Full Text - European Heart Journal

European Heart Journal – Cardiovascular Pharmacotherapy (2015) 1, 205–211
doi:10.1093/ehjcvp/pvv019
REVIEW
Disease management
Overview of the pharmacological challenges facing
physicians in the management of patients with
concomitant cardiovascular disease and chronic
obstructive pulmonary disease
Gianluca Campo 1,2, Rita Pavasini 1, Simone Biscaglia 1, Marco Contoli 3,
and Claudio Ceconi 1,2*
1
Cardiovascular Institute, Azienda Ospedaliero-Universitaria S.Anna, Cona (FE), Italy; 2LTTA Center, Ferrara, Italy; and 3Research Centre on Asthma and COPD, Section of Internal
and Cardio-Respiratory Medicine, University of Ferrara, Ferrara, Italy
Received 8 February 2015; revised 31 March 2015; accepted 1 April 2015; online publish-ahead-of-print 6 April 2015
Cardiovascular disease (CVD), including ischaemic 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). Cardiovascular
disease and COPD association is increasing overtime. Several registries clearly showed a negative impact on the clinical outcome of the concomitant presence of CVD and COPD. Patients with CVD and COPD present an increased risk for myocardial infarction, HF, and hospital admission
for acute exacerbation of COPD, with a negative impact on prognosis. 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, b-blockers, and statins) in COPD patients, with or without concomitant IHD. Furthermore, we report advantages and disadvantages of
respiratory drugs (b2 agonists, anti-cholinergics, and corticosteroids) administration in COPD patients with CVD.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
cardiovascular disease † ischaemic heart disease † heart failure † chronic obstructive pulmonary disease †
b-blockers † ACE inhibitors † statins † acetylcholine antagonists
Introduction
Cardiovascular disease (CVD), including ischaemic 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
impacts on long-term prognosis.3 Cardiovascular disease is the first
cause of death in COPD patients2 and, after acute exacerbation
(AE) 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
(ACE) inhibitor, angiotensin receptor blocker (ARB), b-blocker
(BB), and statin] in COPD patients with or without CVD, and respiratory drugs (b2 agonist, anti-cholinergic, and corticosteroid) in CVD –
COPD patients.
* Corresponding author. Tel: +39 0532237227, Fax: +39 0532241885, Email: ccncld@unife.it; ceconi1@tin.it; claudio.ceconi@unife.it
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com
206
G. Campo et al.
Cardiovascular drugs in chronic
obstructive pulmonary disease
patients with or without
concomitant cardiovascular
disease
Antiplatelet agents, ACE inhibitors or ARB, BB, and statins are the
most commonly prescribed drugs in patients with CVD.1
Antiplatelet agents and chronic
obstructive pulmonary disease
During AE of COPD, the platelet count increased significantly.8
Thrombocytosis during AECOPD is associated with increased
in-hospital and 1-year mortality (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) when compared with 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
(RCTs) is available. All available findings are post hoc analyses from
registries. In patients admitted to hospital for AECOPD (n ¼ 1343),
antiplatelet therapy was associated with a reduced 1-year mortality
(OR 0.63; 95% CI 0.47–0.85).9 Similarly, Ekstro¨m 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 one
of five patients.
In conclusion, there is no evidence for using antiplatelet agents any
differently among COPD patients than in non-COPD patients.
Table 1 Main studies evaluating the role of angiotensin converting enzyme inhibitors or angiotensin receptor blockers in
chronic obstructive pulmonary disease patients
References
Patients (n)
COPD diagnosis
Study population
characteristics
Design
Main findings
...............................................................................................................................................................................
Studies on all-cause mortality
Mortensen
et al. 20
11 212
Previous diagnosis of
COPD (ICD 9)
Hospitalization for AECOPD
and treated with LABA,
ICS, ACh
Retrospective
Reduction 90 days mortality (OR 0.55, 95% CI 0.46 –0.66)
Mancini
et al. 21
5853 cases
116 871
controls
Previous
prescription
of LABA, ICS,
ACh.
Cohort high CV risk
(previous MI and/or
CR); cohort low
CV risk (absence of
previous factors)
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)
Ekstro¨m
et al. 11
2249
Physician diagnosed
COPD
Patients starting long-term
oxygen therapy for COPD
Prospective
observational
multicentre
study
No reduction in mortality.
Zeng et al. 22
220
Spirometry
Hospitalization in geriatric
department
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)
...............................................................................................................................................................................
Studies on pulmonary hypertension
Zielinski
et al. 23
Kanazawa
et al. 24
Morrell
et al. 25
15
Clinical COPD
diagnosis
36
40
COPD patients hospitalized
for right HF
RCT single blind
Captopril does not reduce pulmonary vascular resistance
Clinical COPD
diagnosis
Genotyping of ACE gene
RCT double
blind
Captopril reduces mPAP in ID/II carriers.
Clinical COPD
diagnosis
Patients with both COPD and
pulmonary artery
hypertension
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 b2 agonists; ICS, inhaled corticosteroids; Ach, inhaled anti-cholinergics; 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.
207
CV and respiratory drugs in COPD-CVD patients
Angiotensin II is a powerful vasoconstrictor, inflammatory modulator,
and cellular growth factor.18 Angiotensin II 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 smokers.19 These findings suggest a possible role for ACE inhibitors in modulating smoking effects on lung.19 Angiotensin converting
enzyme 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. MI) and risk factors
(e.g. arterial hypertension).
receptors.26 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 ,40% of eligible patients with MI and concomitant COPD received BB.27 Comparably, in patients with HF, the presence of COPD represents the
prevalent reason for BB avoidance.28 Fisher et al. confirmed that, at
the time of hospital discharge, COPD patients were less likely
treated with evidence-based HF medications, including BB.29 Cardioselective BB produced no change in FEV1 or respiratory symptoms,
as well as they did not affect the FEV1 treatment response to longacting b2 agonists (LABA).30 The use of cardioselective BB in
COPD patients has to be encouraged also considering data on mortality. A meta-analysis 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).31 We reported in Table 2 all studies
published subsequently. We did not have RCT evaluating the relationship between BB, COPD, and mortality.
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.
b-Blockers and chronic obstructive
pulmonary disease
Statins and chronic obstructive pulmonary
disease
b-Blockers are considered selective or not according the ability to
block only b1 adrenergic receptors or both b1 and b2 adrenergic
Statins are able to reduce both systemic and pulmonary cytokinedriven inflammation by inhibiting Rho guanosine triphosphatase
Angiotensin converting enzyme inhibitors
or angiotensin receptor blocker and
chronic obstructive pulmonary disease
Table 2
Main studies evaluating the role of b-blockers in COPD patients
References
Patients (n)
COPD diagnosis
Study population
characteristics
Design
Main findings
...............................................................................................................................................................................
Rutten et al. 32
2230
Age ≥ 45 years and incident
or prevalent diagnosis of
COPD (ICD 9 and 10)
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)
Short et al. 12
5977
GOLD criteria
Hospitalization for
COPD (ICD 9 and 10)
Retrospective cohort study
Reduction in mortality (HR
0.2; 95% CI 0.2–0.4)
Zeng et al. 22
220
Spirometric data
Hospital admission in
Geriatrics department
Retrospective cohort study
No relation with mortality
Quint et al. 27
1063
Previous diagnosis of
COPD
COPD patients
experiencing first MI
Population-based cohort
study
Angeloni
et al. 33
388
GOLD criteria
COPD patients
undergoing CABG
Propensity-matched cohorts
with prospective follow-up
Lee et al. 34
1062
Previous diagnosis of COPD
(ICD 9 and 10)
Outpatient or hospital
diagnosis within
12 months
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)
Increased survival rate in BB
users (91 + 3% vs.
80 + 4%)
No variation in AECOPD
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, b-blockers; LABA, long-acting b2 agonists; CABG, coronary artery bypass graft.
208
G. Campo et al.
proteins.35,36 Simvastatin reverses pulmonary vascular effects of cigarette smoke, including PH and emphysema.37 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 are derived from registries and retrospective
studies (Table 3). Recently, a worthy RCT has been conducted.38
The effect of simvastatin 40 mg on occurrence of AECOPD in
patients with moderate-to-severe COPD has been evaluated in a
prospective RCT.38 The trial did not reached the primary endpoint,
failing to demonstrate a change in the incidence of AECOPD in
patients treated with simvastatin when compared with placebo.38
No effect on hard cardiac endpoints was reported.38
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.
Table 3
Oral anti-coagulants and chronic
obstructive pulmonary disease
Chronic obstructive pulmonary disease emerged as significant
predictor of atrial fibrillation/atrial flutter (23 vs. 11%, P , 0.01)
after adjustment for all confounding factors.41 Warfarin is the most
commonly prescribed oral anti-coagulant in general population.
Retrospective studies reported that anti-coagulation treatment is
inadequate in patients with atrial fibrillation and COPD.41,42 This
may be explained by the higher occurrence of coexisting morbidities
and by the higher risk of bleeding complications in COPD
patients.5,43,44 Nowadays, dabigatran, rivaroxaban, and apixan are
available in the market.45 They significantly reduced bleeding complications.45 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.46
Main studies evaluating the role of statins in chronic obstructive pulmonary disease patients
References
Patients (n)
COPD diagnosis
Study population
characteristics
Design
Main findings
...............................................................................................................................................................................
Mancini
et al. 21
5853 cases
116 871
controls
Previous
prescription of
LABA, ICS, ACh
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)
Soyseth
et al. 13
854
Hospitalization for
AECOPD
Retrospective
cohort study
Reduction in mortality (HR 0.57; 95% CI 0.38–0.87)
Mortensen
et al. 20
Sheng et al. 14
11212
Previous diagnosis
of COPD (ICD
9 and 10)
Previous diagnosis of
COPD (ICD 9)
Previous diagnosis
of COPD (ICD
9 and 10)
Hospitalization for
AECOPD
Outpatients
Retrospective
Reduction in 90 days mortality (OR 0.51, 95%
CI 0.4–0.64)
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%
I 0.13– 0.7)
Lawes et al. 39
1687
Diagnosis of COPD
(ICD 10)
Outpatients
Cohort study
All-cause mortality reduction (HR 0.69; 95%
CI 0.58– 0.84)
Ekstro¨m
et al. 11
2249
Physician diagnosed
COPD
Patients starting
long-term oxygen
therapy for
COPD
Prospective
multicentre study
No significant reduction in mortality
Lahousse
et al. 40
363 cases vs.
2345
controls
Spirometric data
Outpatients
Nested case–
control analysis
from a
population-based
cohort study
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)
1717
Retrospective
cohort study
COPD, chronic obstructive pulmonary disease; LABA, long-acting b2 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.
209
CV and respiratory drugs in COPD-CVD patients
In conclusion, although COPD patients are at higher risk of bleeding complications, oral anti-coagulants should not be denied if clinically indicated.
Respiratory drugs in patients with
concomitant chronic obstructive
pulmonary disease and ischaemic
heart disease
Treatment of COPD is based on long-acting inhaled bronchodilators
(anti-cholinergics 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).47 The cardiovascular
effects of inhaled anti-cholinergics have been evaluated in several
studies (both RCT and registries). Some registries and post hoc analyses suggested a higher risk of cardiac adverse events in COPD
patients receiving anti-cholinergics. 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).48 To explain the differences, a relationship between formulation (dry-powder vs. aqueous solution), dose (18 vs. 5 mg), and the
outcome has been suggested. Accordingly, the TIOSPIR trial has
been planned. This was a large-scale (n ¼ 17183 patients), randomized, prospective evaluation of the safety and efficacy of tiotropium
Respimat, when compared with tiotropium HandiHaler.49 No difference in mortality, exacerbations, causes of death and major cardiovascular adverse events has been observed.49
In conclusion, the administration of inhaled anti-cholinergics is safe
and effective in COPD patients, also with concomitant CVD.
Table 4 Inhaled respiratory drugs and mortality/cardiac adverse events in chronic obstructive pulmonary disease
patients (data from meta-analyses)
References
Patients
(no.)
Studies type
Studies
included
Drug
Salpeter
et al. 50
6855
Sin et al. 51
Main findings
RCT
20
LABA vs. placebo
Increased risk of CV adverse event (RR 2.5; 95% CI 1.6– 4)
No difference in MACE
5085
RCT
7
ICS vs. placebo
Salpeter
et al. 52
15276
RCT
22
B2A vs.
anti-cholinergic
vs. placebo
ICS reduced all-cause mortality by 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)
Anti-cholinergic reduces severe AECOPD (RR 0.7, 95% CI 0.5– 0.9)
Anti-cholinergic 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)
Gartlehner
et al. 53
4300
Double-blinded
RCT
13
ICS vs. placebo
No difference in overall mortality
Drummond
et al. 54
14 426
Double-blinded
RCT
11
ICS vs. placebo
No difference in 1-year mortality
Rodrigo
et al. 55
18 111
RCT
19
Inhaled
tiotropium vs.
placebo
No difference in CV adverse events
No increase in CV mortality
No increase in nonfatal MI
No increase in nonfatal stroke
Loke et al. 56
23 396
RCT and controlled
observational
studies
–
ICS vs. placebo
Singh et al. 57
6522
Parallel group RCT
5
Tiotropium
inhaler vs.
placebo
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
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)
Dong et al. 58
52 516
RCT
42
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
COPD, chronic obstructive pulmonary disease; RCT, randomized clinical trials; LABA, long-acting b2 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.
210
Long-acting b2 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.59 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).59
In conclusion, LABA administration is safe. It showed only minor
cardiac side effects and did not influence long-term mortality.
Inhaled corticosteroids
Inhaled corticosteroids 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).60 Of note,
the adequate use of spacer device reduced significantly these complications (0.26, 95% CI 0.2 –0.34).60 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.
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.
Conflict of interest: none declared.
References
1. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).
Guidelines on myocardial revascularization. Eur Heart J 2014;35:2541 –2619.
2. Global Initiative for chronic obstructive lung disease – global strategy for the diagnosis, management and prevention for chronic obstructive pulmonary disease.
Updated 2014.
3. Maclay D, MacNee W. Cardiovascular disease in COPD. Chest 2013;143:798 –807.
G. Campo et al.
4. Donaldson GC, Hurst JR, Smith CJ, Hubbard RB, Wedzicha JA. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010;137:
1091 –1097.
5. Campo G, Guastaroba P, Marzocchi A, Santarelli A, Varani E, Vignali L, Sangiorgio P,
Tondi S, Serenelli C, De Palma R, Saia F. Impact of COPD on long-term outcome
after ST-segment elevation myocardial infarction receiving primary percutaneous
coronary intervention. Chest 2013;144:750 –757.
6. Wakabayashi K, Gonzalez MA, Delhaye C, Ben-Dor I, Maluenda G, Collins SD, Syed AI,
Gaglia MA Jr, Torguson R, Xue Z, Suddath WO, Satler LF, Kent KM, Lindsay J,
Pichard AD, Waksman R. Impact of chronic obstructive pulmonary disease on acutephase outcome of myocardial infarction. Am J Cardiol 2010;106:305–309.
7. Berger JS, Sanborn TA, Sherman W, Brown DL. Effect of chronic obstructive pulmonary disease on survival of patients with coronary heart disease having percutaneous coronary intervention. Am J Cardiol 2004;94:649 – 651.
8. Wang RT, Li JY, Cao ZG, Li Y. Mean platelet volume is decreased during an acute
exacerbation of chronic obstructive pulmonary disease. Respirology 2013;18:
1244 –1248.
9. Harrison MT, Short P, Williamson PA, Singanayagam A, Chalmers JD, Schembri S.
Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy?
Thorax 2014;69:609 –615.
10. Campo G, Pavasini R, Pollina A, Tebaldi M, Ferrari R. On-treatment platelet reactivity
in patients with chronic obstructive pulmonary disease undergoing percutaneous
coronary intervention. Thorax 2014;69:80 –81.
11. Ekstro¨m MP, Hermansson AB, Stro¨m KE. Effects of cardiovascular drugs on mortality
in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:
715 –720.
12. Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. Effect of beta blockers in
treatment of chronic obstructive pulmonary disease: a retrospective cohort study.
BMJ 2011;342:d2549.
13. Søyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with reduced mortality in COPD. Eur Respir J 2007;29:279 –283.
14. Sheng X, Murphy MJ, MacDonald TM, Schembri S, Simpson W, Winter J, Winter JH,
Wei L. Effect of statins on total cholesterol concentrations, cardiovascular morbidity, and all-cause mortality in chronic obstructive pulmonary disease: a populationbased cohort study. Clin Ther 2012;34:374 –384.
15. Alexopoulos D, Xanthopoulou I, Deftereos S, Sitafidis G, Kanakakis I, Hamilos M,
Vavuranakis M, Davlouros P, Ntalas I, Angelidis C, Hahalis G, Triposkiadis F, Vardas P,
Stefanadis C, Goudevenos JA. Contraindications/special warnings and precautions
for use of contemporary oral antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Circ J 2014;78:180–187.
16. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J,
Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG,
Storey RF, Harrington RA. Ticagrelor versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med 2009;361:1045 –1057.
17. Butler K, Maya J, Teng R. Effect of ticagrelor on pulmonary function in healthy elderly
volunteers and asthma or chronic obstructive pulmonary disease patients. Curr Med
Res Opin 2013;29:569 –577.
18. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med 2000;343:268 –280.
19. Petersen H, Sood A, Meek PM, Shen X, Cheng Y, Belinsky SA, Owen CA, Washko G,
Pinto-Plata V, Kelly E, Celli B, Tesfaigzi Y. Rapid lung function decline in smokers is a
risk factor for COPD and is attenuated by angiotensin-converting enzyme inhibitor
use. Chest 2014;145:695 –703.
20. Mortensen EM, Copeland LA, Pugh MJ, Restrepo MI, de Molina RM, Nakashima B,
Anzueto A. Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respir Res 2009;10:45 –50.
21. Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction
of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and
angiotensin receptor blockers in patients with chronic obstructive pulmonary
disease. J Am Coll Cardiol 2006;47:2554 –2560.
22. Zeng LH, Hu YX, Liu L, Zhang M, Cui H. Impact of beta2-agonists, beta-blockers, and
their combination on cardiac function in elderly male patients with chronic obstructive pulmonary disease. Clin Interv Aging 2013;8:1157 –1165.
23. Zielinski J, Hawrylkiewicz I, Gorecka D, Gluskowski J, Koscinska M. Captopril effects
on pulmonary and systemic hemodynamics in chronic cor pulmonale. Chest 1986;90:
562 –565.
24. Kanazawa H, Hirata K, Yoshikawa J. Effects of captopril administration on pulmonary
haemodynamics and tissue oxygenation during exercise in ACE gene subtypes in
patients with COPD: a preliminary study. Thorax 2003;58:629 – 631.
25. Morrell N, Higham M, Phillips P, Shakur B, Robinson P, Beddoes R. Pilot study of
losartan for pulmonary hypertension in chronic obstructive pulmonary disease.
Respir Res 2005;6:88 –92.
26. Pavasini R, Spitalieri G, Marcantoni M, Campo G, Ferrari R. b-Blockers across the
cardiovascular continuum: cardioprotection and cardioselectivity. Hot Topics in
Cardiology 2014;36:1 –20.
27. Quint JK, Herrett E, Bhaskaran K, Timmis A, Hemingway H, Wedzicha JA, Smeeth L.
Effect of b blockers on mortality after myocardial infarction in adults with COPD:
211
CV and respiratory drugs in COPD-CVD patients
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
population based cohort study of UK electronic healthcare records. BMJ 2013;347:
f6650.
Parissis JT, Andreoli C, Kadoglou N, Ikonomidis I, Farmakis D, Dimopoulou I,
Iliodromitis E, Anastasiou-Nana M, Lainscak M, Ambrosio G, Mebazaa A,
Filippatos G, Follath F. Differences in clinical characteristics, management and shortterm outcome between acute heart failure patients chronic obstructive pulmonary
disease and those without this co-morbidity. Clin Res Cardiol 2014;103:733–741.
Fisher K, Stefan M, Darling C, Lessard D, Goldberg RJ. Impact of COPD on the mortality and treatment of patients hospitalized with acute decompensated heart failure.
Chest 2015;147:637 –645.
Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;4:CD003566.
Etminan M, Jafari S, Carleton B, FitzGerald JM. Beta-blocker use and COPD mortality: a systematic review and meta-analysis. BMC Pulm Med 2012;12:48.
Rutten FH, Zuithoff NPA, Hak E, Grobbee DE, Hoes AW. Beta-blockers may reduce
mortality and risk of exacerbations of patients with chronic obstructive pulmonary
disease. Arch Intern Med 2010;170:880–887.
Angeloni E, Melina G, Roscitano A, Refice S, Capuano F, Lechiancole A, Comito C,
Benedetto U, Sinatra R. b-Blockers improve survival of patients with chronic obstructive pulmonary disease after coronary artery bypass grafting. Ann Thorac Surg
2013;95:525 –531.
Lee DS, Markwardt S, McAvay GJ, Gross CP, Goeres LM, Han L, Peduzzi P, Lin H,
Dodson JA, Tinetti ME. Effect of b-blockers on cardiac and pulmonary events and
death in older adults with cardiovascular disease and chronic obstructive pulmonary
disease. Med Care 2014;52(Suppl. 3):S45 – S51.
Young RP, Hopkins R, Eaton TE. Pharmacological actions of statins: potential utility in
COPD. Eur Respir Rev 2009;18:222 –232.
Morimoto K, Janssen WJ, Fessler MB, McPhillips KA, Borges VM, Bowler RP,
Xiao YQ, Kench JA, Henson PM, Vandivier RW. Lovastatin enhances clearance of
apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary
disease. J Immunol 2006;176:7657 –7665.
Wright JL, Zhou S, Preobrazhenska O, Marshall C, Sin DD, Laher I, Golbidi S,
Churg AM. Statin reverses smoke-induced pulmonary hypertension and prevents
emphysema but not airway remodeling. Am J Respir Crit Care Med 2011;183:50 –58.
Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, Cooper JA Jr,
Curtis JL, Dransfield MT, Han MK, Make B, Marchetti N, Martinez FJ,
Niewoehner DE, Scanlon PD, Sciurba FC, Scharf SM, Sin DD, Voelker H,
Washko GR, Woodruff PG, Lazarus SC. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med 2014;370:2201 –2210.
Lawes CM, Thornley S, Young R, Hopkins R, Marshall R, Chan WC, Jackson G. Statin
use in COPD patients is associated with a reduction in mortality: a national cohort
study. Prim Care Respir J 2012;21:35 –40.
Lahousse L, Loth DW, Joos GF, Hofman A, Leufkens HG, Brusselle GG, Stricker BH.
Statins, systemic inflammation and risk of death in COPD: the Rotterdam Study. Pulm
Pharmacol Ther 2013;26:212 –217.
Konecny T, Park JY, Somers KR, Konecny D, Orban M, Soucek F, Parker KO,
Scanlon PD, Asirvatham SJ, Brady PA, Rihal CS. Relation of chronic obstructive pulmonary disease to atrial and ventricular arrhythmias. Am J Cardiol 2014;114:272–277.
Huang B, Yang Y, Zhu J, Liang Y, Zhang H, Tian L, Shao X, Wang J. Clinical characteristics and prognostic significance of chronic obstructive pulmonary disease in
patients with atrial fibrillation: results from a multicenter atrial fibrillation registry
study. J Am Med Dir Assoc 2014;15:576–581.
Lahousse L, Vernooij MW, Darweesh SK, Akoudad S, Loth DW, Joos GF, Hofman A,
Stricker BH, Ikram MA, Brusselle GG. Chronic obstructive pulmonary disease and
cerebral microbleeds. The Rotterdam Study. Am J Respir Crit Care Med 2013;188:
783 –788.
44. Huang KW, Luo JC, Leu HB, Lin HC, Lee FY, Chan WL, Lin SJ, Chen JW, Chang FY.
Chronic obstructive pulmonary disease: an independent risk factor for peptic ulcer
bleeding: a nationwide population-based study. Aliment Pharmacol Ther 2012;35:
796 –802.
45. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P,
Camm AJ, Kirchhof P. EHRA practical guide on the use of new oral anticoagulants
in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J
2013;34:2094 – 2106.
46. Goodman SG, Wojdyla DM, Piccini JP, White HD, Paolini JF, Nessel CC,
Berkowitz SD, Mahaffey KW, Patel MR, Sherwood MW, Becker RC, Halperin JL,
Hacke W, Singer DE, Hankey GJ, Breithardt G, Fox KA, Califf RM. Factors associated
with major bleeding events: insights from the ROCKETAF trial. J Am Coll Cardiol 2014;
63:891–900.
47. Division of Pulmonary-Allergy Drugs Advisory Committee and Office of Surveillance
and Epidemiology, US Food and Drug Administration. FDA Briefing Document, 2009.
48. Celli B, Decramer M, Kesten S, Liu D, Mehra S, Tashkin DP; UPLIFT Study Investigators. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:948 –955.
49. Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, Dusser D, Joseph E,
Kattenbeck S, Koenen-Bergmann M, Pledger G, Calverley P. Tiotropium respimat
inhaler and the risk of death in COPD. N Engl J Med 2013;369:1491 –1501.
50. Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in
patients with asthma and COPD: a meta-analysis. Chest 2004;125:2309 –2321.
51. Sin DD, Wu L, Anderson JA, Anthonisen NR, Buist AS, Burge PS, Calverley PM,
Connett JE, Lindmark B, Pauwels RA, Postma DS, Soriano JB, Szafranski W,
Vestbo J. Inhaled corticosteroids and mortality in chronic obstructive pulmonary
disease. Thorax 2005;60:992 – 997.
52. Salpeter SR, Buckley NS, Salpeter EE. Meta-analysis: anticholinergics, but not
beta-agonists, reduce severe exacerbations and respiratory mortality in COPD.
J Gen Intern Med 2006;21:1011 –1019.
53. Gartlehner G, Hansen RA, Carson SS, Lohr KN. Efficacy and safety of inhaled corticosteroids in patients with COPD: a systematic review and meta-analysis of health
outcomes. Ann Fam Med 2006;4:253 –262.
54. Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic
review and meta-analysis. JAMA 2008;26:2407 –2416.
55. Rodrigo GJ, Castro-Rodriguez JA, Nannini LJ, Plaza Moral V, Schiavi EA. Tiotropium
and risk for fatal and nonfatal cardiovascular events in patients with chronic obstructive pulmonary disease: systematic review with meta-analysis. Respir Med 2009;103:
1421 –1429.
56. Loke YK, Kwok CS, Singh S. Risk of myocardial infarction and cardiovascular death
associated with inhaled corticosteroids in COPD. Eur Respir J 2010;35:1003 –1021.
57. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist
inhaler in patients with chronic obstructive pulmonary disease: systematic review
and meta-analysis of randomised controlled trials. BMJ 2011;342:d3215.
58. Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of
inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax 2013;68:48–56.
59. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Crim C,
Willits LR, Yates JC, Vestbo J. Cardiovascular events in patients with COPD:
TORCH study results. Thorax 2010;65:719 –725.
60. Hansen RA, Tu W, Wang J, Ambuehl R, McDonald CJ, Murray MD. Risk of adverse
gastrointestinal events from inhaled corticosteroids. Pharmacotherapy 2008;28:
1325 –1334.
Erratum
doi:10.1093/ehjcvp/pvv018
.............................................................................................................................................................................
Non-steroidal anti-inflammatory drugs and
incident atrial fibrillation
.
Original Editorial url: http://ehjcvp.oxfordjournals.org/content/1/2/115
The Publisher regrets that the original Editorial was published without corrections to the affiliation and to the references section. These
have been amended in the online issue.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com