International Journal of Cardiology 184 (2015) 552–558
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Palliative needs for heart failure or chronic obstructive pulmonary disease: Results of a multicenter observational registry☆ Antonello Gavazzi a,⁎,1, Renata De Maria b,1, Lamberto Manzoli c,1, Paolo Bocconcelli d,1, Antonio Di Leonardo e,1, Maria Frigerio f,1, Stefano Gasparini g,1, Franco Humar h,1, Gianpiero Perna i,1, Roberto Pozzi j,1, Fausto Svanoni k,1, Marcello Ugolini l,1, Alberto Deales m,1 a
FROM Research Foundation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy Istituto di Fisiologia Clinica CNR, Dipartimento Cardiotoracovascolare, Azienda Ospedaliera Ospedale Niguarda-Ca' Granda, Milano, Italy c Dipartimento di Medicina e Scienze dell'Invecchiamento, Università G. D'Annunzio, Chieti, Italy d Divisione di Cardiologia, Ospedale San Salvatore, Pesaro, Italy e Servizio di Cure Palliative, Ospedale Salvini, Garbagnate, Italy f Dipartimento Cardiotoracovascolare, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Milano, Italy g Divisione di Pneumologia, Ospedali Riuniti, Ancona, Italy h Centro Cardiovascolare, Azienda Sociosanitaria 1 Triestina, Trieste, Italy i Dipartimento di Scienze Cardiologiche Medico-Chirurgiche, Ospedali Riuniti, Ancona, Italy j Divisione di Cardiologia, Ospedale San Luigi Gonzaga, Orbassano, Italy k Direzione Sanitaria, Ospedale Papa Giovanni XXIII, Bergamo, Italy l Divisione di Pneumologia, Ospedale San Salvatore, Pesaro, Italy m Area Governo Clinico, Agenzia Regionale Sanitaria Regione Marche, Ancona, Italy b
a r t i c l e
i n f o
Article history: Received 11 July 2014 Received in revised form 26 January 2015 Accepted 3 March 2015 Available online 5 March 2015 Keywords: Palliative care Advanced heart failure Advanced chronic obstructive pulmonary disease Mortality Symptom burden Quality of life
a b s t r a c t Background: Heart failure (HF) and chronic obstructive pulmonary disease (COPD) share a common organ failure trajectory marked by prognostic uncertainty, which is a barrier to appropriate provision of palliative care. We describe in a prospective cohort from specialist hospital services the epidemiology and late clinical course of these chronic diseases to trace criteria for transition to palliative care in the community. Methods and results: Seven centers enrolled 267 patients with advanced HF (n = 174) or COPD (n = 93) using common (multiple hospitalizations or severely impaired functional status or cachexia) and disease-specific (HF: systolic dysfunction, NYHA classes III–IV, end-organ hypoperfusion; COPD: very severe airflow obstruction, hypoxemia, hypercapnia, or long-term oxygen therapy) entry criteria. These patients represented 7.2% and 13% respectively of the overall HF and COPD population hospitalized during one year. They showed similar symptom burden, functional and quality of life impairment, recurrent hospitalizations, and 6-month mortality (39% and 37%, respectively). Organ failure progression was the cause of death in N75%. In-hospital overall stay during the previous year was the main mortality predictor in both. Disease-specific predictors included anemia, hyponatremia, no beta-blockers in HF; older age, hypercapnia in COPD. Conclusions: Patients with advanced HF/COPD represent almost 10% of subjects hospitalized yearly with a primary diagnosis of HF or COPD, have similarly impaired functional status, disabling symptoms and reduced survival. Overall days spent in-hospital during the previous year, a “red flag” in the late clinical course of both diseases, might be used as a simple, reliable screening tool for appropriate transition to palliative care in the community. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction
☆ Grant support: Supported by the Italian Ministry of Health Grant RF-MAR-2007679550. The sponsor had no role in study design, the collection, analysis and interpretation of data, the writing of the report, and in the decision to submit the article for publication. ⁎ Corresponding author at: FROM Fondazione per la Ricerca, Azienda Ospedaliera Papa Giovanni XXIII, Piazza Organizzazione Mondiale Sanità 1, 24127 Bergamo (BG), Italy. E-mail address: [email protected] (A. Gavazzi). 1 This author takes responsability for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
http://dx.doi.org/10.1016/j.ijcard.2015.03.056 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are systemic disorders with potentially overlapping pathophysiological process [1] and represent global epidemics [2,3]. Both are chronic debilitating conditions and incur significant morbidity and mortality. Their natural history is typical of the organ failure trajectory [4], with symptom burden and functional impairment comparable to advanced cancer [5–7], but frustrating prognostic uncertainty [8,9]. Outcome assessment is challenging and relatively unpredictable in individuals [9–14], particularly in
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advanced stages [9,15–17]. The clinical course of both HF and COPD is marked by heavy use of health services and more common aggressive treatment than in comparably end-stage malignant disease [18,19]. The more linear decline of patients with advanced cancer has traditionally been the model to approach end-stage disease, when decisions on lifeprolonging treatment should be considered. Organ specialist physicians, such as cardiologists and pulmonologists, are traditionally treatmentfocused and may lack the symptom management perspective, which becomes increasingly meaningful to patients as they progress to end-stage. A better understanding of the late clinical course of organ failure conditions, such as HF and COPD, helps calibrate expectations, guide communication, and inform rational decisions which may benefit patients and their families. The importance of a palliative care approach, as a key component of management in advanced disease, has been highlighted in recent scientific society statements [20–23]. Furthermore, a palliative approach integrating standard care should decrease the hospitalization rate of these very ill patients, improving patients' quality of life and diminishing the economic burden of the disease. Palliative care in Italy has recently developed to improve standards for oncological diseases, but still few patients with non-malignant disease access the network [24]. Furthermore national criteria for referral of patients with HF or COPD to palliative care services by general practitioners or organ specialists have not yet been defined. Under this rationale, the study was funded by the Italian Health Ministry (Grant RFMAR-2007-679550) in a call devoted to research on health services organization. We set-up a multicenter observational registry of patients with HF and COPD accessing hospital care in order to 1) define the proportion of subjects who access hospital care meeting criteria for advanced disease, 2) compare the late clinical course of advanced HF or COPD, expressed as symptom burden, functional status, quality of life, recurrent hospitalization and mortality, and 3) identify, as support to national initiatives directed at organizing the provision of health care services, patient characteristics associated with a mid-term negative outcome, for whom transition to targeted palliative interventions in the community, may be warranted.
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to severe mitral insufficiency), New York Heart Association (NYHA) functional classes III–IV dyspnea, clinical or laboratory signs of end organ hypoperfusion, including glomerular filtration rate b 60 ml/min, sodium b 135 mEq/L, hemoglobin b 11 g/dL, and total bilirubin N 1.2 mg/dL. - Patients with COPD had to show very severe airflow obstruction (Forced Expiratory Volume in 1 s [FEV1] b 30%), or hypoxemia (PaO2 b 55 mm Hg), or hypercapnia (PaCO2 N 45 mm Hg, i.e. above the upper normalcy threshold), OR to be on long-term oxygen therapy N 8 h/day.
2.3. Measurements
From March 2010 till March 2012, patients with HF or COPD were identified at 7 enrolling sites from the cardiology or pulmonology outpatient clinics and from institutional hospital discharge databases using International Classification of Disease 9 primary diagnosis codes for HF and COPD. Patients' clinical records were reviewed at each center.
Patients were recalled for an outpatient visit to confirm eligibility. The diagnosis of HF or COPD was based on the European Society of Cardiology [3] or Global Initiative for Chronic Obstructive Lung Disease [2], respectively. Demographics, clinical and laboratory data were recorded. Comorbidities were assessed by history and chart review. Patients were then questioned about their current symptoms. Dyspnea was graded from 1 (none) to 5 (too breathless to leave the house) using the Medical Research Council Scale [27]. Pain intensity was measured using the Visual Analogue Scale for Pain (VAS Pain) [28]. Cognitive impairment was screened by The Mini Mental State Examination using a cut-off threshold of b24 [29]. Functional status was assessed by the Karnofsky Performance Status Scale [30] and Basic Activities of Daily Living [31]. Quality of life was assessed through the following generic and disease-specific validated tools: SF12, a shortened version of the Short Form 36 of the Medical Outcomes Study [32] for all, plus the Minnesota Living with Heart Failure for HF [33], and the Airways Questionnaire 20 for COPD [34]. Whenever feasible, to quantitatively assess their functional performance, patients underwent a single six-minute walking test using the American Thoracic Society criteria [35]; the total distance walked in meters was recorded to assess functional impairment and expressed as percent of predicted values [36]. For COPD patients, the composite Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index [14] was calculated. On June 30, 2012, vital status and mode of death and hospital admissions were ascertained through telephone interview with patients or caregivers and review of hospital records. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval of the Ethics Committee of each participating institution. Patients gave their written informed consent to participate.
2.2. Eligibility criteria
2.4. Statistical analysis
We enrolled in an observational registry consecutive patients meeting the following general eligibility criteria, valid for both HF and COPD: ≥ 2 hospital admissions for the index diagnosis within the previous 12 months; in patients with b 2 admissions, an overall length of stay N 40 days (twice the threshold value set by the Italian Ministry of Health as abnormal length of stay for reimbursement criteria) as a clue to difficulties in stabilizing the patient was required as an alternative criterion, OR Karnofsky performance status b 50 or dependent in 3 or more basic activities of daily living, OR cachexia, defined as unintentional loss of N10% body weight within the previous 12 months [25], or a body mass index b 21 kg/m2 [26] and serum albumin b 2.5 g/dL as supportive criterion. In addition to the general criteria, the following disease-specific criteria had to be fulfilled:
Categorical variables are presented as frequency percent and continuous variables as mean ± standard deviation or median [interquartile range]. Between-group differences were tested by chi-square test and Student's t-test or non-parametric tests according to normal or nonnormal variable distribution. Kaplan–Meier survival analysis was used to examine the association between COPD and HF, or both coexisting conditions, and all-cause mortality. The validity of constant incidence ratios over the follow-up was checked using Nelson–Aalen cumulative hazard estimates. Cox proportional hazards analysis was used to calculate the adjusted relative hazards of death by each considered variable [37], which were selected according to p b 0.10, 20% change of the hazards ratios of other significant variables, missing data b 30% of the sample, age, gender and body mass index were included a priori. Schoenfeld's test was performed to check the validity of proportional hazards assumption. A p value of b0.05 was considered significant for all analyses, which were performed using STATA 10.1 (Stata Corporation, College Station,
2. Methods 2.1. Participants
- Patients with HF had to show severely depressed pump function (left ventricular ejection fraction b 30% or b40% with moderate
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TX, USA, 2007). Reporting of the study conforms with STROBE, along with references to STROBE and the broader EQUATOR guidelines [38]. 3. Results The study cohort included 267 patients, 174 with advanced HF and 93 with COPD, which represented 7.2% and 13%, respectively, of the overall HF and COPD population hospitalized during one year, as identified by the International Classification of Disease codes from discharge database. Baseline characteristics are reported in Table 1. 3.1. Demographic and clinical characteristics Both groups had a significant burden of associated medical conditions, but HF patients, although younger, had on average a significantly higher number of comorbidities than COPD patients. Comorbid COPD was found in one out of four HF patients. Overall 54% and 36% respectively had spent over 40 days in the hospital (p = 0.009). Both populations complained of troubling symptoms. Dyspnea, the most recurrent, was more common and severe in COPD patients, as demonstrated by a higher proportion of patients who were homebound for dyspnea (p = 0.041). Severe fatigue, anorexia and moderate to severe pain were equally present in both groups, while upper gastrointestinal symptoms occurred more frequently in HF patients (p = 0.002). Moreover, 90% of study patients were unable to work and one third were unable to perform 3 or more basic activities of daily living (Fig. 1). Cognitive impairment was common and overall one third had
a score below the threshold cut-off for the clinical diagnosis of dementia, with a higher prevalence among HF patients. Multi-organ failure was evident from laboratory data in both groups, but with a significantly more prominent kidney dysfunction and anemia in HF patients. A marked reduction in the distance walked at the six-minute walking test in comparison to reference normal values was recorded in both groups (Table 1). Quality of life was poor: perceptions of physical functioning were universally below the 25th percentile of the age and gender-matched general population, but also mental health was severely affected in over 70% of cases (Fig. 1). Among HF patients (Table 2), pump function was severely depressed and elevated natriuretic peptides indicated persistent congestion. Forty-seven percent of patients had a cardioverter defibrillator implanted and 39% had undergone cardiac resynchronization therapy. High dose furosemide was prescribed in most patients to relieve persistent congestion. Rates of renin–angiotensin system inhibitors and mineralocorticoid receptor antagonists treatment were relatively low, in keeping with the prevalence of kidney dysfunction. Conversely, prescription of beta-blockers, a cornerstone of HF therapy, was high, and heart rate was accordingly well controlled, despite neurohormonal activation. About one third of patients were on intermittent or continuous inotropic support. Among COPD patients (Table 2), the average BODE index, a composite score that takes into account both airways' flow limitation and the systemic effects of COPD, was 10, indicating severe multidimensional impairment and 88% were on long-term oxygen therapy.
Table 1 Baseline characteristics of the study population. Characteristics
Heart failure (n = 174)
Chronic obstructive pulmonary disease (n = 93)
p value
Age (years) Male gender (%) Days spent in hospital within 12 months (n) Body mass index (kg/m2) Body mass index ≤ 21 kg/m2 (%) Weight loss N 10% within 12 months (%) Cachexia any of 3 criteria (%) Comorbidities Comorbidities number History of hypertension (%) Diabetes and target organ damage (%) Liver dysfunction (%) COPD (%) Ischemic heart disease (%) Anemia (Hemoglobin b 11 g/dL) (%) Chronic kidney dysfunction (%) Peripheral vessel disease (%) Cerebrovascular disease (%) Obstructive sleep apnoea syndrome (%) Atrial fibrillation (%) Cognitive impairment (MMSE b 24) (%) MMSE Symptoms Dyspnea MRC class 4 (home-bound) (%) Severe fatigue (%) Anorexia (%) Upper gastrointestinal symptoms (%) Moderate to severe pain (VAS ≥ 4/10) % Functional capacity Basic activities of daily living Karnofsky performance status Six minutes walking distance (% predicted) Laboratory data Glomerular filtration rate (ml/min/1.73 m2) Urea (mg/dl) Albumin (mg/dl) Albumin b 2.5 mg/dl (%) Total bilirubin (mg/dl) Sodium (mEq/l) Hemoglobin (g/dL)
72 ± 12 73 41 ± 34 25 ± 5 (n = 158) 18 (n = 158) 7 19
75 ± 9 67 48 ± 35 27 ± 6 16 9 29
0.08 0.323 0.097 0.31 0.86 0.615 0.085
4 ± 1.8 54 20 17 26 79 34 42 33 16 11 30 39 (n = 101) 24.4 ± 5
3.6 ± 1.6 57 11 5 – 36 17 13 13 13 39 6 21 (n = 73) 25.6 ± 4
0.037 0.699 0.083 0.007 – 0.0001 0.004 0.0001 0.0001 0.590 0.007 0.0001 0.13 0.082
23 23 58 47 52
39 23 52 27 56
0.041 1 0.369 0.002 0.567
4.1 ± 2.2 (n = 120) 50.4 ± 17 44 ± 77
3.7 ± 2.0 49.8 ± 14 37 ± 29
0.16 0.778 0.05
48 ± 25 94 ± 66 3.45 ± 0.7 5.0 (n = 141) 1.24 ± 1 138 ± 4 11.9 ± 1.8
66 ± 32 65 ± 41 (n = 80) 3.22 ± 0.7 3.4 (n = 88) 1.18 ± 1 140 ± 3 12.2 ± 1.7
0.0001 0.0001 0.013 0.745 0.691 0.13 0.238
Data are expressed as number (percentage) or mean ± SD. MMSE, Mini Mental State Examination; MRC, Medical Research Council; VAS, Visual Analogue Scale.
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Fig. 1. Proportion of patients with ≤3 preserved basic activities of daily living (BADL), activity levels, SF12 mental (MCS) and physical (PCS) components b 25th percentile of the age and gender-matched general population (n = 179), among heart failure (HF, dark boxes) and chronic obstructive pulmonary disease (COPD, empty boxes) patients.
Table 2 Disease-specific clinical characteristics. Heart failure patients
N = 174
Ischaemic etiology (%) Systolic blood pressure (mm Hg) Heart rate (bpm) Left ventricular ejection fraction (%) Left bundle branch block (%) Implantable cardioverter defibrillator (%) Cardiac resynchronization therapy (%) Furosemide dose (median [Interquartile range]) (mg) Spironolactone (%) ACE-inhibitors or ARBs (%) Beta-blockers (%) Digoxin (%) Oral anticoagulant agents (%) Inotropes (%) NTproBNP (median [Interquartile range]) (pg/ml) BNP (median [Interquartile range]) (ng/ml) Quality of life MLHFQ (n = 82) total score MLHFQ physical dimension MLHFQ emotional dimension
77 118 ± 22 76 ± 14 26 ± 5 37 49 37 125 [137] 51 57 74 27 53 32 2617 [3724] 639 [1242] 49 ± 20 22 ± 9 10 ± 7
Chronic obstructive pulmonary disease patients
N = 93
BODE index Oxygen saturation (%) PaO2 (mm Hg) PaCO2 (mm Hg) Forced expiratory volume in 1 s (% of predicted) Furosemide (mg/day)* Oral corticosteroids (%) Inhaled corticosteroids (%) Long acting beta agonists (%) Long acting muscarinic antagonists (%) Hours of oxygen therapy/day (n) Long-term oxygen therapy ≤ 15 h/day (%) Long-term oxygen therapy N 15 h/day (%) Non-invasive ventilation (%) Quality of life: Airways Questionnaire-20 score (n = 62)
10 ± 3 93 ± 4 67 ± 15 50 ± 13 45 ± 11 50 [100] 54 97 95 87 17 ± 10 29 59 19 16 ± 3
Data are expressed as frequency % of patients or mean ± SD or * Median [Interquartile range]. ACE, Angiotensin Converting Enzyme; ARBs, Angiotensin Receptor Blockers; BODE, Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity; BNP, Brain Natriuretic Peptide; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NtproBNP, N terminal pro-brain natriuretic peptide.
Patients with coexistent HF and COPD (n = 45) showed more frequently cachexia (38.6%) than those with either HF (19%) or COPD (26.9%) alone (p = 0.033). No differences were found in Basic Activities of Daily Living, Karnofsky performance status and MiniMental Status Examination score among the 3 groups. 3.2. Outcome During a mean follow-up of 6 ± 4 months, 39% of HF and 37% of COPD patients died. Survival by Kaplan–Meier analysis (Fig. 2) was similar in the two groups (log rank test p = 0.58), with a mortality rate near to 40% at 6 months. The incidence of sudden death was low (15% in HF and 6% in COPD), while the most common cause of demise was progression of pump failure in HF (83%) and respiratory failure in COPD (74%). In both groups hospital readmissions during follow-up were frequent (60% of HF and 49% of COPD patients were hospitalized at least once) and length of stay was prolonged, with a median of 30 [interquartile
COPD HF HF + COPD
Fig. 2. Kaplan–Meier survival curves of patients with heart failure (dotted line), chronic obstructive pulmonary disease (continuous line), or coexistent heart failure and chronic obstructive pulmonary disease (hatched line) enrolled in the registry.
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range 56] days in HF and 27 [interquartile range 49] days in COPD (p = 0.599). Six-month mortality was 31% for coexistent COPD and HF vs 37% for HF and 41% for COPD, but patients with both HF and COPD were admitted more frequently during follow-up (mean admission number 1.91 vs 1.31 for HF, and 0.87 for COPD; p = 0.003). None of the patients at the time of recruitment was in a palliative care program, nor were specific provisions taken within the protocol for referral to specialist palliative care. 3.3. Prognostic stratification To assess independent predictors of all-cause mortality the following variables were entered in multivariable Cox proportional hazards models (Table 3): age, gender, body mass index, Medical Reasearch Council dyspnea scale, number of comorbidities, Karnofsky performance status, and overall days in hospital during previous year for the whole cohort, with the addition of hemoglobin, beta-blockers, and sodium for HF patients, and PaCO2, BODE index, and long-term oxygen therapy for COPD patients. Overall, only the sum of days spent in hospital in the previous year was independently associated with outcome, whereas Karnofsky performance status reached borderline significance. In the HF cohort, lower hemoglobin and sodium levels and lack of beta-blocker therapy were independent predictors of death. Among COPD patients, only older age and hypercapnia predicted a negative outcome. 4. Discussion Our multicenter observational registry offers insights in the epidemiology and late clinical course of patients affected by advanced HF or COPD, which may aid cardiologists and pulmonologists in understanding the turning point from life-prolonging strategies to supportive and palliative care. The main findings of this study are that patients with advanced HF or COPD represented almost 10% of those accessing hospital care for these diseases yearly and had overlapping disabling symptoms, similarly impaired functional status, and comparably reduced survival. Time spent in hospital during the previous year was the main predictor of mortality in both patient groups, whereas disease-specific predictors of outcome included anemia, low serum sodium, and lack of betaTable 3 Cox multivariate model for all-cause mortality. Hazard ratio (95% CI) Overall cohort Days in hospital during previous year (per unit increase) Karnofsky performance status (per unit increase) Medical Research Council dyspnea scale (per unit increase) Age (per unit increase) Gender (male vs female) Number of comorbidities (per unit increase) Body mass index (per unit increase) Heart failure patients Hemoglobin (per 1 g/dl increase) Beta-blockers (yes vs no) Sodium (for each 1 mEq/l increase) Medical Research Council dyspnea scale (per unit increase) Age (per unit increase) Gender (male vs female) Chronic obstructive pulmonary disease patients Age (per unit increase) PaCO2 (per unit increase) Gender (male vs female) BODE index (per unit increase) Long-term oxygen therapy (yes vs no)
p value
1.00 (1.00–1.01) 0.037 0.98 (0.96–1.00) 0.06 1.30 (0.97–1.75) 0.07 1.02 (0.99–1.05) 1.35 (0.79–2.30) 1.08 (0.95–1.24) 1.01 (0.96–1.05)
0.13 0.26 0.22 0.78
0.78 (0.67–0.92) 0.54 (0.30–0.97) 0.94 (0.88–0.99) 1.21 (0.88–1.66)
0.003 0.041 0.045 0.22
1.02 (0.98–1.04) 0.23 0.99 (0.52–1.89) 0.98
1.09 (1.03–1.16) 1.03 (1.00–1.06) 1.83 (0.73–4.61) 1.06 (0.89–1.27) 1.42 (0.61–3.27)
BODE, Body mass index, airway Obstruction, Dyspnea, and Exercise capacity.
0.003 0.052 0.19 0.48 0.41
blocker treatment in HF patients, and older age and hypercapnia in COPD patients. This study was planned from the perspective of cardiology and pulmonology specialist centers, to assess the burden of advanced HF or COPD to hospital services and to analyze whether specific criteria could improve palliative referral of patients with advanced disease and heavy use of acute hospital services. In the contemporary literature, data on the prevalence of advanced HF or COPD stages, according to disease-specific criteria coupled to severely impaired performance status and high symptom burden, are, to the best of our knowledge, scanty and not to comparable to ours because of different study designs [39,40]. Criteria for inclusion in our registry coupled well-established scales of functional impairment, commonly used to express disability and the cumulative care burden in a wide spectrum of illnesses [30,31], to specific markers of advanced organ disease [2,3,23]. Indeed the correlation between NYHA class and Karnofsky performance status has recently been reported to be poor [41], indicating that for a comprehensive assessment of the care burden in the daily life, both indexes should be used. The patients enrolled in our registry represent a sizable proportion of those requiring acute hospital care each year for HF (7.2%) or COPD (13%). The prevalence of COPD in patients with HF in the present hospital-based series is 25.8%, while in previous reports it ranges widely from 9 to 52%, depending on the population studied, diagnostic criteria applied, measurement tools, and surveillance systems [1]. Symptom burden and quality of life impairment of both HF and COPD patients were similar to previously reported data [5–7,42]. In our registry the only differences in symptoms are probably linked to disease-specific pathophysiology, e.g. COPD patients had a worse dyspnea, due to severe chronic hypoxemia, while HF patients complained more frequently of upper gastrointestinal symptoms, due to splanchnic congestion. Within 6 months a comparably high proportion of both groups had died, the main cause being progression of organ failure. This subset with high symptoms burden, poor quality of life and short-term poor outcome represents the ideal group where to concentrate every effort to reduce the re-hospitalization rate and to implement specific programs to palliative care transition in the community. The quest for simple markers to draw attention on potential candidates to palliative care is important from an organizational stand point to plan access to often strained palliatice care services. Investigations in the natural history of HF have highlighted the very poor prognosis in advanced stages, with 30 to 50% 1-year mortality [10, 16,21]. Patients who fulfilled the enrollment criteria in our study had an even worse outcome, with a 6 month mortality of 39%, indicating that they truly had an end-stage condition, where no improvement with conventional HF treatment is to be reasonably expected and palliative care should first complement and then take the lead of care. In agreement with published data [11–23], disease-specific predictors of outcome in our HF series included multiple clinical characteristics, such as serum sodium concentration, a marker of congestion and neurohormonal activation, anemia, a multifactorial comorbidity, and lack of beta-blocker treatment, expressing drug intolerance as proxy for labile haemodynamic status, frequently observed in advanced HF. Despite the high prevalence of COPD, relatively less is known, in comparison with HF, about the late clinical course of this disease: previous studies included small mostly single-center series enrolled after hospital admission for acute exacerbation [43]. In the early 90's the landmark SUPPORT study [44] enrolled a cohort of 1016 COPD patients, who had hypercapnia at the time of hospital admission for an acute exacerbation: mortality and readmission rates at 6 months were 33% and 50%, respectively. In a recent review of relevant studies, a median survival of 2–4 years was reported for patients with severe COPD, but for those hospitalized for an exacerbation, median survival may be b6 months, according to age, functional and clinical characteristics, and repeated hospitalizations [45].
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Our findings underscore the poor prognosis of patients with severe COPD and are in close agreement with data from SUPPORT [44]. Consistently with their advanced disease stage, most patients had severe systemic manifestations, as summarized by an average BODE index of 10, in the very high risk range: in patients with long standing COPD these values have been previously associated with 3-year mortality rates of 54.4% [14,46]; therefore, the lack of predictive value that we found in our series is not surprising. The association with outcome of hypercapnia, a common finding in patients with advanced COPD as a marker of both severe ventilation–perfusion mismatch and the inability to adequately increase ventilation, is controversial in the overall spectrum of COPD [15]. Hypercapnia was the only relevant mortality predictor, together with age, in our COPD patients with severe end-stage disease. In this respect, home non-invasive ventilation, which was performed in one fifth of our population, may contribute to symptom relief and improve quality of life [47]. The coexistence of HF and COPD has been reported to exert a negative synergism on functional status and outcome [1,48], with complex management problems due to the possible adverse effects of betablockers on airways reactivity, and on the detrimental effects of longacting beta2-agonists on heart rate. In the SUPPORT cohort [44], comorbid HF and cor pulmonale were actually protective against mortality. In our series, more severe systemic manifestations, but similar functional status were observed. Moreover, despite a higher number of readmissions, survival did not differ from patients with either condition alone (Fig. 2). Overall, patients affected by advanced HF or COPD that enrolled in our registry show during a short-term follow-up not only the same negative outcome, but also the same high incidence of prolonged rehospitalization, mainly for organ-related failure. Difficult prognostication in individual patients with advanced HF and COPD is frequently perceived as an obstacle inhibiting discussions regarding end of life. The only significant predictor by Cox multivariate analysis in the overall population of the present study was the number of days in the hospital during the 12 months prior to enrolment. This finding highlights the relevance of organ failure-related hospitalizations as key sentinel events in the late clinical course of patients with either HF or COPD and may be used as a screening tool for appropriate referral to palliative care in the community after discharge. The relevance of this finding is that it can be derived from administrative data, allows to recognize at discharge the patients more prone to a negative outcome and may be considered as a “red flag”. Patients and caregivers should be made aware of the likelihood of poor outcomes following repeated hospitalization for exacerbation of organ-related failure. These patients with high symptom burden, emotional distress, heavy use of acute care and poor quality of life, stand for almost 10% of subjects hospitalized with a primary diagnosis of HF or COPD and represent ideal candidates for a palliative approach. Appropriate programs of palliative care in the community should be offered to this subset of very ill patients with non-malignant organ diseases [49], to improve their quality of life and reduce hospitalization rates, therefore diminishing the economic burden of end-stage disease [50].
Study limitations The source of data was a multicenter observational registry, where enrolment was limited to patients with very advanced stages of HF with reduced ejection or COPD. Outcomes would probably differ in a larger cohort considering less stringent entry criteria. Among the seven participating centers, two are large, tertiary referral centers: outcomes may change in smaller community hospitals, where the majority of patients with HF or COPD probably receive a different care. The diagnosis of HF with preserved ejection fraction requires the confirmation of diastolic dysfunction by Doppler echocardiography, a test which may not be routinely available, making the differential diagnosis with other causes of symptoms (e.g. dyspnea) difficult. The exclusion of HF patients
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with preserved ejection fraction from enrolment might have led to the underestimation of the global palliative care burden for HF. We did not record data from all patients admitted with decompensated HF or exacerbation of COPD, but only for those meeting the eligibility criteria for inclusion; therefore, a comparison of mortality between all patients hospitalized for HF or COPD was not possible. However, our national contemporary data indicate that six-month mortality is approximately 20% for patients hospitalized for worsening HF with reduced ejection fraction in cardiology units [51] and 15% for those admitted with a severe COPD exacerbation [52]. 5. Conclusions Patients with advanced HF or COPD have overlapping disabling symptoms, similarly impaired functional status, and comparably reduced survival. These very ill patients have a poor quality of life, require a heavy use of acute care and stand for almost 10% of subjects hospitalized with a primary diagnosis of HF or COPD. The length of organrelated hospitalization during the previous year is the main predictor of mortality in both groups. This should be considered as a “red flag” in the late clinical course of patients with HF or COPD and might be used as a screening tool for appropriate referral after discharge to palliative care in the community. Conflict of interest The authors have no conflict of interest to declare. Acknowledgments The authors gratefully acknowledge the contribution of Marinella Sommaruga and Paola Gremigni for help with quality of life questionnaire scoring and interpretation, Marilisa Ambrosio for expert secretarial assistance, and Franco Falcone for thoughtful advice. Appendix A. Study sites and investigators (all in Italy) Ospedale Salvini, Garbagnate: Michele Sofia, Cristina Arosio, Antonio Di Leonardo, Vittorio Guardamagna, Roberto Luigi Monticchio, Sergio Stefano Pardea, Vivian Sardo, Stefano Spagnotto. Azienda Ospedaliera Ospedale Niguarda-Ca' Granda, Milano: Maria Frigerio, Enrico Ammirati, Renata De Maria, Maria Grazia Gambato, Fabrizio Oliva. Azienda Sociosanitaria 1 Triestina, Trieste: Andrea Di Lenarda, Elena Abate, Luisa Giove, Franco Humar, Donatella Radini, Marina Riosa, Kira Stellato. Ospedale San Luigi Gonzaga, Orbassano: Roberto Pozzi, Marta Fenoglio, Laura Montagna, Domenico Osella. Ospedali San Salvatore, Pesaro: Paolo Testarmata, Lucia Cantarini, Marcello Ugolini. Ospedali Riuniti di Ancona: Giampiero Perna, Ilaria Battistoni, Martina Bonifazi, Stefano Gasparini. Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (previous Ospedali Riuniti di Bergamo): Antonello Gavazzi, Marilisa Ambrosio, Anna Caffi, Marco Marino, Rachele Ramponi, Fausto Svanoni. References [1] N.M. Hawkins, M.C. Petrie, P.S. Jhund, G.W. Chalmers, F.G. Dunn, J.J.V. McMurray, Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology, Eur. J. Heart Fail. 11 (2009) 130–139. [2] GOLD Global Initiative for Chronic Obstructive Lung Disease, Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report 2006Updated 2006 http://www.goldcopd.com/. [3] K. Swedberg, J. Cleland, H. Dargie, et al., Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology, Eur. Heart J. 26 (2005) 1115–1140.
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[30] D.A. Karnofsky, J.H. Burchenal, The clinical evaluation of chemotherapeutic agents in cancer, in: C.M. MacLeod (Ed.), Evaluation of Chemotherapeutic Agents, Columbia Univ Press, 1949, p. 196. [31] Staff of The Benjamin Rose Hospital, Multidisciplinary studies of illness in aged persons: ii. A new classification of functional status in activities of daily living, J. Chronic Dis. 9 (1959) 55–62. [32] J.E. Ware, M. Kosinski, S.D. Keller, A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity, Med. Care 34 (1966) 220–233. [33] T. Rector, J. Cohn, Patients' self-assessment of their congestive heart failure, part 2: content, reliability and validity of a new measure, the Minnesota Living with Heart Failure questionnaire, Heart Fail. 3 (1987) 198–209. [34] F.H. Quirk, P.W. Jones, Repeatability of two new short airways questionnaires, Thorax 49 (1994) 1075. [35] ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories, ATS statement: guidelines for the six-minute walk test, Am. J. Respir. Crit. Care Med. 166 (2002) 111–117. [36] P.L. Enright, D.L. Sherrill, Reference equations for the six-minute walk in healthy adults, Am. J. Respir. Crit. Care Med. 158 (1998) 1384–1387. [37] E. Von Elm, D.G. Altman, M. Egger, S.J. Pocock, P.C. Gotzche, J.P. Vandenbroucke, for the STROBE Initiative, The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies, J. Clin. Epidemiol. 61 (2008) 344–349. [38] D.W. Hosmer, S. Lemeshow, Applied Survival Analysis, John Wiley & Sons, New York, 1999. [39] R. Harding, T. Beynon, F. Hodson, et al., Provision of palliative care for chronic heart failure inpatients: how much do we need? BMC Palliat. Care 8 (2009) 8. [40] F. Zannad, S. Briancon, Y. Juilliere, et al., Incidence, clinical and etiologic features, and outcomes of advanced chronic heart failure: the EPICAL study. Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine, J. Am. Coll. Cardiol. 33 (1999) 734–742. [41] M.J. Johnson, J.M. Bland, P.M. Davidson, et al., The relationship between two performance scales: New York Heart Association Classification and Karnofsky Performance Status Scale, J. Pain Symptom Manag. 47 (2014) 652–658. [42] K. Moens, I.J. Higginson, R. Harding, EURO IMPACT, Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review, J. Pain Symptom Manag. (2014 May 3)http://dx.doi.org/10.1016/j.jpainsymman. 2013.11.009 (pii: S0885-3924(14)00077-3). [43] J. Steer, G.J. Gibsob, S.C. Bourke, Predicting outcomes following hospitalization for acute exacerbations of COPD, Q. J. Med. 103 (2010) 817–829. [44] A.F. Connors Jr., N.V. Dawson, C. Thomas, et al., SUPPORT Investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments), Outcomes following acute exacerbation of severe chronic obstructive lung disease, Am. J. Respir. Crit. Care Med. 154 (1996) 959–967. [45] S.R. Salpeter, E.J. Luo, D.S. Malter, B. Stuart, Systematic review of noncancer presentations with a median survival of 6 months or less, Am. J. Med. 125 (2012) 512.e1–512.e6. [46] J.M. Marin, C.G. Cote, O. Diaz, et al., Prognostic assessment in COPD: health related quality of life and the BODE index, Respir. Med. 105 (2011) 916–921. [47] E. Clini, C. Sturani, A. Rossi, et al., The Italian multicenter study on noninvasive ventilation in chronic obstructive pulmonary disease patients, Eur. Respir. 20 (2002) 529–538. [48] T.H. Lejemtel, M. Padeletti, S. Jelic, Diagnostic and therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure, J. Am. Coll. Cardiol. 49 (2007) 171–180. [49] S. Murray, K. Boyd, Using the ‘surprise question’ can identify people with advanced heart failure and COPD who would benefit from a palliative care approach, Palliat. Med. 25 (2011) 382. [50] K.T. Unroe, M.A. Greiner, A.F. Hernandez, et al., Resource use in the last 6 months of life among medicare beneficiaries with heart failure, 2000–2007, Arch. Intern. Med. 171 (2011) 196–203. [51] M. Senni, A. Gavazzi, F. Oliva, et al., IN HF Outcome Investigators, In-hospital and 1year outcomes of acute heart failure patients according to presentation (de novo vs. worsening) and ejection fraction. Results from IN-HF Outcome Registry, Int. J. Cardiol. 173 (2014) 163–169. [52] F. Blasi, G. Cesana, S. Conti, et al., The clinical and economic impact of exacerbations of chronic obstructive pulmonary disease: a cohort of hospitalized patients, PLoS ONE 9 (2014) e101228. http://dx.doi.org/10.1371/journal.pone.0101228.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Palliative needs for heart failure or chronic obstructive pulmonary disease: Results of a multicenter observational registry☆ Antonello Gavazzi a,⁎,1, Renata De Maria b,1, Lamberto Manzoli c,1, Paolo Bocconcelli d,1, Antonio Di Leonardo e,1, Maria Frigerio f,1, Stefano Gasparini g,1, Franco Humar h,1, Gianpiero Perna i,1, Roberto Pozzi j,1, Fausto Svanoni k,1, Marcello Ugolini l,1, Alberto Deales m,1 a
FROM Research Foundation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy Istituto di Fisiologia Clinica CNR, Dipartimento Cardiotoracovascolare, Azienda Ospedaliera Ospedale Niguarda-Ca' Granda, Milano, Italy c Dipartimento di Medicina e Scienze dell'Invecchiamento, Università G. D'Annunzio, Chieti, Italy d Divisione di Cardiologia, Ospedale San Salvatore, Pesaro, Italy e Servizio di Cure Palliative, Ospedale Salvini, Garbagnate, Italy f Dipartimento Cardiotoracovascolare, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Milano, Italy g Divisione di Pneumologia, Ospedali Riuniti, Ancona, Italy h Centro Cardiovascolare, Azienda Sociosanitaria 1 Triestina, Trieste, Italy i Dipartimento di Scienze Cardiologiche Medico-Chirurgiche, Ospedali Riuniti, Ancona, Italy j Divisione di Cardiologia, Ospedale San Luigi Gonzaga, Orbassano, Italy k Direzione Sanitaria, Ospedale Papa Giovanni XXIII, Bergamo, Italy l Divisione di Pneumologia, Ospedale San Salvatore, Pesaro, Italy m Area Governo Clinico, Agenzia Regionale Sanitaria Regione Marche, Ancona, Italy b
a r t i c l e
i n f o
Article history: Received 11 July 2014 Received in revised form 26 January 2015 Accepted 3 March 2015 Available online 5 March 2015 Keywords: Palliative care Advanced heart failure Advanced chronic obstructive pulmonary disease Mortality Symptom burden Quality of life
a b s t r a c t Background: Heart failure (HF) and chronic obstructive pulmonary disease (COPD) share a common organ failure trajectory marked by prognostic uncertainty, which is a barrier to appropriate provision of palliative care. We describe in a prospective cohort from specialist hospital services the epidemiology and late clinical course of these chronic diseases to trace criteria for transition to palliative care in the community. Methods and results: Seven centers enrolled 267 patients with advanced HF (n = 174) or COPD (n = 93) using common (multiple hospitalizations or severely impaired functional status or cachexia) and disease-specific (HF: systolic dysfunction, NYHA classes III–IV, end-organ hypoperfusion; COPD: very severe airflow obstruction, hypoxemia, hypercapnia, or long-term oxygen therapy) entry criteria. These patients represented 7.2% and 13% respectively of the overall HF and COPD population hospitalized during one year. They showed similar symptom burden, functional and quality of life impairment, recurrent hospitalizations, and 6-month mortality (39% and 37%, respectively). Organ failure progression was the cause of death in N75%. In-hospital overall stay during the previous year was the main mortality predictor in both. Disease-specific predictors included anemia, hyponatremia, no beta-blockers in HF; older age, hypercapnia in COPD. Conclusions: Patients with advanced HF/COPD represent almost 10% of subjects hospitalized yearly with a primary diagnosis of HF or COPD, have similarly impaired functional status, disabling symptoms and reduced survival. Overall days spent in-hospital during the previous year, a “red flag” in the late clinical course of both diseases, might be used as a simple, reliable screening tool for appropriate transition to palliative care in the community. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction
☆ Grant support: Supported by the Italian Ministry of Health Grant RF-MAR-2007679550. The sponsor had no role in study design, the collection, analysis and interpretation of data, the writing of the report, and in the decision to submit the article for publication. ⁎ Corresponding author at: FROM Fondazione per la Ricerca, Azienda Ospedaliera Papa Giovanni XXIII, Piazza Organizzazione Mondiale Sanità 1, 24127 Bergamo (BG), Italy. E-mail address: [email protected] (A. Gavazzi). 1 This author takes responsability for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
http://dx.doi.org/10.1016/j.ijcard.2015.03.056 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are systemic disorders with potentially overlapping pathophysiological process [1] and represent global epidemics [2,3]. Both are chronic debilitating conditions and incur significant morbidity and mortality. Their natural history is typical of the organ failure trajectory [4], with symptom burden and functional impairment comparable to advanced cancer [5–7], but frustrating prognostic uncertainty [8,9]. Outcome assessment is challenging and relatively unpredictable in individuals [9–14], particularly in
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advanced stages [9,15–17]. The clinical course of both HF and COPD is marked by heavy use of health services and more common aggressive treatment than in comparably end-stage malignant disease [18,19]. The more linear decline of patients with advanced cancer has traditionally been the model to approach end-stage disease, when decisions on lifeprolonging treatment should be considered. Organ specialist physicians, such as cardiologists and pulmonologists, are traditionally treatmentfocused and may lack the symptom management perspective, which becomes increasingly meaningful to patients as they progress to end-stage. A better understanding of the late clinical course of organ failure conditions, such as HF and COPD, helps calibrate expectations, guide communication, and inform rational decisions which may benefit patients and their families. The importance of a palliative care approach, as a key component of management in advanced disease, has been highlighted in recent scientific society statements [20–23]. Furthermore, a palliative approach integrating standard care should decrease the hospitalization rate of these very ill patients, improving patients' quality of life and diminishing the economic burden of the disease. Palliative care in Italy has recently developed to improve standards for oncological diseases, but still few patients with non-malignant disease access the network [24]. Furthermore national criteria for referral of patients with HF or COPD to palliative care services by general practitioners or organ specialists have not yet been defined. Under this rationale, the study was funded by the Italian Health Ministry (Grant RFMAR-2007-679550) in a call devoted to research on health services organization. We set-up a multicenter observational registry of patients with HF and COPD accessing hospital care in order to 1) define the proportion of subjects who access hospital care meeting criteria for advanced disease, 2) compare the late clinical course of advanced HF or COPD, expressed as symptom burden, functional status, quality of life, recurrent hospitalization and mortality, and 3) identify, as support to national initiatives directed at organizing the provision of health care services, patient characteristics associated with a mid-term negative outcome, for whom transition to targeted palliative interventions in the community, may be warranted.
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to severe mitral insufficiency), New York Heart Association (NYHA) functional classes III–IV dyspnea, clinical or laboratory signs of end organ hypoperfusion, including glomerular filtration rate b 60 ml/min, sodium b 135 mEq/L, hemoglobin b 11 g/dL, and total bilirubin N 1.2 mg/dL. - Patients with COPD had to show very severe airflow obstruction (Forced Expiratory Volume in 1 s [FEV1] b 30%), or hypoxemia (PaO2 b 55 mm Hg), or hypercapnia (PaCO2 N 45 mm Hg, i.e. above the upper normalcy threshold), OR to be on long-term oxygen therapy N 8 h/day.
2.3. Measurements
From March 2010 till March 2012, patients with HF or COPD were identified at 7 enrolling sites from the cardiology or pulmonology outpatient clinics and from institutional hospital discharge databases using International Classification of Disease 9 primary diagnosis codes for HF and COPD. Patients' clinical records were reviewed at each center.
Patients were recalled for an outpatient visit to confirm eligibility. The diagnosis of HF or COPD was based on the European Society of Cardiology [3] or Global Initiative for Chronic Obstructive Lung Disease [2], respectively. Demographics, clinical and laboratory data were recorded. Comorbidities were assessed by history and chart review. Patients were then questioned about their current symptoms. Dyspnea was graded from 1 (none) to 5 (too breathless to leave the house) using the Medical Research Council Scale [27]. Pain intensity was measured using the Visual Analogue Scale for Pain (VAS Pain) [28]. Cognitive impairment was screened by The Mini Mental State Examination using a cut-off threshold of b24 [29]. Functional status was assessed by the Karnofsky Performance Status Scale [30] and Basic Activities of Daily Living [31]. Quality of life was assessed through the following generic and disease-specific validated tools: SF12, a shortened version of the Short Form 36 of the Medical Outcomes Study [32] for all, plus the Minnesota Living with Heart Failure for HF [33], and the Airways Questionnaire 20 for COPD [34]. Whenever feasible, to quantitatively assess their functional performance, patients underwent a single six-minute walking test using the American Thoracic Society criteria [35]; the total distance walked in meters was recorded to assess functional impairment and expressed as percent of predicted values [36]. For COPD patients, the composite Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index [14] was calculated. On June 30, 2012, vital status and mode of death and hospital admissions were ascertained through telephone interview with patients or caregivers and review of hospital records. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval of the Ethics Committee of each participating institution. Patients gave their written informed consent to participate.
2.2. Eligibility criteria
2.4. Statistical analysis
We enrolled in an observational registry consecutive patients meeting the following general eligibility criteria, valid for both HF and COPD: ≥ 2 hospital admissions for the index diagnosis within the previous 12 months; in patients with b 2 admissions, an overall length of stay N 40 days (twice the threshold value set by the Italian Ministry of Health as abnormal length of stay for reimbursement criteria) as a clue to difficulties in stabilizing the patient was required as an alternative criterion, OR Karnofsky performance status b 50 or dependent in 3 or more basic activities of daily living, OR cachexia, defined as unintentional loss of N10% body weight within the previous 12 months [25], or a body mass index b 21 kg/m2 [26] and serum albumin b 2.5 g/dL as supportive criterion. In addition to the general criteria, the following disease-specific criteria had to be fulfilled:
Categorical variables are presented as frequency percent and continuous variables as mean ± standard deviation or median [interquartile range]. Between-group differences were tested by chi-square test and Student's t-test or non-parametric tests according to normal or nonnormal variable distribution. Kaplan–Meier survival analysis was used to examine the association between COPD and HF, or both coexisting conditions, and all-cause mortality. The validity of constant incidence ratios over the follow-up was checked using Nelson–Aalen cumulative hazard estimates. Cox proportional hazards analysis was used to calculate the adjusted relative hazards of death by each considered variable [37], which were selected according to p b 0.10, 20% change of the hazards ratios of other significant variables, missing data b 30% of the sample, age, gender and body mass index were included a priori. Schoenfeld's test was performed to check the validity of proportional hazards assumption. A p value of b0.05 was considered significant for all analyses, which were performed using STATA 10.1 (Stata Corporation, College Station,
2. Methods 2.1. Participants
- Patients with HF had to show severely depressed pump function (left ventricular ejection fraction b 30% or b40% with moderate
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TX, USA, 2007). Reporting of the study conforms with STROBE, along with references to STROBE and the broader EQUATOR guidelines [38]. 3. Results The study cohort included 267 patients, 174 with advanced HF and 93 with COPD, which represented 7.2% and 13%, respectively, of the overall HF and COPD population hospitalized during one year, as identified by the International Classification of Disease codes from discharge database. Baseline characteristics are reported in Table 1. 3.1. Demographic and clinical characteristics Both groups had a significant burden of associated medical conditions, but HF patients, although younger, had on average a significantly higher number of comorbidities than COPD patients. Comorbid COPD was found in one out of four HF patients. Overall 54% and 36% respectively had spent over 40 days in the hospital (p = 0.009). Both populations complained of troubling symptoms. Dyspnea, the most recurrent, was more common and severe in COPD patients, as demonstrated by a higher proportion of patients who were homebound for dyspnea (p = 0.041). Severe fatigue, anorexia and moderate to severe pain were equally present in both groups, while upper gastrointestinal symptoms occurred more frequently in HF patients (p = 0.002). Moreover, 90% of study patients were unable to work and one third were unable to perform 3 or more basic activities of daily living (Fig. 1). Cognitive impairment was common and overall one third had
a score below the threshold cut-off for the clinical diagnosis of dementia, with a higher prevalence among HF patients. Multi-organ failure was evident from laboratory data in both groups, but with a significantly more prominent kidney dysfunction and anemia in HF patients. A marked reduction in the distance walked at the six-minute walking test in comparison to reference normal values was recorded in both groups (Table 1). Quality of life was poor: perceptions of physical functioning were universally below the 25th percentile of the age and gender-matched general population, but also mental health was severely affected in over 70% of cases (Fig. 1). Among HF patients (Table 2), pump function was severely depressed and elevated natriuretic peptides indicated persistent congestion. Forty-seven percent of patients had a cardioverter defibrillator implanted and 39% had undergone cardiac resynchronization therapy. High dose furosemide was prescribed in most patients to relieve persistent congestion. Rates of renin–angiotensin system inhibitors and mineralocorticoid receptor antagonists treatment were relatively low, in keeping with the prevalence of kidney dysfunction. Conversely, prescription of beta-blockers, a cornerstone of HF therapy, was high, and heart rate was accordingly well controlled, despite neurohormonal activation. About one third of patients were on intermittent or continuous inotropic support. Among COPD patients (Table 2), the average BODE index, a composite score that takes into account both airways' flow limitation and the systemic effects of COPD, was 10, indicating severe multidimensional impairment and 88% were on long-term oxygen therapy.
Table 1 Baseline characteristics of the study population. Characteristics
Heart failure (n = 174)
Chronic obstructive pulmonary disease (n = 93)
p value
Age (years) Male gender (%) Days spent in hospital within 12 months (n) Body mass index (kg/m2) Body mass index ≤ 21 kg/m2 (%) Weight loss N 10% within 12 months (%) Cachexia any of 3 criteria (%) Comorbidities Comorbidities number History of hypertension (%) Diabetes and target organ damage (%) Liver dysfunction (%) COPD (%) Ischemic heart disease (%) Anemia (Hemoglobin b 11 g/dL) (%) Chronic kidney dysfunction (%) Peripheral vessel disease (%) Cerebrovascular disease (%) Obstructive sleep apnoea syndrome (%) Atrial fibrillation (%) Cognitive impairment (MMSE b 24) (%) MMSE Symptoms Dyspnea MRC class 4 (home-bound) (%) Severe fatigue (%) Anorexia (%) Upper gastrointestinal symptoms (%) Moderate to severe pain (VAS ≥ 4/10) % Functional capacity Basic activities of daily living Karnofsky performance status Six minutes walking distance (% predicted) Laboratory data Glomerular filtration rate (ml/min/1.73 m2) Urea (mg/dl) Albumin (mg/dl) Albumin b 2.5 mg/dl (%) Total bilirubin (mg/dl) Sodium (mEq/l) Hemoglobin (g/dL)
72 ± 12 73 41 ± 34 25 ± 5 (n = 158) 18 (n = 158) 7 19
75 ± 9 67 48 ± 35 27 ± 6 16 9 29
0.08 0.323 0.097 0.31 0.86 0.615 0.085
4 ± 1.8 54 20 17 26 79 34 42 33 16 11 30 39 (n = 101) 24.4 ± 5
3.6 ± 1.6 57 11 5 – 36 17 13 13 13 39 6 21 (n = 73) 25.6 ± 4
0.037 0.699 0.083 0.007 – 0.0001 0.004 0.0001 0.0001 0.590 0.007 0.0001 0.13 0.082
23 23 58 47 52
39 23 52 27 56
0.041 1 0.369 0.002 0.567
4.1 ± 2.2 (n = 120) 50.4 ± 17 44 ± 77
3.7 ± 2.0 49.8 ± 14 37 ± 29
0.16 0.778 0.05
48 ± 25 94 ± 66 3.45 ± 0.7 5.0 (n = 141) 1.24 ± 1 138 ± 4 11.9 ± 1.8
66 ± 32 65 ± 41 (n = 80) 3.22 ± 0.7 3.4 (n = 88) 1.18 ± 1 140 ± 3 12.2 ± 1.7
0.0001 0.0001 0.013 0.745 0.691 0.13 0.238
Data are expressed as number (percentage) or mean ± SD. MMSE, Mini Mental State Examination; MRC, Medical Research Council; VAS, Visual Analogue Scale.
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Fig. 1. Proportion of patients with ≤3 preserved basic activities of daily living (BADL), activity levels, SF12 mental (MCS) and physical (PCS) components b 25th percentile of the age and gender-matched general population (n = 179), among heart failure (HF, dark boxes) and chronic obstructive pulmonary disease (COPD, empty boxes) patients.
Table 2 Disease-specific clinical characteristics. Heart failure patients
N = 174
Ischaemic etiology (%) Systolic blood pressure (mm Hg) Heart rate (bpm) Left ventricular ejection fraction (%) Left bundle branch block (%) Implantable cardioverter defibrillator (%) Cardiac resynchronization therapy (%) Furosemide dose (median [Interquartile range]) (mg) Spironolactone (%) ACE-inhibitors or ARBs (%) Beta-blockers (%) Digoxin (%) Oral anticoagulant agents (%) Inotropes (%) NTproBNP (median [Interquartile range]) (pg/ml) BNP (median [Interquartile range]) (ng/ml) Quality of life MLHFQ (n = 82) total score MLHFQ physical dimension MLHFQ emotional dimension
77 118 ± 22 76 ± 14 26 ± 5 37 49 37 125 [137] 51 57 74 27 53 32 2617 [3724] 639 [1242] 49 ± 20 22 ± 9 10 ± 7
Chronic obstructive pulmonary disease patients
N = 93
BODE index Oxygen saturation (%) PaO2 (mm Hg) PaCO2 (mm Hg) Forced expiratory volume in 1 s (% of predicted) Furosemide (mg/day)* Oral corticosteroids (%) Inhaled corticosteroids (%) Long acting beta agonists (%) Long acting muscarinic antagonists (%) Hours of oxygen therapy/day (n) Long-term oxygen therapy ≤ 15 h/day (%) Long-term oxygen therapy N 15 h/day (%) Non-invasive ventilation (%) Quality of life: Airways Questionnaire-20 score (n = 62)
10 ± 3 93 ± 4 67 ± 15 50 ± 13 45 ± 11 50 [100] 54 97 95 87 17 ± 10 29 59 19 16 ± 3
Data are expressed as frequency % of patients or mean ± SD or * Median [Interquartile range]. ACE, Angiotensin Converting Enzyme; ARBs, Angiotensin Receptor Blockers; BODE, Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity; BNP, Brain Natriuretic Peptide; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NtproBNP, N terminal pro-brain natriuretic peptide.
Patients with coexistent HF and COPD (n = 45) showed more frequently cachexia (38.6%) than those with either HF (19%) or COPD (26.9%) alone (p = 0.033). No differences were found in Basic Activities of Daily Living, Karnofsky performance status and MiniMental Status Examination score among the 3 groups. 3.2. Outcome During a mean follow-up of 6 ± 4 months, 39% of HF and 37% of COPD patients died. Survival by Kaplan–Meier analysis (Fig. 2) was similar in the two groups (log rank test p = 0.58), with a mortality rate near to 40% at 6 months. The incidence of sudden death was low (15% in HF and 6% in COPD), while the most common cause of demise was progression of pump failure in HF (83%) and respiratory failure in COPD (74%). In both groups hospital readmissions during follow-up were frequent (60% of HF and 49% of COPD patients were hospitalized at least once) and length of stay was prolonged, with a median of 30 [interquartile
COPD HF HF + COPD
Fig. 2. Kaplan–Meier survival curves of patients with heart failure (dotted line), chronic obstructive pulmonary disease (continuous line), or coexistent heart failure and chronic obstructive pulmonary disease (hatched line) enrolled in the registry.
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range 56] days in HF and 27 [interquartile range 49] days in COPD (p = 0.599). Six-month mortality was 31% for coexistent COPD and HF vs 37% for HF and 41% for COPD, but patients with both HF and COPD were admitted more frequently during follow-up (mean admission number 1.91 vs 1.31 for HF, and 0.87 for COPD; p = 0.003). None of the patients at the time of recruitment was in a palliative care program, nor were specific provisions taken within the protocol for referral to specialist palliative care. 3.3. Prognostic stratification To assess independent predictors of all-cause mortality the following variables were entered in multivariable Cox proportional hazards models (Table 3): age, gender, body mass index, Medical Reasearch Council dyspnea scale, number of comorbidities, Karnofsky performance status, and overall days in hospital during previous year for the whole cohort, with the addition of hemoglobin, beta-blockers, and sodium for HF patients, and PaCO2, BODE index, and long-term oxygen therapy for COPD patients. Overall, only the sum of days spent in hospital in the previous year was independently associated with outcome, whereas Karnofsky performance status reached borderline significance. In the HF cohort, lower hemoglobin and sodium levels and lack of beta-blocker therapy were independent predictors of death. Among COPD patients, only older age and hypercapnia predicted a negative outcome. 4. Discussion Our multicenter observational registry offers insights in the epidemiology and late clinical course of patients affected by advanced HF or COPD, which may aid cardiologists and pulmonologists in understanding the turning point from life-prolonging strategies to supportive and palliative care. The main findings of this study are that patients with advanced HF or COPD represented almost 10% of those accessing hospital care for these diseases yearly and had overlapping disabling symptoms, similarly impaired functional status, and comparably reduced survival. Time spent in hospital during the previous year was the main predictor of mortality in both patient groups, whereas disease-specific predictors of outcome included anemia, low serum sodium, and lack of betaTable 3 Cox multivariate model for all-cause mortality. Hazard ratio (95% CI) Overall cohort Days in hospital during previous year (per unit increase) Karnofsky performance status (per unit increase) Medical Research Council dyspnea scale (per unit increase) Age (per unit increase) Gender (male vs female) Number of comorbidities (per unit increase) Body mass index (per unit increase) Heart failure patients Hemoglobin (per 1 g/dl increase) Beta-blockers (yes vs no) Sodium (for each 1 mEq/l increase) Medical Research Council dyspnea scale (per unit increase) Age (per unit increase) Gender (male vs female) Chronic obstructive pulmonary disease patients Age (per unit increase) PaCO2 (per unit increase) Gender (male vs female) BODE index (per unit increase) Long-term oxygen therapy (yes vs no)
p value
1.00 (1.00–1.01) 0.037 0.98 (0.96–1.00) 0.06 1.30 (0.97–1.75) 0.07 1.02 (0.99–1.05) 1.35 (0.79–2.30) 1.08 (0.95–1.24) 1.01 (0.96–1.05)
0.13 0.26 0.22 0.78
0.78 (0.67–0.92) 0.54 (0.30–0.97) 0.94 (0.88–0.99) 1.21 (0.88–1.66)
0.003 0.041 0.045 0.22
1.02 (0.98–1.04) 0.23 0.99 (0.52–1.89) 0.98
1.09 (1.03–1.16) 1.03 (1.00–1.06) 1.83 (0.73–4.61) 1.06 (0.89–1.27) 1.42 (0.61–3.27)
BODE, Body mass index, airway Obstruction, Dyspnea, and Exercise capacity.
0.003 0.052 0.19 0.48 0.41
blocker treatment in HF patients, and older age and hypercapnia in COPD patients. This study was planned from the perspective of cardiology and pulmonology specialist centers, to assess the burden of advanced HF or COPD to hospital services and to analyze whether specific criteria could improve palliative referral of patients with advanced disease and heavy use of acute hospital services. In the contemporary literature, data on the prevalence of advanced HF or COPD stages, according to disease-specific criteria coupled to severely impaired performance status and high symptom burden, are, to the best of our knowledge, scanty and not to comparable to ours because of different study designs [39,40]. Criteria for inclusion in our registry coupled well-established scales of functional impairment, commonly used to express disability and the cumulative care burden in a wide spectrum of illnesses [30,31], to specific markers of advanced organ disease [2,3,23]. Indeed the correlation between NYHA class and Karnofsky performance status has recently been reported to be poor [41], indicating that for a comprehensive assessment of the care burden in the daily life, both indexes should be used. The patients enrolled in our registry represent a sizable proportion of those requiring acute hospital care each year for HF (7.2%) or COPD (13%). The prevalence of COPD in patients with HF in the present hospital-based series is 25.8%, while in previous reports it ranges widely from 9 to 52%, depending on the population studied, diagnostic criteria applied, measurement tools, and surveillance systems [1]. Symptom burden and quality of life impairment of both HF and COPD patients were similar to previously reported data [5–7,42]. In our registry the only differences in symptoms are probably linked to disease-specific pathophysiology, e.g. COPD patients had a worse dyspnea, due to severe chronic hypoxemia, while HF patients complained more frequently of upper gastrointestinal symptoms, due to splanchnic congestion. Within 6 months a comparably high proportion of both groups had died, the main cause being progression of organ failure. This subset with high symptoms burden, poor quality of life and short-term poor outcome represents the ideal group where to concentrate every effort to reduce the re-hospitalization rate and to implement specific programs to palliative care transition in the community. The quest for simple markers to draw attention on potential candidates to palliative care is important from an organizational stand point to plan access to often strained palliatice care services. Investigations in the natural history of HF have highlighted the very poor prognosis in advanced stages, with 30 to 50% 1-year mortality [10, 16,21]. Patients who fulfilled the enrollment criteria in our study had an even worse outcome, with a 6 month mortality of 39%, indicating that they truly had an end-stage condition, where no improvement with conventional HF treatment is to be reasonably expected and palliative care should first complement and then take the lead of care. In agreement with published data [11–23], disease-specific predictors of outcome in our HF series included multiple clinical characteristics, such as serum sodium concentration, a marker of congestion and neurohormonal activation, anemia, a multifactorial comorbidity, and lack of beta-blocker treatment, expressing drug intolerance as proxy for labile haemodynamic status, frequently observed in advanced HF. Despite the high prevalence of COPD, relatively less is known, in comparison with HF, about the late clinical course of this disease: previous studies included small mostly single-center series enrolled after hospital admission for acute exacerbation [43]. In the early 90's the landmark SUPPORT study [44] enrolled a cohort of 1016 COPD patients, who had hypercapnia at the time of hospital admission for an acute exacerbation: mortality and readmission rates at 6 months were 33% and 50%, respectively. In a recent review of relevant studies, a median survival of 2–4 years was reported for patients with severe COPD, but for those hospitalized for an exacerbation, median survival may be b6 months, according to age, functional and clinical characteristics, and repeated hospitalizations [45].
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Our findings underscore the poor prognosis of patients with severe COPD and are in close agreement with data from SUPPORT [44]. Consistently with their advanced disease stage, most patients had severe systemic manifestations, as summarized by an average BODE index of 10, in the very high risk range: in patients with long standing COPD these values have been previously associated with 3-year mortality rates of 54.4% [14,46]; therefore, the lack of predictive value that we found in our series is not surprising. The association with outcome of hypercapnia, a common finding in patients with advanced COPD as a marker of both severe ventilation–perfusion mismatch and the inability to adequately increase ventilation, is controversial in the overall spectrum of COPD [15]. Hypercapnia was the only relevant mortality predictor, together with age, in our COPD patients with severe end-stage disease. In this respect, home non-invasive ventilation, which was performed in one fifth of our population, may contribute to symptom relief and improve quality of life [47]. The coexistence of HF and COPD has been reported to exert a negative synergism on functional status and outcome [1,48], with complex management problems due to the possible adverse effects of betablockers on airways reactivity, and on the detrimental effects of longacting beta2-agonists on heart rate. In the SUPPORT cohort [44], comorbid HF and cor pulmonale were actually protective against mortality. In our series, more severe systemic manifestations, but similar functional status were observed. Moreover, despite a higher number of readmissions, survival did not differ from patients with either condition alone (Fig. 2). Overall, patients affected by advanced HF or COPD that enrolled in our registry show during a short-term follow-up not only the same negative outcome, but also the same high incidence of prolonged rehospitalization, mainly for organ-related failure. Difficult prognostication in individual patients with advanced HF and COPD is frequently perceived as an obstacle inhibiting discussions regarding end of life. The only significant predictor by Cox multivariate analysis in the overall population of the present study was the number of days in the hospital during the 12 months prior to enrolment. This finding highlights the relevance of organ failure-related hospitalizations as key sentinel events in the late clinical course of patients with either HF or COPD and may be used as a screening tool for appropriate referral to palliative care in the community after discharge. The relevance of this finding is that it can be derived from administrative data, allows to recognize at discharge the patients more prone to a negative outcome and may be considered as a “red flag”. Patients and caregivers should be made aware of the likelihood of poor outcomes following repeated hospitalization for exacerbation of organ-related failure. These patients with high symptom burden, emotional distress, heavy use of acute care and poor quality of life, stand for almost 10% of subjects hospitalized with a primary diagnosis of HF or COPD and represent ideal candidates for a palliative approach. Appropriate programs of palliative care in the community should be offered to this subset of very ill patients with non-malignant organ diseases [49], to improve their quality of life and reduce hospitalization rates, therefore diminishing the economic burden of end-stage disease [50].
Study limitations The source of data was a multicenter observational registry, where enrolment was limited to patients with very advanced stages of HF with reduced ejection or COPD. Outcomes would probably differ in a larger cohort considering less stringent entry criteria. Among the seven participating centers, two are large, tertiary referral centers: outcomes may change in smaller community hospitals, where the majority of patients with HF or COPD probably receive a different care. The diagnosis of HF with preserved ejection fraction requires the confirmation of diastolic dysfunction by Doppler echocardiography, a test which may not be routinely available, making the differential diagnosis with other causes of symptoms (e.g. dyspnea) difficult. The exclusion of HF patients
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with preserved ejection fraction from enrolment might have led to the underestimation of the global palliative care burden for HF. We did not record data from all patients admitted with decompensated HF or exacerbation of COPD, but only for those meeting the eligibility criteria for inclusion; therefore, a comparison of mortality between all patients hospitalized for HF or COPD was not possible. However, our national contemporary data indicate that six-month mortality is approximately 20% for patients hospitalized for worsening HF with reduced ejection fraction in cardiology units [51] and 15% for those admitted with a severe COPD exacerbation [52]. 5. Conclusions Patients with advanced HF or COPD have overlapping disabling symptoms, similarly impaired functional status, and comparably reduced survival. These very ill patients have a poor quality of life, require a heavy use of acute care and stand for almost 10% of subjects hospitalized with a primary diagnosis of HF or COPD. The length of organrelated hospitalization during the previous year is the main predictor of mortality in both groups. This should be considered as a “red flag” in the late clinical course of patients with HF or COPD and might be used as a screening tool for appropriate referral after discharge to palliative care in the community. Conflict of interest The authors have no conflict of interest to declare. Acknowledgments The authors gratefully acknowledge the contribution of Marinella Sommaruga and Paola Gremigni for help with quality of life questionnaire scoring and interpretation, Marilisa Ambrosio for expert secretarial assistance, and Franco Falcone for thoughtful advice. Appendix A. Study sites and investigators (all in Italy) Ospedale Salvini, Garbagnate: Michele Sofia, Cristina Arosio, Antonio Di Leonardo, Vittorio Guardamagna, Roberto Luigi Monticchio, Sergio Stefano Pardea, Vivian Sardo, Stefano Spagnotto. Azienda Ospedaliera Ospedale Niguarda-Ca' Granda, Milano: Maria Frigerio, Enrico Ammirati, Renata De Maria, Maria Grazia Gambato, Fabrizio Oliva. Azienda Sociosanitaria 1 Triestina, Trieste: Andrea Di Lenarda, Elena Abate, Luisa Giove, Franco Humar, Donatella Radini, Marina Riosa, Kira Stellato. Ospedale San Luigi Gonzaga, Orbassano: Roberto Pozzi, Marta Fenoglio, Laura Montagna, Domenico Osella. Ospedali San Salvatore, Pesaro: Paolo Testarmata, Lucia Cantarini, Marcello Ugolini. Ospedali Riuniti di Ancona: Giampiero Perna, Ilaria Battistoni, Martina Bonifazi, Stefano Gasparini. Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (previous Ospedali Riuniti di Bergamo): Antonello Gavazzi, Marilisa Ambrosio, Anna Caffi, Marco Marino, Rachele Ramponi, Fausto Svanoni. References [1] N.M. Hawkins, M.C. Petrie, P.S. Jhund, G.W. Chalmers, F.G. Dunn, J.J.V. McMurray, Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology, Eur. J. Heart Fail. 11 (2009) 130–139. [2] GOLD Global Initiative for Chronic Obstructive Lung Disease, Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report 2006Updated 2006 http://www.goldcopd.com/. [3] K. Swedberg, J. Cleland, H. Dargie, et al., Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology, Eur. Heart J. 26 (2005) 1115–1140.
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