Prognosis of heart failure patients with reduced and preserved ejection fraction and coexistent chronic obstructive pulmonary disease

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1 European Journal of Heart Failure (2010) 12, doi: /eurjhf/hfq157 Prognosis of heart failure patients with reduced and preserved ejection fraction and coexistent chronic obstructive pulmonary disease Beom-June Kwon, Dong-Bin Kim*, Sung-Won Jang, Ki-Dong Yoo, Keun-Woong Moon, Byung Ju Shim, Seo-Hee Ahn, Eun-Ju Cho, Tae-Ho Rho, and Jae-Hyung Kim Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul , Republic of Korea Received 1 February 2010; revised 24 April 2010; accepted 4 June 2010; online publish-ahead-of-print 22 September 2010 Aims The long-term prognosis of patients with heart failure with preserved left ventricular ejection fraction (HFPEF) and coexistent chronic obstructive pulmonary disease (COPD) has not been previously investigated. The primary aim of this study was to determine whether the long-term prognosis of HFPEF patients with COPD differs from that of heart failure patients with reduced left ventricular ejection fraction (HFREF) and COPD. The secondary aim was to identify independent predictors of event-free survival in patients with HF and COPD.... Methods We investigated 184 patients with coexistent HF and COPD. Heart failure with preserved left ventricular ejection and results fraction was present in 98 cases (53%) and HFREF in the remaining 86 cases (47%). Mean follow-up time was days. Cardiovascular/pulmonary hospitalization or mortality occurred in 71 patients (39%). No significant difference was observed between the two study groups in terms of event-free survival (P ¼ 0.457), but event-free survival was found to be independently associated with New York Heart Association (NYHA) class [III vs. I, hazard ratio (HR) 2.92, 95% confidence interval (CI) ], Global initiative for chronic Obstructive Lung Disease (GOLD) stage (III vs. I, HR 3.20, 95% CI ), systemic hypertension (SHT; HR 2.99, 95% CI ), and pulmonary hypertension (PH; HR 4.35, 95% CI ).... Conclusion In HF patients with coexisting COPD, cardiovascular and pulmonary event-free survival of HFPEF was found to be similar to that of HFREF over 3 years follow-up. Furthermore, severe NYHA class, severe GOLD stage, SHT, and PH were found to be independent predictors of event-free survival Keywords Heart failure COPD Left ventricular systolic function Prognosis Introduction Co-morbidities play an important role in heart failure (HF). 1 Heart failure and chronic obstructive pulmonary disease (COPD) are commonly encountered in clinical practise. The prevalence of COPD is 20 40% among patients with HF, and the prevalence of HF is 20 30% among patients with COPD. 2 6 Among the co-morbid conditions commonly associated with HF, COPD frequently delays the diagnosis of HF, and vice versa. Either HF or COPD is a predictor of prognosis in patients with each condition Limited data are available on the natural course of coexistent HF and COPD, and most of the studies performed have focused on HF with reduced left ventricular ejection fraction (HFREF). 2,5 The prevalence of diastolic heart failure (DHF) or HF with preserved left ventricular ejection fraction (HFPEF) is as 1,11 13 high as 30 55% among those with HF and they have similar re-admission rates, but lower mortality than HFREF. 11,14,15 The long-term prognosis of PEF patients with combined HF and COPD is not known. In this study, we aimed to evaluate the long-term prognosis of HFPEF with COPD when compared with that of HFREF with COPD, and also to identify common prognostic factors in patients with coexistent HF and COPD. * Corresponding author. Tel: , Fax: , dbkimmd@empas.com Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oxfordjournals.org.

2 1340 B.-J. Kwon et al. Methods Study population We conducted a retrospective cohort study of 494 patients with coexistent HF and COPD. Patients were followed in the outpatient clinic of St. Paul s Hospital, Seoul, Korea, between 1 February 2002 and 30 December Exclusion criteria were: New York Heart Association (NYHA) functional class IV, Consecutive Global initiative for chronic Obstructive Lung Disease (GOLD) stage IV, age,30 years, chronic pulmonary thromboembolism, cor pulmonale, right ventricular HF, primary pulmonary hypertension (PH), or any serious co-morbid disease. Overall, 184 patients with coexistent HF and COPD were included. Heart failure was diagnosed according to the ALLHAT criteria based on 1 sign (rales, ankle oedema 2+, tachycardia 120 b.p.m., cardiomegaly by chest X-ray, chest X-ray characteristics of HF, S 3 gallop, or jugular venous distension) and 1 concurrent symptom (paroxysmal nocturnal dyspnoea, orthopnoea, or dyspnoea at rest or on ordinary exertion). 16 The diagnosis of COPD was made using spirometric pulmonary function testing. The following measures of lung function were used: forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. COPD patients were divided into three GOLD stages (I, II, and III). GOLD stage I (mild COPD) was defined as post-bronchodilator FEV1/FEV ratio of,70% and post-bronchodilator FEV1.80% of predicted. GOLD stage II (moderate COPD) was defined as post-bronchodilator FEV1/FEV ratio of,70% and post-bronchodilator FEV % of predicted, and GOLD stage III (severe COPD) was defined as postbronchodilator FEV1/FEV ratio of,70% and post-bronchodilator FEV % of predicted. 17 Patients were dichotomized by left ventricular systolic function into HFPEF and HFREF groups, based on left ventricular ejection fractions (LVEF) of 50% or of,50% as determined by transthoracic echocardiography (TTE). 5 Echocardiograms were performed in the stable stages of HF and COPD treatment, and LVEF was calculated from the conventional apical two- and fourchamber images, using the modified Simpson s method. Demographic data, co-morbidities, laboratory results, and medications were abstracted from medical records. The outcome events examined were cardiovascular/pulmonary hospitalization or mortality. Clinical follow-up was censored at 3 years (1095 days). We defined a current smoker as a person who had smoked any cigarettes in the last month. Systemic hypertension (SHT) was defined as a systolic blood pressure 140 mmhg or a diastolic blood pressure 90 mmhg, 18 chronic renal disease (CKD) as an estimated glomerular filtration rate by Modification of Diet in Renal Disease (MDRD) formula,60 ml/min/1.73m 2, anaemia as a haemoglobin,13.0 g/dl in men or,12.0 g/dl in women based on WHO criteria. Pulmonary hypertension was defined as a pulmonary artery systolic pressure.35 mmhg at rest in the absence of pulmonary outflow obstruction by TTE, 19,20 hypercholesterolaemia as a total cholesterol 5.7 mmol/l, weight loss as a percentage reduction in body mass of.5% vs. baseline within 1 year, and left ventricular hypertrophy as a left ventricular mass index [LVMI; left ventricular mass (g)/body surface area (m 2 )]. 125 g/m 2 in men or 110 g/m 2 in women. 21 Body mass index (BMI) was defined as body weight in kilograms divided by the square of the patient s height in metres and was categorized as,18.5, , or.25 kg/m Statistical analysis We summarized baseline characteristics in the HFPEF and HFREF groups using means and standard deviations for continuous variables, and numbers and percentages for categorical variables. The independent samples t-test and the x 2 test were used to analyse continuous and categorical variables, respectively. Observed cardiovascular or pulmonary hospitalization or mortality was summarized using Kaplan Meier survival curves and the independence of relationships was determined using a Cox proportional hazards regression model. Univariate variables with a P-value of,0.20 were entered into the multivariate logistic models. Statistical significance was accepted for P-values of,0.05. Results Baseline characteristics of the heart failure with preserved left ventricular ejection fraction and heart failure with reduced left ventricular ejection fraction groups with coexisting COPD Of the 184 patients with coexistent HF and chronic obstructive pulmonary disease, HFPEF was present in 98 cases (53%) and HFREF in the remaining 86 (47%). Mean follow-up time was days, and a maximum follow-up of 3 years was achieved for 63 (34%) patients. Baseline clinical and medication characteristics of patients are shown in the Tables 1 and 2. Prognosis of heart failure with preserved left ventricular ejection fraction compared with heart failure with reduced left ventricular ejection fraction in patients with coexisting COPD Cardiovascular/pulmonary hospitalization or mortality occurred in 71 patients (38.6%) during the follow-up period: 33 (38%) in the HFPEF group and 39 (39%) in the HFREF group. No significant difference was found between the HFPEF and HFREF groups in terms of event-free survival over 3 years of follow-up (P ¼ 0.457; Figure 1). Furthermore, there was also no significant difference between the two groups at 1 year of follow-up (P ¼ 0.117, data not shown). In addition, there was no difference in the incidence of cardiovascular or pulmonary events between the two groups (Table 3). Of 71 events, 64 were due to hospitalizations (23 to acute decompensated HF, 3 to ischaemic heart disease, 3 to arrhythmia, 2 to stroke, and 33 to pulmonary events) and the remaining 7 were due to deaths (2 to HF, 1 to ischaemic heart disease, 1 to arrhythmia, and 3 to pulmonary events). Univariate analysis for predictors of cardiovascular or pulmonary event-free survival in patients with coexistent heart failure and COPD Cardiovascular or pulmonary event-free survival was associated with NYHA class (P ¼ 0.003), GOLD stage (P ¼ 0.002), and BMI (P ¼ 0.042; Table 4). Other variables were not found to be significantly associated.

3 Long-term prognosis in HF/chronic obstructive pulmonary disease 1341 Table 1 Baseline characteristics of patients with heart failure with preserved left ventricular ejection fraction and heart failure with reduced left ventricular ejection fraction Variables HFPEF (n 5 98) HFREF (n 5 86) All HF (n 5 184)... Age (years) Male [n (%)] 38 (39) 54 (63) 92 (50) Current smoker [n (%)] 30 (31) 26 (29) BMI (kg/m 2 ) NYHA class [n (%)] I 15 (15) 19 (22) 34 (19) II 61 (62) 37 (43) 98 (53) III 22 (23) 30 (35) 52 (28) Ejection fraction (%) Ischaemic aetiology of HF 16 (16) 35 (41) 51 (28) GOLD stage [n (%)] I 47 (47) 24 (28) 71 (39) II 25 (26) 38 (44) 63 (34) III 26 (27) 24 (28) 50 (27) Co-morbid conditions Diabetes [n (%)] 29 (30) 29 (34) 58 (32) Hypertension [n (%)] 43 (44) 47 (55) 90 (49) CKD [n (%)] 33 (34) 36 (42) 69 (38) Anaemia [n (%)] 48 (49) 49 (57) 97 (53) PH [n (%)] 20 (22) 20 (23) 40 (22) Atrial fibrillation 43 (44) 26 (30) 69 (38) Biochemical markers BNP (pg/ml) Hs-CRP (mg/dl) TC (mmol/l) Weight loss [n (%)] 27 (28) 27 (31) 54 (29) LVMI (g/m 2 ) Values are expressed as means + SD, unless otherwise stated. HFPEF, heart failure with preserved left ventricular ejection fraction; HFREF, heart failure with reduced left ventricular ejection fraction; n, number of patients; GOLD, Global initiative for chronic Obstructive Lung Disease; CKD, chronic renal disease; PH, pulmonary hypertension; TC, total cholesterol; BMI, body mass index; Hs-CRP, high sensitive C-reactive protein; LVMI, Left ventricular mass index. Multivariate Cox proportional hazards regression model analysis for cardiovascular or pulmonary event-free survival in patients with coexistent heart failure and COPD Age, NYHA class, GOLD stage, SHT, PH, high sensitive C-reactive protein, and BMI, which were all P, 0.20 by univariate analysis, were subjected to Cox proportional hazards regression analysis (Table 5). Cardiovascular or pulmonary event-free survival was found to be independently associated with NYHA class [III vs. I, hazard ratio (HR) 2.92, 95% confidence interval (CI) ], GOLD stage (III vs. I, HR 3.20, 95% CI ), SHT (HR 2.99, 95% CI ), and PH (HR 4.35, 95% CI ). Discussion The present study demonstrates for the first time that the long-term prognosis of patients with coexistent HF and chronic obstructive pulmonary disease are similar regardless of left ventricular systolic function, and that NYHA class, GOLD stage, SHT, and PH were predictors of prognosis. Most importantly, we directly compared the long-term prognosis between HFPEF and HFREF in patients with coexistent chronic obstructive pulmonary disease. Our study differs from previous studies in many ways. 2 4,23 First, we included patients with both HFPEF and HFREF. Second, we observed cardiovascular/pulmonary hospitalizations or mortality over a relatively long follow-up of 3 years. Third, we included a relatively large number of subjects when compared with previous studies. 5

4 1342 B.-J. Kwon et al. Table 2 Medication at baseline in patients with coexistent heart failure and chronic obstructive pulmonary disease, according to the presence of heart failure with preserved left ventricular ejection fraction or heart failure with reduced left ventricular ejection fraction Variables HFPEF HFREF All HF (n 5 98) (n 5 86) (n 5 184) Cardiovascular drugs Beta-blocker [n (%)] 15 (15) 24 (28) 39 (22) ACEI and ARB [n (%)] 52 (53) 51 (59) 103 (56) CCB [n (%)] 22 (22) 10 (12) 32 (17) Diuretics [n (%)] 81 (83) 76 (88) 157 (85) Spironolactone [n (%)] 56 (57) 57 (67) 113 (61) Digoxin [n (%)] 50 (52) 61 (72) 111 (60) Pulmonary drugs Theophylline [n (%)] 75 (77) 66 (77) 141 (77) Beta-2 agonist [n (%)] 40 (41) 37 (43) 77 (42) Steroid [n (%)] 31 (32) 33 (38) 64 (35) Values are expressed as means + standard deviation, unless otherwise stated. HF, heart failure; COPD, chronic obstructive pulmonary disease; HFPEF, heart failure with preserved left ventricular ejection fraction; HFREF, heart failure with reduced left ventricular ejection fraction; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker. Figure 1 Survival curves for each group according to left ventricular systolic function. There was no difference in event-free survival between the two groups with coexistent heart failure and chronic obstructive pulmonary disease. Our results show that the prognosis of HFPEF is similar to that of HFREF irrespective of accompanying chronic obstructive pulmonary disease. Despite markedly different degrees of left Table 3 Cause of hospitalization or mortality in patients with heart failure with preserved left ventricular ejection fraction and heart failure with reduced left ventricular ejection fraction Variable HFPEF HFREF P-value (n 5 33) (n 5 38) Cardiovascular events [n (%)] 19 (58) 16 (42) Acute decompensated HF (n) Ischaemic heart disease (n) 2 2 Arrhythmia (n) 3 1 Stroke (n) 1 1 Pulmonary events [n (%)] (Acute exacerbation of COPD or Pneumonia) 14 (42) 22 (58) HFPEF, heart failure with preserved left ventricular ejection fraction; HFREF, heart failure with reduced left ventricular ejection fraction; n, number of patients; HF, heart failure; COPD, chronic obstructive pulmonary disease. ventricular systolic function, remodelling, and structure, HFPEF has pathophysiological abnormalities that are qualitatively similar to those of HFREF, including severely reduced exercise performance, neuroendocrine activation, and reduced quality of life. 24 Furthermore, similar rates of cardiac arrest, acute coronary syndrome, renal failure, and admission to the intensive care unit or coronary care unit 11 and common predictors of death 25 have been reported in the two groups. Despite similar rates of complications, patients with a HFPEP are less likely to receive primary care from a cardiologist and are less likely to have had a cardiology consultation than patients with a HFREF. 7 In addition, although there have been considerable advances in the treatment of HFREF, relatively little progress has been made in the management of HFPEF. 26 Heart failure with preserved left ventricular ejection fraction and DHF are not the same entities. A diagnosis of DHF is particularly difficult to establish in patients with chronic obstructive pulmonary disease. In the present study, we measured only LVEF and therefore could not confirm the necessary parameters for diagnosis of true DHF by TTE. 27 Accordingly, it is not certain whether our results on HFPEF can be extrapolated to true DHF combined with chronic obstructive pulmonary disease. The prevalences of HFPEF and HFREF in patients with coexistent chronic obstructive pulmonary disease were 53 and 47% in the present study. In another study, the reported prevalences of HFPEF (LVEF 45%) with chronic obstructive pulmonary disease and HFREF (LVEF, 45%) with chronic obstructive pulmonary disease were 49 and 51%, respectively. 2 NYHA class, GOLD stage, SHT, and PH were found to be independent predictors of event-free survival in patients with coexistent HF and chronic obstructive pulmonary disease. NYHA class and GOLD stage have previously been identified as significant predictors of survival in HF 28 and chronic obstructive pulmonary disease, 17 respectively, and according to our results these relationships are preserved even in cases of coexistent HF and chronic obstructive pulmonary disease. In a previous study, GOLD stage also showed a trend towards a higher risk of adverse events in

5 Long-term prognosis in HF/chronic obstructive pulmonary disease 1343 Table 4 Univariate analysis for prediction of cardiovascular or pulmonary event-free survival in patients with coexistent heart failure and chronic obstructive pulmonary disease Variables HR (95% CI) P-value Age 1.46 ( ) Male 0.93 ( ) NYHA class NYHA I NYHA II 0.87 ( ) NYHA III 2.58 ( ) Ischaemic origin of HF 1.44 ( ) GOLD stage GOLD I GOLD II 0.93 ( ) GOLD III 2.27 ( ) Ejection fraction (%) 1.00 ( ) Current smoker 0.99 ( ) Diabetes 1.17 ( ) Hypertension 1.58 ( ) CKD 1.28 ( ) Hypercholesterolaemia 0.78 ( ) Anaemia 1.02 ( ) Pulmonary hypertension 1.44 ( ) Atrial fibrillation 0.96 ( ) BNP (pg/ml) I(,100) II ( 100 and,500) 1.07 ( ) III ( 500) 1.12 ( ) Hs-CRP 2.23 ( ) BMI (kg/m 2 ) I(,18.5) II ( 18.5 and,25) 0.52 ( ) III ( 25) 0.40 ( ) Weight loss 1.00 ( ) LVH 0.67 ( ) HF, congestive heart failure; COPD, chronic obstructive pulmonary disease; GOLD, Global initiative for chronic Obstructive Lung Disease; CKD, chronic kidney disease; Hs-CRP, high sensitive C-reactive protein; BMI, body mass index; LVH, left ventricular hypertrophy; HR, hazard ratio; CI, confidence interval. patients with coexistent HF and chronic obstructive pulmonary disease, which reached significance at GOLD stages III and IV in HF. 2 Chronic obstructive pulmonary disease has been shown to increase the risk of cardiovascular disease two- to three-fold. 29 Systemic hypertension is a common and important cause of HF, 30 and our study shows that SHT is also an important predictor of survival in cases of coexistent HF and chronic obstructive pulmonary disease. Pulmonary hypertension is known to be a predictor of prognosis in HF 31 and chronic obstructive pulmonary disease, 32 and was also found to be an independent predictor of event-free survival in patients with coexistent HF and chronic obstructive pulmonary disease in our study. Table 5 Multivariate Cox proportional hazards regression model analysis for cardiovascular or pulmonary event-free survival in patients with coexistent heart failure and chronic obstructive pulmonary disease Variables HR (95% CI) P NYHA class NYHA I NYHA II 0.67 ( ) NYHA III 2.92 ( ) GOLD stage GOLD I GOLD II 1.09 ( ) GOLD III 3.20 ( ) System hypertension 2.98 ( ) Pulmonary hypertension 4.35 ( ),0.001 HF, heart failure; COPD, chronic obstructive pulmonary disease; NYHA, New York Heart Association; GOLD, Global initiative for chronic Obstructive Lung Disease; HR, hazard ratio; CI, confidence interval. Our study has several limitations. First, it is limited by its retrospective nature. Second, although we included a relatively large population when compared with previous studies, the sample size was still relatively small. Third, some overlap between HFPEP and HFREF groups may exist in terms of pathophysiology and outcomes, because of the relatively high mean LVEF of % in the HFREF group. Because of the limited sample size, our findings concerning the prognostic predictors should be confirmed in larger studies. In conclusion, these findings indicate that in patients with coexistent HF and chronic obstructive pulmonary disease, the cardiovascular or pulmonary event-free survival of HFPEF and HFREF are similar over a follow-up of 3 years. Severe NYHA class, severe GOLD stage, SHT, and PH were found to be independent prognostic predictors of event-free survival in patients with coexistent HF and chronic obstructive pulmonary disease. Acknowledgements The statistical analyses performed in this article were advised by Catholic Medical Center Clinical Research Coordinating Center. Conflict of interest: none declared. References 1. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K. 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 J Heart Fail 2008;10: Mascarenhas J, Lourenco P, Lopes R, Azevedo A, Bettencourt P. Chronic obstructive pulmonary disease in heart failure. Prevalence, therapeutic and prognostic implications. Am Heart J 2008;155:

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