Company. The other authors report no conflicts of interest.
Acknowledgements This work was supported by a grant from the French Health Ministry (Direction générale de la santé); the French Society of Cardiology offered an administrative and technical support to the general management of the ODIN cohort. The authors thank Professor Tabassome Simon, Director of the Clinical Research Unit (URC-Est) of the Assistance publique des hôpitaux de Paris and University Paris 6, for directing clinical research technicians. The authors gratefully acknowledge the ODIN patients for their participation and cooperation throughout the study. The French ODIN cohort participants are as follows: F. Rodriguez, MD, C. Brunie, RN, C. Drege, RN, (CHG SaintEsprit, Agen); Ph. Fromage, MD, C. Bastard, RN, N. Coudurier, RN (CHG Annemasse-Bonneville); A. RacineMorel, MD, V. Robert, RN (CHG Autun); J.P. Darracq, MD, S. Egron, RN (CHG Samuel Pozzi, Bergerac); J. Ph. Labarre, MD, C. Valmary, RN (clinique Château de Vernhes, Bondigoux); P. Dominguez-Dos Santos, MD, F. Picard, MD, M.J. Betato, RN, A. Gard, RN, M. Lartigue, RN, F. Lacotte, RN (CHU hôpital du Haut-Lévêque, Bordeaux-Pessac); P. Coulon, MD, M. Lucbert, RN, F. Mendy, RN, C. Bacle, RN (CHU hôpital SaintAndré, Bordeaux); F. Bire, MD, N. Caminade, RN (HIA Robert Piqué, Bordeaux-Villenave d’Ornon); C. Labarrere, MD, M.H. Jaureguiberry, RN (réadaptation cardiaque, CHG CyranoGrancher, Cambo-les-Bains); Ph. Cantie, MD, I. Albert, RN, I. Grand, RN, E. Heral, RN, M. Nouret, RN (CHG CastresMazamet); A. Dellinger, MD, C. Duc, RN, D. Guitton, RN (CHG William Morey, Chalon-sur-Saône); L. Mankoubi, MD, M. Collard, RN, C. Ipcar, RN, C. Soreau, RN (CHG Louis Pasteur, Chartres-Le Coudray); A. Tuambilangana, MD, S. Nogues, RN (CHG Louis Pasteur, Cherbourg-Octeville); M. Fauvel, MD, M.J. Taudou-Martinel, MD, C. Bareille, RN, F. Moles, RN (Clinique des Cèdres, Cornebarrieu-Blagnac); J.C. Eicher, MD, O. Brenot, RN, M. Guerot, RN, F. Moreau, RN (CHU du Bocage,
Prescription of cardiovascular drugs in the French ODIN cohort Dijon); J.M. Gbonon, MD, Y. Fix, RN (clinique médicale de cardio-pneumologie, Durtol); N. Ghanem, MD, M. Quirin, RN (CHG Simone Veil, Eaubonne); S. Hackenberger, MD, S. Giga, RN, I. Lebreton, RN (CHG Evreux); A. Gabriel, MD, C. Geisler, RN, S. Velt (CHG Freyming-Merlebach); M. Gabrovescu, MD, C. Assulin, RN, M. Desenclos, RN (CHG Emmanuel Rain, Gonesse); M. Noirclerc, MD, C. Sicken, RN (réadaptation cardiaque, hôpital Sud, Grenoble-Echirolles); S. Marliere, MD, M. Salvat, MD, N. Hailley, RN (CHU, hôpital Albert Michalon, Grenoble-La Tronche); C. Weber-Stenger, MD, N. Griette, RN, M. Peterle, RN (hôpital Alpha Santé, Hayange); C. Gerard, MD, C. Bonnin, RN, S. Deroche, RN (CHG Hôtel-Dieu, Le Creusot); J.P. Favier, MD, N. Festy, RN (CHG Montivilliers, Le Havre-Montivilliers); S. Tondeux-Lefebvre, MD, S. Mucklisch, RN (CHG Léon Schwartzenberg, Le Quesnoy); F. Mouquet, MD, V. Hazebrouck, RN, A.M. Lebleu, RN, A. Willens, RN (CHU, Lille); F. Dany, MD, M. Faye, RN (ICARLIM Heart Failure Network, Limoges); S. Baleynaud, MD, G. Malarce, RN, M.P. Treguier, RN (KALONIC Heart Failure Network, CHG Bretagne Sud, Lorient); O. Ferry, MD, N. Arend, RN (CHG, Lunéville); B. Maitre, MD, N. Gelin, RN, A.M. Lanctuit, RN (ERIC Heart Failure Network, CHG des Chanaux, Mâcon); N. Baille, MD, N. Kremer, RN (hôpital Sainte-Blandine, Metz); M.F. Deforet, MD, C. Gaiffe, RN, A. Part, RN, E. Simon-Adig, RN (CHG Belfort-Montbéliard); G. Rebuffat, MD, C. Amoros, RN, C. Hebrard, RN, C. Perret, RN (CHG Montélimar); D. Kenizou, MD, M. Bindler, RN, A. Robo, RN (CHG Emile Muller, Mulhouse); Y. Juilliere, MD, G. Bosser, MD, N. Genchi, RN, N. Gouriou, RN, S. Weitkunat, RN, C. Wendling, RN (institut Lorrain du coeur et des vaisseaux, CHU Brabois, Nancy); J.N. Trochu, MD, V. Hossler, MD, A.L. Laprerie, MD, G. Lacaze, RN, H. Lambert, RN, C. Mariaux, RN (RESPECTICOEUR Heart Failure Network, CHU G. et R. Laennec, Nantes); C. AchePapillon, MD, C. Gonzales, RN (CHG Oloron-Sainte-Marie); M.C. Aumont, MD, G. Jondeau, MD, J. Charles, RN (CHU Bichat, Paris); F. Ledru, MD, M. Girault, RN (CHU hôpital européen Georges Pompidou, Paris); F. Beauvais, MD, D. Combres, RN (CHU Lariboisière, Paris); F. Pousset, MD, F. Allab, RN, M. Geoffrain, RN, M. Marlay, RN (CHU PitiéSalpétrière, Paris); B. Lequeux, MD, C. Bobier, RN (RADIC Heart Failure Network, CHU La Milétrie, Poitiers); P. Jourdain, MD, A. Boireau, RN, H. Lebras, RN (CHG René Dubos, Pontoise); C. Leclercq, MD, M.A. Foret, RN, S. Le Maitre, RN, C. Marquer, RN, N. Pellen, RN, I. Timonier, RN (centre cardiopneumologique, CHU Pontchaillou, Rennes); V. Berder, MD, P. Guillo, MD, S. Bertrand, RN, N. Tallec, RN (réadaptation cardiovasculaire, clinique Saint-Yves, Rennes); F. Bauer, MD, S. Cordier-Pouchin, RN, E. Benmokhtar, RN (CHU Charles Nicolle, Rouen); P. Webert, MD, M. Schweitzer, RN (CHG Lemire, Saint-Avold); F. Cadi, MD, S. Lassere-Remy, MD, V. Dolbeau, RN (réadaptation cardiaque, CRF Val Rosay, SaintDidier au Mont d’Or); M. Diallo, MD, S. Martin, RN (Mémorial France-Etats-Unis, Saint-Lo); B. Ouattara, MD, M.F. Aubry, RN, C. Cadieu, RN (hôpital Broussais, Saint-Malo); P. Coulon, MD, I. Flaus, RN (CHG Saint-Nicolas, Sarrebourg); A. Pinzani, MD, J.P. Bazanau, RN, B. Celka, RN, CHG Sète; J.M. Taupin, MD, B. Amaury, RN (pôle prévention et éducation du patient, Soissons); Th. Beard, MD, R. Dos Santos, RN (clinique de l’Ormeau, Tarbes); M. Galinier, MD, A. Pathak, MD, J. Roncalli, MD, S. Mazzon, RN, L. Spinazze-Fournier, RN (CHU Rangueil, Toulouse); A. Belin, MD, C. Dossetto, MD, L. More, RN, M. Pougheul, RN (centre de réadaptation,
31 Trouville-sur-Mer); L. Desprets, MD, M. Linne, RN, CHG Valenciennes; S. Allam, MD, S. Laurent, RN (CHG SaintNicolas, Verdun); A. Atallah, MD, V. Marcel, RN, J. Plantier, RN, N. Saminadin, RN (CHG Basse Terre, Guadeloupe); C. Mimran, MD, Th. Hoarau, RN (CHG Sud-Réunion, SaintPierre, La Réunion).
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