Download Chronic obstructive pulmonary disease in heart failure: accurate

REVIEW
European Journal of Heart Failure (2014) 16, 1273–1282
doi:10.1002/ejhf.183
Chronic obstructive pulmonary disease
in heart failure: accurate diagnosis
and treatment
Gülmisal Güder1,2,3, Susanne Brenner2,3, Stefan Störk2,3,
Arno Hoes1, and Frans H. Rutten1*
1 Julius
Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; 2 Comprehensive Heart Failure Center, University of
Würzburg, Würzburg, Germany; and 3 Department of Internal Medicine–Cardiology, University Hospital Würzburg, Germany
Received 4 July 2014; revised 8 September 2014; accepted 12 September 2014 ; online publish-ahead-of-print 27 October 2014
Coincidence of COPD and heart failure (HF) is challenging as both diseases interact on multiple levels with each other, and thus impact
significantly on diagnosis, disease severity classification, and choice of medical therapy. The current overview aims to educate caregivers
involved in the daily management of patients with HF and (possibly) concurrent COPD in how to deal with clinically relevant issues such as
interpreting spirometry, the potential role of extensive pulmonary function testing, and finally, the potential beneficial, but also detrimental
effects of medication used for HF and COPD on either disease.
..........................................................................................................
Heart failure •
COPD misdiagnosis •
Severity classification
Introduction
‘A 60 year old man (110 kg, 170 cm) consults his general practitioner (GP) because of progressive dyspnoea on minimal exertion.
The patient is an active smoker (40 pack-years) with a history
of diabetes type 2, obesity, hyperlipidaemia, and hypertension. He
reported a weight gain of 4 kg within the last 3 days. At clinical
examination the GP detects increased jugular venous pressure, pulmonary expiratory wheezing, a broadened and sustained apex beat
in the lateral decubitus position, ankle oedema, and a high systolic
blood pressure of 180 mmHg. The forced expiratory volume in
1 s/forced vital capacity ratio (FEV1 /FVC) measured by a hand-held
spirometer is 0.60 post-bronchodilator and thus would be compatible with pulmonary obstruction as seen in COPD. The reversibility
of the FEV1 value, 15 min after salbutamol inhalation, lies in the grey
zone, i.e. 9%.’
This scenario describes a common dilemma in everyday clinical
practice. Does this patient have COPD, heart failure (HF), or both?
In order to arrive at an accurate diagnosis, the recent guidelines
on HF and COPD both emphasize not to rely on the assessment
...........................................................
Keywords
of clinical symptoms only, but recommend additional investigations
aiming to detect structural or functional cardiac or pulmonary
abnormalities.1,2 In many previously published studies, a patient
recall of suffering from COPD was deemed sufficient for the ‘diagnosis’ of COPD.3 However, even with spirometry, a misdiagnosis
and over-rating of COPD severity is likely in patients with HF,
because HF on its own may mimic an obstructive pattern compatible with COPD.4 More importantly, current guidelines advocate
the same COPD/HF therapy in patients with co-morbid COPD and
HF without acknowledging the lack of accurate evidence on bronchodilator therapy in patients with severe HF.1,2 Specific information on defining COPD and COPD severity grading in the presence
of HF is also not given.1,2
The current review takes a pragmatic approach in that it aims to
educate doctors and nurses involved in the daily management of
patients with HF and/or COPD in how to deal with some clinically
relevant issues that have not been addressed in depth by previous
reviews. This includes a detailed discussion on the diagnostic
approach of how to establish and grade COPD in patients with
HF, and the potential beneficial but also detrimental effects of
*Corresponding author. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85060, Stratenum 6.131, 3508 AB Utrecht, The
Netherlands. Tel: +31 88 7568193, Fax: +31 88 7569028, E-mail: [email protected]
© 2014 The Authors
European Journal of Heart Failure © 2014 European Society of Cardiology
1274
The definition of chronic
obstructive pulmonary disease
Chronic obstructive pulmonary disease is defined as ‘persistent
airflow limitation that is progressive over time’ and, if diagnosed by
the GOLD criteria (global strategy for the diagnosis, management,
and prevention of chronic obstructive pulmonary disease), requires
a post-bronchodilator ratio of the forced expiratory volume in
1 s (FEV1 ) to the forced vital capacity (FVC) <0.7.1 This criterion
is adequate in clear-cut cases with severe obstruction, but may
be problematic in ‘borderline’ cases, when the strictly defined
ratio reaches its limits of diagnostic certainty.5 Application of
the strict ratio in older persons has been repeatedly criticized
for not acknowledging the age-associated physiological decline
of the FEV1 /FVC ratio, thus risking overdiagnosis of COPD in
this population.6 Alternatively, an age- and sex-adjusted approach
was proposed employing the lower limit of normal (LLN) of the
FEV1 /FVC ratio, but the superiority of the LLN over the GOLD
definition has not generally been accepted.5 Diagnosing COPD
using the LLN threshold also has considerable shortcomings. There
are several equations (and thresholds) available. resulting in a lack
of consistency,7 and the LLN approach has poor accuracy in the
early stages of COPD.
A validated consensus diagnosis of an expert panel of pulmonologists using all diagnostic information, including extensive pulmonary function testing, physical examination, patient’s medical
history, and smoking status, may be viewed as the current reference standard for the diagnosis of COPD in the research setting.8
Adequate reporting of the procedure of the panel, however, is
required.9
When compared with an expert panel of pulmonologists who
used the comprehensive information from spirometry, but also
from body box and diffusion measurements, LLN was inferior to
the GOLD definition.10 Compared with such an expert panel, a
diagnosis based on the GOLD definition was more sensitive but
less specific, and better predicted future exacerbations than the
LLN approach in clinically stable elderly patients aged 65 years or
over and suspected of COPD.10 Thus, both a fixed FEV1 /FVC ratio
and the LLN approach appear to be insufficient as a single criterion
for the diagnosis of COPD, especially in early COPD. Although
the GOLD guidelines acknowledge these limitations of the current
definition, they still adhere to the fixed ratio for its simplicity and
applicability to a broader, worldwide range of caregivers.1
In conclusion: especially in ‘borderline cases’, the commonly
used fixed ratio of FEV1 /FVC as measured with spirometry, and the
LLN approach both bear the risk of over- and underdiagnosing true
COPD, respectively. A gold standard for diagnosing COPD is lacking, but may be best approached by a validated consensus diagnosis
of an expert panel of pulmonologists in the research setting.8 For
routine clinical practice, consultation of a pulmonologist in unclear
cases or repeated pulmonary function testing would be both a pragmatic and an adequate approach.
........................................................................................................................................................................
medication used for HF and COPD on either condition, in both
the acute and non-acute setting.
G. Güder et al.
Concurrence of heart failure
and chronic obstructive
pulmonary disease
Chronic obstructive pulmonary disease and HF are common
diseases of the elderly,11 although COPD develops on average
∼10 years earlier than HF (>55 vs. >65 years).1,2 Both conditions
can be considered—at least partly—as ‘premature organ ageing’,
with profound systemic effects and a chronic progressive course
impacting heavily on exercise tolerance and health-related quality
of life. Both conditions share non-specific, but very common symptoms such as breathlessness and fatigue, and cigarette smoking as
a major risk factor. It is estimated that >90% of cases with COPD
in the Western world are due to cigarette smoking.12 Interestingly,
in patients with HF, the proportion of patients with ‘COPD’ had
a smoking history less often than would be expected. Some of
these studies reported prevalence rates of never-smokers as high
as 20–50%, 4,13,14 which may raise the suspicion of overdiagnosis
of COPD in patients with HF (Table 1).
In recent years, systemic inflammation has increasingly been
recognized as another important common pathway for both
conditions.15 Systemic inflammation expressed by increased
levels of cytokines, such as tumour-necrosis factor (TNF)-𝛼,
interleukin-1 (IL-1), and IL-6, might accelerate and perpetuate
disease progression and exacerbation of both diseases.16 Hence,
systemic low-grade inflammation is regarded more and more
as a critical link between pulmonary disease and cardiovascular
conditions.15 The significance of each disease to the development
of the other is, however, still unanswered.16 Also other inflammatory conditions such as rheumatoid arthritis and inflammatory
bowel diseases are associated with COPD,17,18 but the associations
are much weaker than in HF (prevalence rates 4–8% vs. 25%,
respectively).17 – 19
Moreover, although in 60% of patients with heart failure with
reduced ejection fraction (HFrEF) an ischaemic cause can be
detected in coronary angiography2 and both CAD and COPD
share the same risk factors as smoking and low-grade inflammation,
the prevalence of CAD or a history of myocardial infarction
was similar between HF patients with and without COPD,4,14,20
indicating that an additional risk factor may influence the high
co-incidence of COPD and HF.
In conclusion: smoking and low-grade systemic inflammation
seem the most important common risk factors for the concurrence
of COPD and HF but do not entirely explain the high co-incidence
of both conditions.
Prevalence of chronic obstructive
pulmonary disease in patients
with heart failure
Published estimates on the prevalence of COPD in patients with
HFrEF varied considerably among studies, ranging from 8% to 52%.
Differences in these rates may be due to numerous factors such as
geographical region, age and sex distribution, urban environment,
© 2014 The Authors
European Journal of Heart Failure © 2014 European Society of Cardiology
1275
Accurate diagnosis and treatment of COPD in HF
Table 1 Prevalence of concurrent chronic obstructive pulmonary disease as spirometrically defined by a
post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio <70% assessed in patients with heart
failure.
Beta-blocker
use, % (differences
in patients
with or without
COPD)
...........................................................................................................................................
First author,
year,
reference no.
n
HF
phenotype
Time point
of measurements
Iversen, 200814
532
Mixed
1–3 days after
hospitalization for
acute HF
Mascarenhas, 200822
223
309
186
HFpEF, (LVEF ≥45%)
HFrEF, (LVEF <45%)
HFrEF (LVEF <45%)
Apostolovic, 201113
Macchia, 201120
Boschetto, 201224
Stable HF, outpatients
department
174
HFrEF (LVEF<45%)
Stable HF, outpatients
department
201
HFrEF (LVEF ≤40%)
Stable, outpatients
department
118 Mixed (mean LVEF 40%) Stable HF, outpatients
department
Steinacher, 201226
89
Mixed (3% HFpEF)
Brenner, 20134
272
HFrEF (LVEF <40%)
619
HFrEF (LVEF <40%)
Beghé, 201325
124
HFeEF
Minasian, 201323
187
HFrEF (LVEF <40%)
Minasian, 201321
116
HFrEF (LVEF <40%)
Stable, outpatients
department
3–5 days after
hospitalization for
acute HF
Stable, outpatients
department
Stable, outpatients
department
Stable, outpatients
department
Stable, outpatients
department
Prevalence Prevalence of
of COPDa never-smokers
in patients
with COPD
35%b
41%b
31%b
39%
27.6%
37%
30%
44%
20%
29% (no)
No specification, 49% in
the total cohort
54%
87% (no)
No specification for
GOLD-COPD
0%, >10 pack-years of
smoking was an
inclusion criterion
No specification for
GOLD-COPD
Not mentioned
19%
9
100% no)
83% (no)
98% (no)
92% (no)
28%
91% (no)
83% (no)
32
0%, >10 pack-years of
smoking was an
inclusion criterion
5%
34
6%
34%
92% (no information
on differences)
91% (no information
on differences)
and smoking prevalence of the study population, but importantly
also depend on the diagnostic criteria and definition of COPD
applied, and whether patients underwent spirometry while in
a euvolaemic and stable condition of HF.19 Surprisingly, only a
few studies included spirometry to determine the presence of
COPD (Table 1).4,13,14,20 – 26 Most studies relied rather on medical
recordings or patients self-report to diagnose COPD.19 Reliable
estimates of the prevalence of COPD in a representative sample
of HF patients in a stable situation with preserved ejection fraction
(HFpEF) are still lacking.27
There are major concerns about interpreting pulmonary function testing in patients with HF when based solely on the FEV1 /FVC
ratio. HF may induce restrictive pulmonary changes (proportional
reduction in lung volumes) due to enlargement of the heart,
.........................................
FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity; HF, heart failure; HFpEF heart failure with preserved ejection fraction; HFrEF, heart failure with reduced
ejection fraction.
a COPD prevalence in patients with HF according to the GOLD definition (post-bronchdilator FEV /FVC ratio <0.7).
1
b Exclusion of GOLD stage I patients (FEV >80% of predicted).
1
© 2014 The Authors
European Journal of Heart Failure © 2014 European Society of Cardiology
pulmonary congestion, or pleural effusion, and—in long-standing
HF with repetitive decompensations—fibrotic alterations of the
pulmonary interstitium.28 Obesity is another frequent cause of
such externally induced pulmonary restriction.29 In stable HFrEF,
both FEV1 and FVC are reduced on average by 20% compared
with age-, sex-, and height-matched controls from the general
population, thus, fortunately, not affecting the FEV1 /FVC ratio.30
Occasionally, however, HF may reduce the FEV1 /FVC ratio by causing a larger reduction in FEV1 than in FVC, and thus produce an
obstructive ventilatory pattern in spirometry.5 Importantly, pulmonologists often only consider intrabroncheolar obstruction as
a cause for reduction in FEV1 /FVC, while extrabroncheolar (fluid)
and attenuated thoracic muscle function (both of which often occur
in HF patients) can cause such a reduction as well.31,32 In a study
1276
Alternatives to diagnose chronic
obstructive pulmonary disease
in heart failure
Body plethysmography results can improve the diagnostic accuracy
of detecting COPD. Determining the ratio of residual volume
and total lung capacity (RV/TLC) is worthwhile,4 because COPD
is very often accompanied by air-trapping and hyperinflation.36
Hyperinflation (high RV/TLC ratio) is a valid indicator of true
COPD, especially in patients with decompensated HF.4 Hence,
before considering long-term bronchodilator therapy in patients
with HF and suspected COPD, comprehensive pulmonary function
testing should be considered.
In conclusion: hyperinflation (high RV/TLC ratio) is a valid
indicator of true COPD in patients with HF, even when performed
when patients were recently decompensated.
........................................................................................................................................................................
conducted in patients with stable HFrEF, i.v. infusion of ∼1 L of
saline over 30 min resulted in a decreased FEV1 and FEV1 /VC ratio,
without a substantial change in VC, while the same procedure in
healthy subjects did not result in substantial changes in any of these
three measurements.33 Saline infusion results in fluid extravasation
in the lungs in HF patients, but not in healthy subjects. Therefore,
especially in acutely decompensated HF patients, and in HF patients
with chronic pulmonary fluid overload, congestion of the lung may
provoke mechanical obstruction of the bronchi by increased interstitial fluid pressure. This results in a reduction of both FEV1 and
FVC, but to a larger extent of FEV1 , with a reduction of the
FEV1 /FVC ratio as a result.28,31,32,34,35 After re-compensation of HF,
airway conduction may improve or even normalize.4,34,35 Thus, in
unstable HF patients with pulmonary congestion, the FEV1 /FVC
ratio may comply with the GOLD criteria for COPD (FEV1 /FVC
<0.7) in the absence of true COPD, with, as a result, false-positive
COPD diagnosis.35
A study assessing patients hospitalized for symptomatic HF 1–3
days after admission found a prevalence of ‘COPD’ based on the
GOLD criteria (FEV1 /FVC <0.7) of 31% in patients with HFrEF,
and of 41% in patients with HFpEF.14 Another study investigating
patients with established HFrEF by repeat pulmonary function
testing showed that the prevalence of ‘COPD’ in the cohort
changed over time, with a prevalence rate of 19% at 3–5 days
after admission for acute decompensation, and only a rate of
9% at 6 months after discharge, when the majority of patients
were in a stable phase and considered euvolaemic.4 These studies
clearly illustrate that COPD may be overdiagnosed in patients with
HF when based on spirometry performed when HF patients are
(recently) decompensated or not euvolaemic.
In conclusion: overdiagnosis of COPD in HF is very likely when
spirometry is performed when HF patients are unstable. Based
on studies performed in stable HF, the prevalence of COPD
defined according to a post-dilatory value of FEV1 /FVC <70%
varies between 9% and 44% (Table 1), depending on population
characteristics, the timing of pulmonary function testing, and the
method or definition applied to diagnose COPD.
G. Güder et al.
Table 2 Grading of severity of airflow limitation in
chronic obstructive pulmonary diseas based on
post-bronchodilator forced expiratory volume in 1 s as
a percentage of predicted values
Stage
Severity
Post-bronchodilator
FEV1 % of predicted level
................................................................
GOLD 1
GOLD 2
GOLD 3
GOLD 4
Mild
Moderate
Severe
Very severe
≥80%
50 to <80%
30 to <50%
<30 %
Adapted from Vestbo et al.1
Severity grading of COPD according to the GOLD guidelines (postbronchodilator FEV1 /FVC ratio <0.7).
FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity.
Severity grading of chronic
obstructive pulmonary disease
in the presence of heart failure
Until recently, severity of COPD was graded on the reduction of
FEV1 . This approach results in overestimation of COPD severity in
patients with HFrEF, because HF itself causes a 20% reduction in
FEV1 (Table 2).30 Because FEV1 poorly correlates with symptoms
and the risk of exacerbations in COPD, the international guidelines
on COPD introduced a new severity classification system, incorporating symptom load and history of exacerbations in combination
with FEV1 reduction.1 Patients with COPD can thus be classified
into four groups (A–D) and treated according to severity grade
as specified in Figure 1. Breathlessness may be assessed with the
Modified British Medical Research Council (mMRC) questionnaire
or the COPD Assessment Test (CAT).1
These questionnaires cannot discriminate between cardiac- and
pulmonary-induced breathlessness and physical limitations. Moreover, exacerbations of COPD might be confused with or triggered
by episodes of cardiac decompensation. Thus, the new severity
classification system for COPD can also be expected to mediate
over-rating the severity of COPD and consequently overtreatment
with inhaled pulmonary drugs when patients have not only COPD,
but also HF.
In conclusion: because HF itself reduces FEV1 and causes dyspnoea and functional limitations, overestimation of the severity of
COPD is likely in those with concomitant HF and COPD.
Cardiac asthma: the alternative
diagnosis
The term ‘asthma cardiale’ was first mentioned in the literature
>180 years ago and was thought to distinguish bronchial asthma
from the clinical picture seen in acutely decompensated HF.37 The
main trigger of expiratory obstruction with the clinical sign of
wheezing in asthma is an allergen, while in acutely decompensated
HF abrupt pulmonary congestion with increased interstitial fluid
© 2014 The Authors
European Journal of Heart Failure © 2014 European Society of Cardiology
1277
Accurate diagnosis and treatment of COPD in HF
D
D
Alternative choices:
• Long-acting anticholinergic + long-acting beta2-agonist
• Long-acting anticholinergic + phosphodiesterase-4 inhibitor
• Long-acting beta-2 agonist + phosphodiesterase-4 inhibitor
• Inhaled corticosteroid + long-acting anticholinergic +
• long-acting beta2-agonist
• Inhaled corticosteroid + long-acting anticholinergic +
phosphodiesterase-4 inhibitor
• Long-acting anticholinergic + long-acting beta2-agonist
• Long-acting anticholinergic + phosphodiesterase-4 inhibitor
• Short-acting anticholinergic
OR
• Short-acting beta2-agonist
Recommended first-line therapies:
A
A
• Long-acting anticholinergic
OR
• Long-acting beta2-agonist
Alternative choices:
Alternative choice:
• Long-acting anticholinergic
• Long-acting beta2-agonist
• Short-acting anticholinergic + short-acting beta2-agonist
• Long-acting anticholinergic + long-acting beta2-agonist
mMRC < 2
CAT < 10
≥ 2/year
• Inhaled corticosteroid + long-acting beta2-agonist
+ / OR
• Long-acting anticholinergic
Alternative choices:
Recommended first-line therapies:
FEV1 ≥ 50%
Recommended first-line therapies:
C
C
B
B
Exacerbation frequency
• Inhaled corticosteroid + long-acting beta2-agonist
OR
OR
• Long-acting anticholinergic
< 2/year
Spirometry
FEV1 < 50%
Recommended first-line therapies:
mMRC ≥ 2
CAT ≥ 10
Symptoms and quality of life
Figure 1 Proposed grading scheme: patients are allocated to groups A–D according to the forced expiratory volume in 1 s (FEV1 ) % of
pressure causes external, mechanical obstruction and reactive
spasms of the bronchi.38 Wheezing is technically produced by
narrowing or obstruction of the bronchi. A study that defined
‘cardiac asthma’ as the presence of wheezing at initial presentation
found a prevalence of 35% in patients with acute HF.39 Interestingly,
this prevalence is comparable with the overestimated prevalence
of ‘COPD’ found in most of the studies conducted in HF based on
spirometry when patients were unstable (Table 1).
In conclusion: cardiac asthma is a clinical picture based on
externally induced pulmonary obstruction of cardiac origin, and
wheezing may be present in one-third of patients with acutely
decompensated HF.
The use of beta-blockers may
result in over-diagnosing chronic
obstructive pulmonary disease
Only a few studies have assessed the effect of beta-blockers on
spirometry in patients with HF,40 – 44 and in even fewer patients
with HF and coincident COPD (Table 3).45 – 47
..............................................................
predicted level, the number of COPD exacerbations within the last 12 months, and symptoms. Symptoms are assessed using either the
Modified Medical Research Council Dyspnea Scale (mMRC) or the COPD Assessment Test (CAT). The mMRC contains five categories that
describe incremental symptom severity (‘0’ = breathlessness only at strenuous exercise, ‘1’ = dyspnoea when hurrying on level ground or
walking up a slight hill, ‘2’ = walking more slowly than people of the same age because of dyspnoea on level ground, ‘3’ = dyspnoea after walking
∼100 yards or after a few minutes on level ground. ‘4’ = dyspnoea when dressing). The CAT assesses eight questions on typical symptoms of
daily life with COPD. Each question is rated from 0 to 5 points according to severity of symptoms. Questions refer to coughing frequency,
phlegm production, angina pectoris, dyspnoea uphill, limitations at daily activities, functionally fixed to domestic environment due to dypsnoea,
sleep disturbances, and physical energy. Adapted from Vestbo et al.1
© 2014 The Authors
European Journal of Heart Failure © 2014 European Society of Cardiology
In fact, the effects of beta-blocker intake on spirometry results
vary considerably, according to the beta-blocker type used (cardioselective vs. non-selective), duration of beta-blocker treatment,
dose applied, and underlying diseases.48 – 50 Still, it appears that
beta-blockers primarily reduce FEV1 but not FVC. Agostoni et al.
were the first who addressed this question in a randomized
controlled trial (RCT) and showed in a crossover design of 15
patients with HF without COPD that carvedilol, a non-selective
beta-blocker, did not change FEV1 or VC when compared with
placebo. Data were reported without information about whether
bronchodilators were administered.40 Later the same study group
showed that carvedilol inhibited the post-bronchodilator increase
of FEV1 with salbutamol but not the increase of FVC when compared with bisoprolol, 2 months after beta-blocker initiation in 53
patients with HF.42 Intake of beta-blockers also reduced FEV1 significantly in 35 patients with HF, but without substantial effects
on FVC within 12 months of follow-up.41 The largest cohort that
addressed this question was derived from the CIBIS elderly RCT.
In this study, bisoprolol use was associated with significantly higher
levels of FEV1 (50 mL) than carvedilol after 12 weeks of treatment.
1278
G. Güder et al.
Table 3 Effects of beta-blockers on resting spirometry in patients with heart failure only, and in patients with heart
failure and chronic obstructive pulmonary disease
Study design, n,
HF
Studied
Effects on
First author,
study duration
phenotype
beta-blocker
spirometry
year,
refence no.
...........................................................................................................................................
HF
Agostoni, 200240 RCT double blind, crossover HFrEF <40%, COPD
Carvedilol vs. placebo
Difference between carvedilol and
study, n = 15, 4 months
excluded
placebo: no effects on FEV1 , VC,
DLCO
beta-blocker use
Cohort study, n = 35 with
HFrEF <40%, COPD
Carvedilol (n =11),
Difference between baseline and
Witte, 200541
PFT on 12 months
excluded
bisoprolol (n = 24)
follow-up (n = 35): FEV1 , ↓ 84%
(19)% to 79 (21)% (P <0.01); FVC.
follow-up
no effects. No difference between
both beta-blockers
Agostoni, 200742 RCT, double blind crossover HF with NYHA ≥ II or LVEF Carvedilol vs. isoprolol
Difference between carvedilol and
study, n = 53, 2 months
<45%; severe COPD
bisoprolol: FEV1 (L): 2.71 vs.
2.83 L (P = 0.03); VC, no effects.
excluded
Analyses refer to
post-bronchodilator values
Difference between carvedilol and
Dungen, 201143 RCT, open label, n = 714 with HF with NYHA ≥ II or LVEF Carvedilol (n = 365) vs.
PFT, 12 weeks
<45%
bisoprolol (n = 349)
bisoprolol: FEV1 . +50 mL
(P = 0.03) for bisoprolol; FVC, not
reported
HF + COPD
HFrEF <40% and COPD
Bisoprolol (n = 14) vs
Difference between bisoprolol and
Hawkins, 200945 RCT, placebo controlled,
n = 27, 4 months
GOLD 2, 3
placebo (n = 13)
placebo: FEV1 , – 70 vs. 120 mL
(P<0.05); FEV1
post-salbutamol, – 90 vs. 20 mL
(P<0.05). No change on VC, RV,
TLC, PEF
Jabbour, 201146 RCT, open label, triple
HF (mean LVEF 37%), COPD Carvedilol, bisoprolol and
Difference for FVC: no effects in all
crossover study, n = 51,
GOLD 2, 3, 16 HF only 35
metoprolol succinate
subgroups. Difference between
each 6 weeks
CHF + COPD
bisoprolol vs. carvedilol, CHF,
FEV1 , +120 ml for bisoprolol
(P = 0.02); CHF + COPD, FEV1 ,
+150 mL for bisoprolol (P = 0.01)
Difference between metoprolol
vs. carvedilol: total group, FEV1 , +
80 mL for metoprolol (P = 0.04)
Bisoprolol vs. metoprolol: no
difference
Carvedilol (n = 31) vs.
Change in FEV1 between baseline
Lainscak, 201147 RCT, open label, n = 63, 4–6 HFrEF (LVEF <40%) and
weeks after up-titration
COPD ≥ GOLD 2
bisoprolol (n = 32)
and follow-up: bisoprolol, 1561 to
1698 mL (P = 0.046); carvedilol,
1704 to 1734 mL (P = 0.44). No
between-group difference for
FEV1 FVC: no effects
In patients with HF and COPD, beta-blocker-induced reduction of FEV1 might be even stronger. In an RCT conducted
by Hawkins et al., FEV1 was reduced between baseline and 4
months of follow-up with bisoprolol (–70 mL) but not with placebo
(+120 mL).45 Another RCT that compared carvedilol with bisoprolol could show an increase of FEV1 by 137 mL for bisoprolol after
................
All studies were performed in patients with HF when in a stable phase of their disease.
CHF, congestive heart failure; DLCO, diffusing capacity of the lung for carbon monoxide; FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity; HF, heart failure;
HFrEF, heart failure with reduced ejection fraction; PEF, peak expiratory flow; PFT, pulmonary function test; RCT, randomized controlled trial; TLC, total lung capacity; VC,
vital capacity.
6 weeks of treatment but no change for carvedilol.47 In a triple
crossover RCT, the non-selective beta-blocker carvedilol reduced
FEV1 by 150 mL when compared with bisoprolol in patients with
HF and COPD and by 80 mL when compared with metoprolol. No
significant difference was seen between patients on bisoprolol vs.
© 2014 The Authors
European Journal of Heart Failure © 2014 European Society of Cardiology
1279
metoprolol succinate.46 Of note, in all of the mentioned studies,
there was no effect on (F)VC (Table 3).
Thus, use of beta-blockers could result in a reduction of the
FEV1 /FVC ratio and subsequently in overdiagnosing of COPD.42
Importantly, however, beta-blockers were well tolerated in these
studies (>90% continuation within 1 year of follow-up41 ).
Multiple observational studies in patient with COPD suggest that
(cardioselective) beta-blockers reduce the risk of all-cause death
and exacerbations, even in the subpopulation without overt cardiac
disease.51 Most importantly, guidelines on HF and COPD both
recommend cardioselective beta-blockers in patients with HFrEF
with or without co-morbid COPD.1,2
In conclusion: beta-blockers might induce bronchoconstriction,
i.e. reduce FEV1 somewhat without an effect on FVC and thus
facilitate overdiagnosis of COPD when a FEV1 /FVC cut-off-based
definition is applied. Irrespective of this fact, beta-blockers are
well tolerated by COPD patients and beta1-selective beta-blockers
are recommended in any patient with HFrEF with or without
concurrent COPD.
Reversibility testing in patients
with heart failure
An increase of >12% or >200 mL in the baseline FEV1 after
inhalation of a bronchodilator (usually a beta-2-agonist) is an
accepted positive bronchodilator response indicating reversibility
of obstruction.52 A recent study conducted in 116 patients with
stable chronic HFrEF and no history of asthma or COPD detected
a pre-bronchodilator airway obstruction in 55%.21 After administration of bronchodilators (400 μg of salbutamol and 80 μg of ipratropium), FEV1 and the FEV1 /FVC ratio, but not the FVC, increased
slightly but significantly: pre- vs. post-bronchodilator FEV1 /FVC
0.68 ± 0.8 vs. 0.71 ± 0.8, P<0.001. In 22%, post-bronchodilator
FEV1 /FVC values increased to >0.7, thus reducing the percentage of patients with obstruction to 33%.21 Patients with HFrEF
and clinical signs of pulmonary congestion (n = 16) more often had
a FEV1 /FVC <0.7 after bronchodilation than the remaining 100
HF patients without such signs (56% vs. 30%, P = 0.04).21 Moreover, 9 out of 39 patients with persisting pulmonary obstruction
after administration of bronchodilators and therefore ‘spirometrically confirmed COPD’, had a positive ‘reversibility testing’ due
to an increase of FEV1 >200 mL and >12% of baseline values. It is
unclear whether these patients had a true asthmatic component
or whether the reversibility in any way was related to HF. Interestingly, all 116 HF patients experienced amelioration of shortness of
breath shortly after the administration of salbutamol.21
In conclusion: a reversible obstructive pattern in spirometry is
common in stable HFrEF, and a short-acting beta2-agonist applied
during spirometry resulted in immediate symptom relief.
Bronchodilators in heart failure:
beneficial or detrimental?
Beta-2-agonists may increase heart rate,53 worsen cardiac
function, and might decrease potassium levels, thus facilitating
........................................................................................................................................................................
Accurate diagnosis and treatment of COPD in HF
© 2014 The Authors
European Journal of Heart Failure © 2014 European Society of Cardiology
hypokalaemia-induced arrhythmias and tachycardias, as well as
sudden cardiac death.53 – 56
Theoretically, however, short-term use of beta-2-agonists may
also exert positive effects in acutely decompensated HF, and
in subjects presenting with wheezing, since they may reduce
pulmonary congestion by increasing transepithelial sodium and
chloride transport, as shown in animal models.53,57,58 In addition,
small sized studies showed that short-term use of beta-2-agonists
increases FEV1 ,59 improves peripheral oxygen delivery,53 increases
cardiac index, and decreases systemic vascular resistance, even
in stable patients with HFrEF.53 So in acutely decompensated HF,
short-acting bronchodilators may result in immediate symptom
relief, and bridge the time gap until i.v. diuretics and nitrates start
working. On the other hand, the described adverse effects of
beta-2 agonists may limit even the short-term use in both acutely
decompensated and stable HF.
The ongoing Study to Understand Mortality and Morbidity in
COPD (SUMMIT) is a four-armed study investigating the effect
of a beta-2 agonist (vilanterol) and an inhalative corticosteroid
(fluticasone furoate) as monotherapy and combined vs. placebo
specifically in COPD patients who have established cardiovascular diseases (CAD, peripheral arterial disease, previous stroke or
myocardial infarction, or diabetes mellitus with target organ disease), or if older than 60 years have treatment for two of the
following cardiovascular risk factors: hypertension, diabetes mellitus, hypercholesterolaemia, or treatment for peripheral arterial
disease.60 Importantly, even in the controlled setting of this trial,
patients with severe HF (NYHA IV), and those with an LVEF <30%,
or an implantable cardioverter defibrillator (ICD), were excluded.
The primary bronchodilator therapy48 recommended in patients
with co-morbid HF and COPD is a long-acting anticholinergic
(e.g. tiotropium bromide), as its cardiovascular risk seems to be
more favourable than the risk of long-acting beta-2-agonists.61
However, because patients with underlying cardiac disease are
largely under-represented in RCTs in COPD patients, it is unclear
whether long-acting anticholinergics may be safely used in those
with cardiac disease, including HF. Several large observational
studies with long follow-up periods indicated that long-acting
anticholinergics may be associated with the same cardiovascular
event risk as long-acting beta-2-agonists in patients with cardiac
disease.62,63 The question remains of whether we should prioritize
either a long-acting anticholinergic or a long-acting beta-2-agonist
in patients with HF and true COPD. Although not formally
evidence-based, it may be assumed that in addition to the mentioned side effects, beta-agonists may exert beta-blocker-opposing
effects on cardiac remodelling in the long term. Thus, on a theoretical basis, maybe long-acting anticholinergics should be preferred
over long-acting beta-agonists, but both pulmonary drug classes
should be used under close follow-up.
In conclusion: bronchodilators may improve symptoms in HF
in the short term, even in the absence of COPD, but negative cardiovascular side effects may prevail during long- or even
short-term therapy. When patients need bronchodilation for pulmonary symptom improvement and reduction of the risk of exacerbations, long-acting anticholinergics seem to be preferred over
beta-2-agonists in patients with concurrent HF, although both drugs
1280
Other pulmonary medication
prescribed in chronic obstructive
pulmonary disease
Inhaled or oral corticosteroids are recommended in COPD
patients with GOLD stage 3 or 4.1 Apart from the known adverse
metabolic effects in cardiovascular diseases, corticosteroids are
also known to induce sodium and water retention, and may therefore cause worsening of HF.64 Although the risk is thought to be
rather low with inhaled corticosteroids, prescription of corticosteroids in patients with HF should be considered carefully.
The xanthine derivative theophylline is regarded as a secondchoice bronchodilator in COPD. Theophylline has, however, only
a small therapeutic range and may accumulate easily, especially in
older patients with HF.65 As toxic alterations may also include fatal
arrhythmias, theophylline should preferably be avoided in patients
with HF.
How to manage our case?
Coming back to our patient at the beginning of this review.
What would be the most appropriate diagnostic and therapeutic
approach?
As the patient is obviously decompensated, diuretics are indicated. Bronchodilator therapy with (short-acting) salbutamol might
provide immediate relief of dyspnoea and could therefore be considered as short-term therapy to bridge the time till the diuretics
take effect. Evidence for such an approach is, however, scarce and
has not been proven to be prognostically beneficial.66 Moreover,
one has to consider the risk of tachyarrhythmias, and therefore
low dosing with monitoring of heart rate and rhythm seems mandatory. After initial stabilization, the underlying cause and severity of
HF should be evaluated and medication initiated or optimized as
recommended by the current HF guidelines. The patient should be
encouraged to stop smoking and in the meanwhile considered as
‘suspected of having COPD’. A complete pulmonary function test
should be performed months later when the patient is euvolaemic.
Until COPD is then firmly established, any pulmonary therapy must
be considered experimental.
Conclusions
In patients with HF, a (post-dilatory) FEV1 /FVC ratio <0.7 is insufficient to diagnose true COPD. Because of the potential risk of detrimental effects of bronchodilators in cardiac patients, and in order
to prevent unnecessary polypharmacy, long-acting bronchodilators
should only be started or maintained in subjects with ‘true COPD’.
Inhalative therapy should be preferred over oral, as systemic effects
........................................................................................................................................................................................................................
were related to severe side effects especially in patients with underlying cardiovascular diseases.
In any case, after initiation of bronchodilators, physicians should
carefully monitor symptom improvements and side effects in
patients with HF, and eventually consider drug discontinuation.
G. Güder et al.
are less if therapy is applied locally. A complete pulmonary function
test executed under stable, euvolaemic conditions is a mandatory
prerequisite to establish definitely a diagnosis of COPD. In patients
with co-morbid COPD and HF, accurate severity grading of COPD
is not feasible with currently advocated scores. Adequately powered randomiszd trials are needed to establish the best treatment
approach in patients with concurrent COPD and HF.
Funding
G.G. was supported by a fellowship grant from the Medical Faculty of the University of Würzburg (Habilitationsstipendium). This
work was supported by grants from the German Ministry of Education and Research (BMBF), Berlin, Germany [BMBF 01EO1004;
Comprehensive Heart Failure Center Würzburg].
Conflict of interest: none declared.
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