European Heart Journal - Cardiovascular Pharmacotherapy Advance Access published April 6, 2015
1
Overview of the Pharmacological Challenges facing Physicians in the Management of Patients
with concomitant Cardiovascular Disease and Chronic Obstructive Pulmonary Disease
Gianluca Campo*,†, Rita Pavasini*, Simone Biscaglia*, Marco Contoli‡, Claudio
Ceconi*,†
*
Cardiovascular Institute, Azienda Ospedaliero-Universitaria S.Anna, Cona (FE), Italy
†LTTA
Center, Ferrara, Italy
§Research
Centre on Asthma and COPD, Section of Internal and Cardio-Respiratory
Medicine, University of Ferrara
Address for correspondence: Claudio Ceconi, MD, Cardiovascular Institute, Azienda Ospedaliera
Universitaria S.Anna di Ferrara, Cona (FE), Italy, Phone: 00390532237227, Fax: 00390532241885,
Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2015. For permissions please email: [email protected]
2
ABSTRACT.
Cardiovascular disease (CVD), including ischemic heart disease (IHD) and heart failure (HF), and
chronic obstructive pulmonary disease (COPD) are often concomitant, because they share both risk
factors (smoke) and pathological pathways (systemic inflammation). CVD and COPD association is
increasing overtime. Several registries clearly showed a negative impact on clinical outcome of the
concomitant presence of CVD and COPD. Patients with CVD and COPD present an increased risk
for myocardial infarction, heart failure and hospital admission for acute exacerbation of COPD,
with a negative impact on prognosis. In order to reduce the effect of this negative association, it is
of paramount importance the pharmacological treatment with both cardiovascular and respiratory
drugs, according to current guidelines. Nevertheless, several registries and studies showed that
evidence-based drugs (both cardiovascular and respiratory) are often under administered in this
subset of patients. In this overview, we summarize the available data regarding the use of
cardiovascular drugs (antiplatelet agents, angiotensin converting enzyme inhibitors, beta-blockers,
statins) in COPD patients, with or without concomitant IHD. Furthermore, we report advantages
and disadvantages of respiratory drugs (beta 2 agonists, anticholinergics, corticosteroids)
administration in COPD patients with CVD.
KEYWORDS.
Cardiovascular disease, ischemic heart disease, heart failure, chronic obstructive pulmonary
disease, beta-blockers, ACE-inhibitors, statins, acetylcholine antagonists
3
Introduction
Cardiovascular disease (CVD), including ischemic heart disease (IHD) and heart failure (HF), is
still the first cause of mortality and morbidity in western countries [1]. Chronic obstructive
pulmonary disease (COPD) will soon become the third most common cause of death [2]. Since
CVD and COPD share major risk factors (e.g. cigarette smoking and systemic inflammation), they
are frequently associated [2]. The concomitant presence of CVD and COPD negatively impact on
long-term prognosis [3]. CVD is the first cause of death in COPD patients [2] and, after acute
exacerbation of COPD, we observed a significant increase in the risk of cardiac death and
myocardial infarction (MI) [4]. Similarly, patients admitted to hospital for MI and/or receiving
coronary revascularization (percutaneous or surgical) with concomitant COPD showed a decreased
short- and long-term survival [5-7].
The aim of this overview is to summarize current data regarding cardiovascular drugs (antiplatelet,
angiotensin converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, statin) in
COPD patients with or without CVD, and respiratory drugs (beta 2 agonist, anticholinergic,
corticosteroid) in CVD-COPD patients.
Cardiovascular drugs in COPD patients with or without concomitant CVD.
Antiplatelet agents, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor
blocker (ARB), beta-blockers (BB) and statins are the most commonly prescribed drugs in patients
with CVD [1].

Antiplatelet agents and COPD.
During acute exacerbation (AE) of COPD, the platelet count increased significantly [8].
Thrombocytosis during AECOPD is associated with increased in-hospital and one-year mortality
4
(OR 2.37; 95%CI 1.29-4.34; and 1.53; 95%CI 1.03-2.29, respectively) [9]. We demonstrated that
COPD patients treated with PCI have higher platelet reactivity (PR) if compared to patients without
COPD [10]. Nevertheless, the true clinical impact of antiplatelet agent administration in COPD
patients is still controversial. No data from randomized clinical trials (RCT) is available. All
available findings are post-hoc analyses from registries. In patients admitted to hospital for
AECOPD (n=1343), antiplatelet therapy was associated with a reduced one-year mortality (OR
0.63; 95%CI 0.47-0.85) [9]. Similarly, Ekström et al. showed that antiplatelet agents were
associated with a significant reduction in mortality (HR 0.86; 95%CI 0.75–0.99) [11]. Similar
finding is reported by Short et al. (HR 0.8; 95%CI 0.73-0.88), while other two studies reached to
the opposite conclusion [12-14]. Data regarding new P2Y12 inhibitors (ticagrelor and prasugrel) in
COPD patients are scanty. Recently, Alexopoulus et al. showed that ticagrelor administration was
reduced in COPD patients admitted to hospital for ACS [15]. The limited administration of
ticagrelor may be partially explained by the fact that dyspnoea is one of the most commonly
reported adverse events with ticagrelor [16]. Dyspnoea may occur up to the 20% of patients
receiving ticagrelor (data from RCT) [16]. Two RCTs evaluated the effect of ticagrelor on
respiratory function including healthy subject and patients with asthma or COPD [17]. Ticagrelor
did not alter pulmonary function at rest and during exercise [17]. Although these studies showed no
interference by ticagrelor, physicians should be aware of this potential side effect that can affect up
to 1 out of 5 patients.
In conclusion, there no is evidence for using antiplatelet agents any differently among COPD
patients than in non-COPD patients.

ACE-inhibitors or ARB and COPD.
Angiotensin II (AII) is a powerful vasoconstrictor, inflammatory modulator and cellular growth
factor [18]. AII contributes to the inflammatory response that characterizes COPD [18]. Recently,
Petersen et al. showed that ACE-inhibitor administration was related to lower FEV1 decline in
5
smokers [19]. These findings suggest a possible role for ACE inhibitors in modulating smoking
effects on lung [19]. ACE-inhibitor or ARB administration in COPD patients has been suggested to
manage pulmonary hypertension (PH) and to reduce all-cause mortality (Table 1). Notably, studies
evaluating their effect on PH are mainly small RCT, whereas those on hard clinical endpoints are
post-hoc analyses of observational and retrospective registries (Table 1). No RCT are available
assessing if ACE-inhibitor or ARB reduce mortality or AECOPD in COPD patients (Table 1).
In conclusion, available data are not sufficient to consider ACE-inhibitor or ARB mandatory in
COPD patients. They should be prescribed according concomitant disease (e.g myocardial
infarction) and risk factors (e.g. arterial hypertension).

Beta-blockers and COPD.
Beta-blockers (BB) are considered selective or not according the ability to block only beta 1
adrenergic receptors or both beta 1 and beta 2 adrenergic receptors [20]. Despite the positive effect
of BB in COPD patients with IHD is well established, data on their utilization in daily clinical
practice are not encouraging. Quint et al. reported that less than 40% of eligible patients with MI
and concomitant COPD received BB [21]. Comparably, in patients with HF, the presence of COPD
represents the prevalent reason for BB avoidance [22]. Fisher et al. confirmed that, at the time of
hospital discharge, COPD patients were less likely treated with evidence-based HF medications,
including BB [23]. Cardioselective BB produced no change in FEV1 or respiratory symptoms, as
well as they did not affect the FEV1 treatment response to long-acting beta 2 agonists (LABA) [24].
The use of cardioselective BB in COPD patients has to be encouraged also considering data on
mortality. A metanalysis including studies until 2011, showed a pooled relative risk reduction in
mortality for COPD patients receiving BB (RR 0.69, 95%CI 0.62-0.78) [25]. We reported in Table
2 all studies published subsequently. We did not have RCT evaluating the relationship between BB,
COPD and mortality.
6
In conclusion, BB administration in COPD patients is safe. Cardioselective BB, if indicated, should
be administered in COPD patients, independently to pulmonary comorbidity. Although RCT are
missing, all available studies suggest a mortality reduction in COPD patients assuming BB.

Statins and COPD.
Statins are able to reduce both systemic and pulmonary cytokine driven inflammation by inhibiting
Rho guanosine triphosphatase proteins [26-27]. Simvastatin reverses pulmonary vascular effects of
cigarette smoke, including PH and emphysema [28]. Accordingly, several Authors evaluated the
potential role of statin administration in COPD patients to reduce both all-cause mortality and
AECOPD. The majority of data is derived from registries and retrospective studies (Table 3).
Recently, a worthy RCT has been conducted [29]. The effect of simvastatin 40 mg on occurrence of
AECOPD in patients with moderate to severe COPD has been evaluated in a prospective RCT [29].
The trial did not reached the primary endpoint, failing to demonstrate a change in the incidence of
AECOPD in patients treated with simvastatin as compared to placebo [29]. No effect on hard
cardiac endpoints was reported [29].
In conclusion, the potential benefit of statins in COPD patients has not been demonstrated. If
indicated, statins must be administered to COPD patients, but there is no particular reason to start
statins in COPD patients who do not otherwise have an indication.

Oral anticoagulants and COPD.
COPD emerged as significant predictor of atrial fibrillation/atrial flutter (23% vs. 11%, p<0.01)
after adjustment for all confounding factors [30]. Warfarin is the most commonly prescribed oral
anticoagulant in general population. Retrospective studies reported that anticoagulation treatment is
inadequate in patients with atrial fibrillation and COPD [30-31]. This may be explained by the
higher occurrence of coexisting morbidities and by the higher risk of bleeding complications in
COPD patients [5,32-33]. Nowadays, dabigatran, rivaroxaban and apixan are available in the
7
market [34]. They significantly reduced bleeding complications [34]. Nevertheless, no studies
evaluated if this reduction is confirmed or different in COPD patients. Interestingly, in a substudy
of the ROCKET-AF trial, COPD emerged as independent predictor of major bleeding risk [35].
In conclusion, although COPD patients are at higher risk of bleeding complications, oral
anticoagulants should not be denied if clinically indicated.
Respiratory drugs in patients with concomitant COPD and IHD.
Treatment of COPD is based on long-acting inhaled bronchodilators (anticholinergics or LABA),
inhaled corticosteroids (ICS) or a combination of these agents.

Acetylcholine antagonists.
Ipratropium, oxitropium and tiotropium are the most common anticholinergic drugs [2]. Patients
treated with tiotropium are at higher risk of tachy-arrhythmias (RR 3.70, 95%CI 0.79-17.4) and
atrial tachycardias (RR 7.39, 95%CI 0.92-59.1) [36]. The cardiovascular effects of inhaled
anticholinergics have been evaluated in several studies (both RCT and registries). Some registries
and post-hoc analyses suggested an higher risk of cardiac adverse events in COPD patients
receiving anticholinergics. In view of these concerns, systematic reviews and meta-analyses have
been performed and we reported their results in Table 4. Two main RCT investigated this topic. In
the UPLIFT trial, tiotropium administration was associated with reduced 4-years cardiac mortality
(HR 0.86, 95%CI 0.75-0.99) [37]. To explain the differences, a relationship between formulation
(dry-powder vs. aqueous solution), dose (18 μg vs. 5 μg) and outcome has been suggested.
Accordingly, the TIOSPIR trial has been planned. This was a large-scale (n=17183 patients),
randomized, prospective evaluation of the safety and efficacy of tiotropium Respimat, as compared
with tiotropium HandiHaler [38]. No difference in mortality, exacerbations, causes of death and
major cardiovascular adverse events has been observed [38].
8
In conclusion, the administration of inhaled anticholinergics is safe and effective in COPD patients,
also with concomitant CVD.

Long-acting beta 2 agonists.
The study of the relationship between LABA and cardiac adverse events in patients with
concomitant COPD and CVD showed conflicting results. All data derived from registries. No RCT
are available. Meta-analyses trying to assess the relationship between LABA and cardiac adverse
events are reported in Table 4. A post-hoc analysis of the TORCH study merits a special
consideration [39]. In this analysis it was reported the relationship between salmeterol, fluticasone
(in combination or alone) vs. placebo and the incidence of CV adverse events. The analysis found
that salmeterol alone or in combination with fluticasone did not increase the risk of events (HR
0.89, 95%CI 0.72-1.10) [39].
In conclusion, LABA administration is safe. It showed only minor cardiac side effects and did not
influence long-term mortality.

Inhaled corticosteroids.
ICS are frequently prescribed to control progression and symptoms of COPD [2]. Even ICS cause a
slight increase in gastrointestinal bleedings (HR 1.26, 95%CI 1.02-1.56) [40]. Of note, adequate use
of spacer device reduced significantly these complications (0.26, 95%CI 0.2-0.34) [40]. To evaluate
the safety and effectiveness of ICS in COPD patients, several RCT have been performed. Some
studies have yielded conflicting results regarding survival and risk of MI. Meta-analysis clarifying
this issue are reported in Table 4.
In conclusion, no evidences support a negative relationship between ICS and mortality or cardiac
adverse events in COPD patients with or without concomitant CVD.
9
Conclusions and future perspectives.
Available studies strongly suggest that evidence-based treatment should not be modified in patients
with concomitant presence of COPD and CVD. In daily clinical practice, it is mandatory to obtain
the optimal titration of both cardiovascular and respiratory drugs. Available data strongly suggested
that patients with concomitant COPD and CVD are at higher risk of death and adverse events. This
is confirmed in several registries and trials. The early identification of the comorbidity and a prompt
treatment of each singular disease may significantly improve the quality of life and the prognosis of
these patients. Obviously, we did not have RCT on these topics and the majority of evidences are
extrapolated from registries, observational studies or post-hoc analysis from trials. Nevertheless, all
findings are consistent and, awaiting further data from specific RCT, any effort should be
considered to identify these patients and to optimize their pharmacological treatment.
10
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17
Table 1: Main studies evaluating the role of ACE inhibitors or ARBs in COPD patients.
Patients
COPD diagnosis
(n)
Studies on all-cause mortality
References
Mortensen et
al. [41]
11212
Previous
diagnosis of
COPD (ICD 9)
Mancini et al.
[42]
5853 cases
116871
controls
Previous
prescription of
LABA, ICS,
ACh.
Ekström et al.
[11]
2249
Physician
diagnosed COPD
Zeng et al
220
Spirometry
[43]
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[44]
15
Clinical COPD
diagnosis
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36
Clinical COPD
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[46]
40
Clinical COPD
diagnosis
Study population
characteristics
Design
Hospitalization for
AECOPD and
treated with LABA,
ICS, ACh
Retrospective
Cohort high CV risk
(previous MI and/or
CR); cohort low CV
risk (absence of
previous factors)
Patients starting long
term oxygen therapy
for COPD
Hospitalization in
geriatric department
COPD patients
hospitalized for right
heart failure
Genotyping of ACE
gene
Patients with both
COPD and
pulmonary artery
hypertension
Main findings
Reduction 90-days mortality (OR 0.55, 95%CI 0.46–0.66)
Retrospective
ARBs reduce mortality:
-low CV risk and receiving ICS (HR 0.63, 95%CI 0.44-0.89)
-low CV risk and not receiving ICS (HR 0.62; 95%CI 0.44-0.87)
-high CV risk and receiving ICS (HR 0.61; 95%CI 0.51-0.73)
-high CV risk and not receiving ICS (HR 0.53; 95%CI 0.44-0.64).
ACE-Is do not reduce mortality in high CV risk patients
ACE-Is reduce mortality in low CV risk patients:
-receiving ICS (HR 0.74; 95%CI 0.65-0.85)
- not receiving ICS (HR 0.68; 95%CI 0.60-0.77)
Prospective
observational
multicenter study
No reduction in mortality.
Retrospective
ACE-Is reduce mortality (HR 0.15; 95% CI 0.03-0.68)
ARBs reduce mortality (HR 0.38; 95% CI 0.18-0.82)
RCT single blind
Captopril does not reduce pulmonary vascular resistance.
RCT double blind
Captopril reduces mPAP in ID/II carriers.
RCT double blind
Losartan does not influence trans-tricuspid pressure gradient.
COPD: chronic obstructive pulmonary disease. ACE-I: angiotensin converting enzyme inhibitors. ARB: angiotensin receptor blocker. AECOPD:
acute exacerbation of COPD. LABA: long-acting β2 agonists. ICS: inhaled corticosteroids. Ach: inhaled anticholinergics. Y: yes. OR: odds ratio.
CI: confidence interval. CV: cardiovascular. MI: myocardial infarction.. CR: coronary revascularization. HR: hazard risk. N: no. NS: not specified.
PH: pulmonary hypertension. mPAP: mean pulmonary artery pressure. RCT: randomized clinical trial.
18
Table 2: Main studies evaluating the role of beta-blockers in COPD patients.
References
Patients
(n)
Rutten et al
[47]
2230
Short et al. [12]
5977
GOLD criteria
Zeng et al. [43]
220
Spirometric
data
Quint et al.
[21]
1063
Angeloni et al
[48]
Lee et al. [49]
COPD
diagnosis
Age ≥45 years
and incident or
prevalent
diagnosis of
COPD (ICD9
and 10)
Study population
characteristics
Design
Main findings
Hospitalization for
AECOPD
Observational cohort
study
Reduction of mortality (HR 0.68; 95%CI 0.5-0.8)
Reduction of AECOPD (0.71; 95%CI 0.6-0.8)
Reduction of mortality in BB and LABA users (HR 0.6; 95%CI 0.5-0.8)
Hospitalization for
COPD (ICD9 and 10)
Hospital admission in
Geriatrics
departement
Retrospective cohort
study
Reduction in mortality (HR 0.2; 95%CI 0.2-0.4).
Retrospective cohort
study
No relation with mortality.
Previous
diagnosis of
COPD
COPD patients
experiencing first MI
Population based cohort
study
Reduction of mortality for BB chronically users (HR 0.59, 95%CI 0.4-0.7)
Reduction of mortality for new prescribed BB (HR 0.5, 95%CI 0.3-0.7)
388
GOLD criteria
COPD patients
undergoing CABG
Propensity-matched
cohorts with
prospective follow-up
Increased survival rate in BB users (91±3% vs. 80±4%)
No variation in AECOPD.
1062
Previous
diagnosis of
COPD (ICD9
and 10)
Outpatient or hospital
diagnosis within 12
months
Population based cohort
study
No difference in all-cause mortality.
COPD: chronic obstructive pulmonary disease. GOLD: global initiative for chronic obstructive lung disease. ICD: international classification of
disease. HR: hazard risk. CI: confidence interval. AECOPD: acute exacerbation of chronic obstructive pulmonary disease. BB: beta-blockers.
LABA: long-acting β2 agonists. CABG: coronary artery bypass graft.
19
Table 3: Main studies evaluating the role of statins in COPD patients.
References
Patients
(n)
COPD diagnosis
Study population
characteristics
Mancini et al.
[42]
5853
cases
116871
controls
Previous
prescription of
LABA, ICS, ACh.
Soyseth et al.
[13]
854
Mortensen et
al. [41]
11212
Sheng et al.
[14]
Lawes et al.
[50]
Ekström et
al. [11]
Lahousse et
al. [51]
1717
1687
2249
363
cases vs.
2345
controls
Previous
diagnosis of
COPD (ICD 9
and 10)
Previous
diagnosis of
COPD (ICD 9)
Previous diagnosis
of COPD (ICD 9
and 10)
Diagnosis of
COPD (ICD 10)
Physician
diagnosed COPD
Spirometric data
Design
Main findings
Cohort high CV risk (previous
MI and/or CR); cohort low CV
risk (absence of previous
factors)
Retrospective
Significant reduction in mortality:
-high CV risk receiving ICS (HR 0.5; 95%CI 0.4-0.62)
-high CV risk not receiving ICS (HR 0.53; 95%CI 0.45-0.65)
-low CV risk receiving ICS (HR 0.53; 95%CI 0.44-0.64)
-low CV risk not receiving ICS (HR 0.49; 95%CI 0.41-0.58)
Hospitalization for AECOPD
Retrospective cohort study
Reduction in mortality (HR 0.57; 95%CI 0.38-0.87)
Hospitalization for AECOPD
Retrospective
Reduction in 90-days mortality (OR 0.51, 95%CI 0.4–0.64)
Outpatients
Retrospective cohort study
Primary prevention:
-all-cause mortality reduction (HR 0.6; 95%CI 0.43-0.85)
Secondary prevention:
-all-cause mortality reduction (HR 0.58; 95%CI 0.35-0.97)
-CV mortality reduction (HR 0.32, 95%CI 0.13-0.7)
Outpatients
Cohort study
All-cause mortality reduction (HR 0.69; 95%CI 0.58- 0.84)
Patients starting long term
oxygen therapy for COPD
Prospective multicenter
study
Nested case-control
analysis from a
population-based cohort
study
Outpatients
No significant reduction in mortality.
Reduction in mortality (RR 39; 95%CI 0.38-0.99)
Patients with CRP>3 mg/L: RR 78% (95%CI 0.06-0.74)
COPD: chronic obstructive pulmonary disease. LABA: long-acting β2 agonists. ICS: inhaled corticosteroids. ACh: inhaled anti-cholinergic.
AECOPD: acute exacerbation of COPD. HR: hazard ratio. CI: confidence interval. CV: cardiovascular. GOLD: global initiative for chronic
obstructive lung disease. ICD: international classification of disease. CRP: C-reactive protein. RR: relative risk.
20
Table 4: Inhaled respiratory drugs and mortality/cardiac adverse events in COPD patients (data from meta-analyses).
References
Patients (no.)
studies type
studies
included
drug
Main findings
Salpeter et al.
[52]
6855
RCT
20
LABA vs.
placebo
Sin et al. [53]
5085
RCT
7
ICS vs. placebo
Salpeter et al.
[54]
15276
RCT
22
B2A vs.
anticholinegic
vs. placebo
Increased risk of CV adverse event (RR 2.5; 95%CI 1.6-4)
No difference in MACE
ICS reduced all-cause mortality by about 25%
Mortality reduction in woman (HR 0.6, 95% 0.39-0.91)
Mortality reduction in former smokers (HR 0.6, 95%CI 0.36-0.93)
Anticholinergic reduces severe AECOPD (RR 0.7, 95%CI 0.5-0.9)
Anticholinergic reduces respiratory death (RR 0.3, 95%CI 0.1-0.8)
B2A did not affect severe AECOPD
B2A increases respiratory death (RR 3, 95%CI 1.7-5.5)
13
ICS vs. placebo
No difference in overall mortality
11
ICS vs. placebo
No difference in 1-year mortality
Gartlehner et
al. [55]
Drummond et
al [56]
4300
14426
Double
blinded RCT
Double blind
RCT
No difference in CV adverse events
No increase in CV mortality
No increase in nonfatal MI
No increase in nonfatal stroke
In RCT, no effect on MI
In RCT, no effect on CV death
In RCT, no effect on mortality
In COS, reduction of CV death (RR 0.79, 95%CI 0.72-0.86)
In COS, no effect on mortality
18111
RCT
19
inhaled
tiotropium vs.
placebo
Loke et al.
[58]
23396
RCT and
controlled
observational
studies
-
ICS vs. placebo
Singh et al.
[59]
6522
parallel group
RCT
5
tiotropium
inhaler vs.
placebo
Increased all-cause mortality (RR 1.52, 95%CI 1.06-2.16)
Increased CV mortality (RR 2.05, 95%CI 1.06-3.99)
tiotroprium vs.
LABA vs. ICS
Soft mist inhaler vs. placebo on death (OR 1.5, 95%CI 1.1-2.2)
Soft mist inhaler vs. dry-powder on death(OR 1.7, 95%CI 1.1-2.4)
Soft mist inhaler vs. LABA on death (OR 1.6; 95%CI 1.1-2.5)
Soft mist inhaler vs. LABA-ICS on death (OR 1.9; 95%CI 1.3-2.8)
LABA-ICS was associated with the lowest risk of death
No excess risk was noted for tiotropium dry powder or LABA
Rodrigo et al.
[57]
Dong et al.
[60]
52516
RCT
42
21
COPD: chronic obstructive pulmonary disease. RCT: randomized clinical trials. LABA: long-acting β2 agonists. CV: cardiovascular. MI:
myocardial infarction. MTC: mixed treatment comparison. n: number. RR: relative risk. OR: odds ratio. HR: hazard risk. CI: confidence interval.
AECOPD: acute exacerbation of chronic obstructive pulmonary disease.. ICS: inhaled corticosteroids. MACE: major adverse cardiac event
(ventricular arrhythmias, myocardial infarction and sudden death). COS: controlled observational studies