ISSN: 2581-3684
Archives of Pulmonology and Respiratory Care
Review Article       Open Access      Peer-Reviewed

Heart failure and chronic obstructive airway disease as combined comorbidities. Meta-analysis and Review

Hadi AR Hadi Khafaji* and Asim Cheema

Department of Adult Cardiology, Saint Michael’s Hospital, Toronto University, Canada
*Corresponding author: Hadi AR Hadi Khafaji, Department of Adult Cardiology, Saint Michael’s Hospital, Toronto University, Canada, E-mail: hadi968@hotmail.com; hadiarhadi@yahoo.com
DOI: 10.17352/aprc.000037
Received: 22 July, 2019 | Accepted: 09 August, 2019 | Published: 12 August, 2019
Keywords: Heart failure; COPD; All-cause mortality; Cardiac mortality recurrent heart failure hospitalization

Cite this as

Hadi Khafaji HA, Cheema A (2019) Heart failure and chronic obstructive airway disease as combined comorbidities. Meta-analysis and Review. Arch Pulmonol Respir Care 5(1): 015-022. DOI: 10.17352/aprc.000037

Background: The existence of COPD and heart failure in elderly population adds additional morbidity and mortality risk than if those with only one of the two comorbidities. The aim of the current meta-analysis was to explore the effect of COPD on heart failure patient in terms of all-cause mortality, cardiac mortality and recurrent heart failure hospitalization.

Methods and results: A comprehensive search of PubMed, MEDLINE, Embase and Cochrane was conducted until August 2017. The total standardized mean difference, with 95% (CI), was estimated for fixed and random effects models to present “pooled effect” for continuous outcomes (mean ± standard deviation or median ± interquartile range) & categorical outcomes (Odds risk OR). Statistical heterogeneity among studies was assessed with Cochran’s Q test and the I2 statistic. A total of 15 observational studies were analyzed. COPD and heart failure patients have higher: short term (in hospital, 1-3 months) (P=0.009, 0.0006 respectively), long term all-cause mortality (1& 2-5 years) (P=0.00001, 0.04 respectively), long term cardiac mortality (P=0.02) and more frequent hospitalization for heart failure (P=0.002). GOLD stage II-IV COPD had higher long-term all-cause mortality (P<0.0001) but not long-term cardiac mortality (P=NS). Beta blockers treatments appear to decrease all-cause mortality in COPD with heart failure (P <0.0001).

Conclusion: Heart failure patients with COPD have frequent heart failure hospitalization, higher long-term cardiac mortality, short- and long-term all-cause mortality that is more evident in advanced stage of COPD. Beta blockers use appear to be safe and decrease mortality in these patients.

Introduction

The co-occurrence of heart failure (HF) and chronic obstructive pulmonary disease (COPD) that share common clinical presentation and risk factors is common in the elderly population, such overlap makes the diagnosis of COPD in HF and vice versa challenging [1,2].

The existence of these clinical syndromes in elderly population adds additional morbidity and mortality risk than if those with only one of these diseases [3]. Furthermore, it will add dilemma to recognition of each when these disorders exist and leads to over diagnosis of heart failure in COPD patient or under diagnosis of COPD in heart failure patients [4]. Treatment interaction, the more complex issue is that the treatment of one may adversely affect the other [5], as bronchodilator may cause tachycardia and may precipitate heart failure furthermore beta blockers and diuretics may adversely affect COPD.

The above 2 clinical presentation has not analyzed systematically, with the presence of only observational studies that supply both cardiologist and internist with inconsistent information. We choose to systematically analyze the available research article, so we can reach final conclusion about the morbidity and mortality interaction between these conditions when heart failure patient with COPD presented with acute exacerbation.

The aim of the current meta-analysis was to explore the effect of COPD on heart failure patient in term of short- and long-term all-cause mortality and cardiac mortality and the effect of COPD on recurrent heart failure hospitalization.

Methods

Search strategy & data collection

A comprehensive search of PubMed, MEDLINE, Embase and Cochrane was conducted until August 2017, using combination of keywords; heart failure, COPD, all-cause mortality, cardiac mortality recurrent heart failure hospitalization. Along with available studies electronic search was done for abstracts, conference proceedings, unpublished and observational studies. References cited in the studies were reviewed for additional information. The flow diagram shown in Figure 1, the search strategy yields 15 observational studies that met the study criteria.

Figure 1: Flow diagram of study selection process.
Criteria for study selection and qualitative assessment

The inclusion and exclusion criteria for the studies in the current meta-analysis are shown in Figure 2. Data regarding publication status, study design, patient-related characteristics, treatment regimens, outcome methods and results was extracted according to the standard protocol independently by 2 individual researchers. Any conflicts or incongruities were resolved by mutual agreement.

Figure 2: Inclusion/Exclusion Criteria.
Clinical end points studied

The clinical endpoints that were analyzed in this meta-analysis are short- and long-term all-cause mortality, early and late cardiac mortality in all COPD patient and in subgroups as per COPD GOLD stages, recurrent heart failure hospitalization and the effect of B blocker treatment on all-cause mortality.

Statistical analysis

Review manager 5.3 (The Nordic Cochrane Centre, The Cochran Collaboration, Copenhagen, Denmark) was used for the analysis. The total standardized mean difference (SMD), with 95% confidence interval (CI), was estimated for fixed and random effects models to present “pooled effect” for continuous outcomes (mean ± standard deviation or median ± interquartile range) & categorical outcomes (Odds risk OR). Statistical heterogeneity among studies was assessed with Cochran’s Q test and the I2 statistic. The studies were considered statistical heterogeneous if p <0.05 and I2 ≥ 50% [6,7]. A random effect model was used for analysis to determine the heterogeneity, and fixed effect model was used in case of homogeneity. Statistical significance value was set at 0.05. Processing of the data and reporting of results were performed according to accepted principles of systemic review and meta-analysis. In order to assess potential publication bias, or “small-study effect”, we used the funnel plot, which provides a good visual evaluation of sampling bias.

Results

A total of 15 observational studies [8-22], were identified, the baseline clinical characteristics of the patients included are shown in Table 2, Males were the predominant gender in these studies with the mean age shown being above 65 years of age with similar rate of CAD hypertension and dyslipidemia.

Table 1: Baseline clinical characteristics of the included studies.  
Author Study design/ period Patients
 COPD vs. Non COPD		 Age
COPD vs. Non COPD		 Male
COPD vs. Non COPD		 DM
COPD vs. No COPD		 Hypertension
 COPD vs. Non COPD		 Dyslipidemia
COPD vs. Non COPD		 History of CAD
COPD vs. Non COPD		 Smoking History
COPD vs. Non COPD
Rothnie KJ 2015 / UK Retrospective Observational 2003-2013 34019 vs. 266142  > 60 years 77% vs. 66% 62% vs. 67%                16 % vs. 15% 45% vs. 44.3%                27% vs. 28%                22% vs. 16%                43% vs. 34%
Polikutina OM 2015/Russia Retrospective study from Jan – Dec 2008 65 vs. 464 67 (56 -75) vs. 62.5 (55 -72) 75% vs. 63% 14% vs. 20% NR NR 34% vs. 26% 54% vs. 41%
Andell P 2014
/ Sweden		 Retrospective analysis SWEDEHEART registry 2005-2010 4867 vs. 76324 75± 9 vs. 70± 13 54%vs. 64% 20% vs. 19% 32% vs. 20% NR 14% vs. 8% 33% vs. 22%
Campo G 2013 /Italy Retrospective analysis of REAL registry 2003-2009 2032 vs. 9086 70 ±12 vs. 65±13  66% vs. 74%  22% vs. 21% 70% vs. 61% 47 % vs. 48 % 17% vs. 14% 24% vs. 27%
Lazzeri C 2013/
/ Italy		 Prospective 2005-2009 71 vs. 747 74 (69–81) vs. 67 (58–76) 66% vs. 73% 34% vs. 27 % 63% vs. 53% NR 21% vs. 13% 76% vs. 62%
Sung PH 2013/
Taiwan		 Prospective observational 2002-2011 124 vs. 1430 68.5 ± 9.9 vs. 60.9 ± 12.6 85% vs. 81% 32% vs. 36% 55% vs. 56% 39% vs. 42% 4.8% vs. 4.4% 37% vs. 35%
Enriquez JR 2013
/ USA		 Retrospective analysis of ACTION registry-GWTG 2008-2010 22624 vs. 136266 68 vs. 63 58% vs. 66% 39% vs. 29% 82% vs. 71% 67% vs. 59% 36% vs. 23% 46% vs. 34%
Stefan MS 2012
/ USA		 Retrospective analysis WHA study 1080 vs. 5210 74 vs.70 52% vs. 57 % 37% vs. 32% 73% vs. 69% NR NR 27% vs. 20%
Quint JK 2011
/ UK*		 Retrospective
Observational 2003-2008 MINAP and GPRD records		 968 vs. 7097 NR NR NR NR NR NR NR
Hadi A 2010
6 Middle Eastern countries		 Retrospective analysis of prospectively collected data GulfRACE registry 2007 434 vs. 7733 64 vs. 55 NR 48% vs. 40% 64% vs. 49% 39% vs 31% 34.8% vs. 23.8% 39% vs. 36%
Dziewierz A 2010/
Poland		 Retrospective analysis of prospectively collected data Krakow ACS registry 2005 & 2006 81 vs. 633 71.8 ± 10.7 vs.
67.9 ± 12.9		 62% vs. 60% 23% vs.23% 76% vs. 71% 37% vs. 47% 35% vs. 29% 41% vs. 32%
Bursi F 2010
/USA		 Retrospective study Rochester Epidemiology Project 1979-2007 415 vs. 3023 73 ± 11 vs. 67 ± 15 59% vs. 57% 23% vs. 21% 68% vs. 57% 43% vs. 39% NR 35% vs. 26%
Wakabayashi K 2010/USA Prospective study
1999-2008		 365 vs. 2884 66.2± 13.6 vs. 60.7± 13.8 59% vs. 68% 36% vs. 29% 87% vs. 80% 85% vs. 83% NR 40% vs. 37%
Hawkins NM 2009
/Multinational		 Retrospective analysis of VALIANT trial in 24 countries 1258 vs. 13445 68.1 ± 9.9 vs. 64.5 ± 11.9 71% vs. 68% 26% vs. 23% 58% vs. 55% 36% vs. 29% 40% vs. 27% 42% vs. 31%
Rha SW 2009
/Korea*		 Retrospective analysis of KAMIR registry 2005-2007 192 vs. 192 71.74 ± 9.97 vs. 63.04 ± 12.66 NR NR NR NR NR 28.4% vs. 14.8%
Salisbury AC 2007
/ USA		  Retrospective analysis PREMIER registry 2003-2004 387 vs. 2094 64.5 ± 12.4 vs. 60.1 ± 13 62 % vs. 68% 37% vs. 27% 68% vs. 63% 50% vs. 49% 30% vs. 20% 38% vs. 33%
Kjoller K 2003
/Denmark		 Retrospective analysis of TRACE study.1990-1992 765 vs. 5904 70.5
vs. 68.2 		68% vs. 67% 11% vs. 11% 18% vs. 23% NR 25% vs. 23% 60% vs. 50%
Behar S 1992/
Israel		 Retrospective analysis of SPRINT study 1981-1983 406 vs. 5433 66.8 ± 9.7 vs. 62.7± 10.8 79% vs. 73% 16% vs. 21% 37% vs. 40% NR 29% vs. 24% 44% vs. 31%
 CAD; Coronary Artery Disease, COPD; Chronic Obstructive Pulmonary Disease, DM; Diabetes Mellitus, NR; Not Registered. * : This study published in abstract form, ACTION; Acute Coronary Treatment and Intervention Outcomes Network, GulfRACE; Gulf Registry of Acute Coronary Events, Krakow Registry ACS; Acute Coronary Syndromes, KAMIR; Korea Acute Myocardial Infarction Registry, MINAP; Myocardial Ischemia National Audit Project, PREMIER : Prospective Registry Evaluating Myocardial Infarction: Event and Recovery , REAL : REgistro AngioPlastiche dell’Emilia Romagna, SWEDENHEART: Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies, SPRINT : Secondary Prevention Re-infarction Israeli Nifidipine Trial, TRACE : TRAndolapril Cardiac Evaluation, VALIANT; VALsartan In Acute myocardial infarction Trial, WHA; Worchester Heart Attack study.  
Table 2: Multivariate analysis of the all cause death predictors in the included studies.
Study Mortality Variable Adjusted OR/ HR 95% C.I. P value
Khafaji H 2015 In hospital STEMI  OR 2.25 1.57 – 3.23 0.001
VHD OR 1.59 1.12 – 2.25 0.009
Stroke OR 1.71 1.13 – 2.60 0.01
Long term Age OR 1.04 1.03 – 1.05 0.001
CKD OR 1.53 1.19 – 1.96 0.001
LVEF≥35 OR 0.74 0.60 – 0.91 0.005
LVEF <35 OR 1.35 1.10 – 1.67 0.005
Yoshihisa A             2014 Long term Age  HR 1.067 1.023–1.114 0.003
Anemia HR 2.689 1.064–6.794 0.037
COPD GOLD II HR 2.645 1.012–7.632 0.036
Arnaudis B              2012 Long term COPD GOLD I HR2.274 (1.218–4.245) 0.010
COPD GOLD II HR 2.813 (1.029–7.687) 0.044
ICD/ CRT  HR1.767 (0.997–3.133) 0.051
De Blois J               2010 Long term Age  HR 1.022 1.015-1.028 <0.001
CKD  HR 1.003 1.002-1.004 <0.001
COPD GOLD II HR 1.188 1.015-1.391 0.03
NYHA Class III/IV HR 1.464 1.286-1.667 <0.001
Diabetes  HR 1.389 1.204-1.601 <0.001
Lainscak M             2009 Long term COPD HR1.38 (1.04–1.83)  
Rusinaru D             2008 Long term LVEF≥35  HR 1.74 1.22–2.49 0.002
LVEF <35 HR 1.48 1.03–2.14 0.035
Staszewsky L 2007 Long term age HR 1.38 (1.14-1.67) 0.0008
Male
CAD
Diabetes
LVEF HR1.25 (1.03-1.52) 0.0215
Macchia A               2007 Long term Age HR1.06 (1.04–1.08) 0.0001
Diabetes HR 1.44 (1.12–1.84) 0.005
PVD HR 1.74 (1.19–2.55) 0.004
Stroke HR1.48 (1.03–2.14) 0.036
COPD HR1.42 (1.09–1.86) 0.010

Patients with COPD and heart failure have higher short term (in-hospital, 1-3 months) (P=0.009, 0.0006 respectively, and long-term mortality (1 year, 2-5 years) (P=0.00001 for both) with moderate heterogeneity between the included studies) Figure 3.

Figure 3: Forest plot: All- cause Short-Term Mortality.

The short-term cardiac mortality appears to be non-significantly (P=0.07) higher in COPD patients while the long-term cardiac mortality appears to be significantly higher (P=0.02) in COPD patient with heart failure with moderate heterogeneity between the included studies Figure 4.

Figure 4: Forest Plot: All- cause intermediate and Long-Term mortality.

COPD patient with heart failure have more frequent hospitalization for heart failure (P=0.002) with mild heterogeneity between the included studies Figure 5.

Figure 5: Forest plot: Short- and Long-Term Cardiac Mortality.

The heterogeneity of all the variable analyzed is shown in Funnel plots in Figure 6.

Figure 6: Forest plot: Heart Failure and Re-infarction Hospitalization.

Patient with advanced stage [11,13,19], of COPD i.e. GOLD stage II-IV when compared to GOLD 0-I and non-COPD had higher long-term all-cause mortality (P<0.0001) [11,19], but not long-term cardiac mortality (P=NS). Figure 7 A,B.

Beta blockers treatments appear to decrease all-cause mortality [8,10,11], in COPD with heart failure as it does with non-COPD with heart failure (P <0.0001) Figure 7 C.

Figure 7:

The multivariate analysis of the all-cause mortality predictors was shown in Table 1. The age, diabetes, COPD stage, low ejection fraction, and impaired renal function were the most frequent predictors in the included studies.

Discussion

Heart failure and COPD as combined comorbidities presents a great diagnostics and therapeutic challenges, because both conditions share features such as; presentation in advanced age, common symptoms of dyspnea and smoking as a risk factor, in addition to that, treatment of one condition may affects the other [1]. Unfortunately, this issue has not been studied systematically in randomized stream and even forgotten in major clinical trials. To the best of our knowledge this the first meta-analysis that explored the impact of COPD in heart failure patient. The absence of randomized trial makes the final result biased in many aspects. As we can see from the current analysis, few conclusions have been withdrawn:

First: The presence of COPD adds an increased risk of both short and long term all-cause and long-term cardiac mortality in period of the follow up of the included studies which appear to be satisfactory in most of the studies that reach up to 5 years.

Second: Heart failure exacerbation on the background of COPD may be explained by many mechanisms; the low-grade inflammation, underuse of β-blockers, and adverse CV effects of bronchodilators [14,15]. The increased hospitalization rates in patients with HF and COPD may also be related to improvement in HF prognosis with contemporary therapies i.e. increase heart failure population. Alternatively, the improved survival of patients with HF and COPD, there is a larger population at risk for hospitalization.

Third: The severity of COPD appears to be directly proportional to the heart failure all-cause mortality and cardiac mortality and it appear that heart failure patient with advanced COPD i.e. GOLD stage ≥ II die from non-cardiac causes that related to associated comorbidities like diabetes and renal failure and advanced age as shown the mortality predictors in Table 2, though the mortality predictors were assessed only in few studies.

Fourth: Treatment of HF as per heart failure guidelines, necessitate the addition of beta blockers even in COPD patients, because there is no evidence that HF should be treated differently in patients with this comorbidity. B-Blockers are strongly recommended in all patients with systolic HF, including those with coexistent COPD [23-25], with cardio-selective b-blockers as the default [26,27]. The result from the current analysis showed that treatment with B blocker had mortality benefit though this issue has been assessed in 3 studies [8,10,11], only, but still it gives the preliminary idea that beta blockers are safe in the patients subset, though we are unable to analyze the beta blocker selectivity as this issue has not been investigated in the included studies and despite concerns regarding β blockers in patients with HF with COPD, there was no evidence that β-blocker selectivity was associated with differences in outcomes for patients with HF with COPD versus those without as in OPTIMIZE-HF registry sub-analysis [28]. The available evidence suggests that COPD patients treated with cardio selective beta-blockers has no significant short-term impact on airway function or COPD exacerbations. However, the trials were small and of short duration. Given their substantiated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardio selective beta-blockers should be considered for patients with COPD, but administered with careful monitoring since data concerning long term administration and their effects during exacerbations is not available on wide scale.

Fifth: The mortality predictors in this patient’s population are variable but there are common predictors as shown in Table 1, these predictors appear to be the combination of mortality risk factors of COPD and HF, such as age, diabetes, chronic kidney disease, low ejection fraction, in addition to well-known other factors like liver disease, low systolic blood pressure, lower serum sodium, lower admission weight, and depression. The use of statins and beta-blockers at discharge was associated with significantly decreased mortality as shown in retrospective analysis of OPTIMIZE-HF registry in patient without COPD [29].

Strength and limitations

The strength of this research is that it is the first meta-analysis done in this field of heart failure patients with COPD who presented acutely or chronically. The current meta-analysis result was extracted from observational studies most of which are retrospective analysis of major heart failure registries that can result in publication bias. In addition, the definition and staging of COPD was not available in many studies and that patient were considered to have COPD as per medical record and no spirometry done in these studies (only one prospective study included), the low number of patients included explore the need for large study that can achieve statistical power. The conclusion regarding B blockers in heat failure patient with COPD need to be interpreted carefully as this include relatively small number of patients from few retrospective studies though one of which was retrospective analysis of major heart failure registry, again necessitate the need for a large randomized controlled trial in this field.

Conclusion

Heart failure patient with COPD appear to have more frequent heart failure hospitalization, higher long-term cardiac mortality, short- and long-term all-cause mortality and this more apparent in advanced stages of COPD reflect the synergistic effect of both comorbidities. Beta blockers use appear to be safe as it decreases mortality in these patients.

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© 2019 Hadi Khafaji HA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 

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