You are on page 1of 25

Drugs Aging (2013) 30:479–502

DOI 10.1007/s40266-013-0080-1


The Pharmacological Approach to the Elderly COPD Patient

Timothy E. Albertson • Michael Schivo •
Amir A. Zeki • Samuel Louie • Mark E. Sutter •

Mark Avdalovic • Andrew L. Chan

Published online: 12 April 2013

 Springer International Publishing Switzerland (outside the USA) 2013

Abstract The elderly patient (65 years and older) with 1 Introduction
chronic obstructive pulmonary disease (COPD) can be a
challenge to the clinician. This begins with the correct and early The burden of chronic obstructive pulmonary disease (COPD)
diagnosis, the assessment of disease severity, recognizing is a global public health problem with causative links to the
complicating comorbidities, determining the burden of symp- worldwide epidemic of cigarette smoking and the continued
toms, and monitoring the frequency of acute exacerbations. exposure to the burning of wood and biomass fuels. COPD is
Comprehensive management of COPD in the elderly patient both a preventable and treatable disease. COPD has become
should improve health-related quality of life, lung function, the third leading cause of death in the USA and ranks as a
reduce exacerbations, and promote patient compliance with major cause of morbidity [1]. As much as 5 % of the adult
treatment plans. Only smoking cessation and oxygen therapy in population in the USA has COPD. Annual spending is nearly
COPD patients with hypoxemia reduce mortality. Bronchodi- US$50 billion for COPD when totaling direct and indirect
lators, corticosteroids, methylxanthines, phosphodiesterase-4 expenses [1]. The prevalence and mortality rates of COPD in
inhibitors, macrolide antibiotics, mucolytics, and pulmonary countries vary and are projected to increase in the coming
rehabilitation improve some outcome measures such as spi- decades. Adjusted COPD prevalence varied significantly
rometry measures and the frequency of COPD exacerbations (P B 0.0001) between five cities in Latin and South America
without improving mortality. International treatment guide- with the lowest found in Mexico City [11.9 % (95 % CI
lines to reduce symptoms and reduce the risk of acute exacer- 11.3–12.5)] and highest reported in Montevideo [19.4 %
bations exist. Relief of dyspnea and control of anxiety are (95 % CI 17.8–22.8)] [2]. The BOLD study examined inter-
important. The approach to each patient is best individualized. national variation in the prevalence of COPD in 12 cities. The
Earlier use of palliative care should be considered when tra- overall prevalence of Global Initiative for Obstructive Lung
ditional pharmacotherapy fails to achieve outcome measures Disease (GOLD) stage II or higher COPD was 10.1 %,
and before consideration of end-of-life issues. 11.8 % for men and 8.5 % for women [3]. The city with the
highest prevalence of stage II or higher COPD was Cape
Town, South Africa (22.4 % men and 16.7 % women) and the
T. E. Albertson (&)  M. Schivo  A. A. Zeki  S. Louie 
lowest city was Reykjavik, Iceland for men (8.5 %) and
M. Avdalovic  A. L. Chan
Division of Pulmonary, Critical Care, and Sleep Medicine, Hannover, Germany for women (3.7 %).
Department of Internal Medicine, University of California, A progressive decline in expiratory airflow with conse-
4150 V Street, Suite 3400, Davis, CA, USA quent static lung hyperinflation and a fall in lung diffusion
capacity are the key pathophysiologic features of COPD.
T. E. Albertson  M. Avdalovic  A. L. Chan This limitation is the result of small airway inflammation
Veteran’s Administration Northern California Health Care (obstructive bronchiolitis), lung parenchymal destruction
System, Mather, CA, USA (emphysema), and airway smooth muscle contraction
(bronchospasm). Pulmonary emphysema reduces lung
T. E. Albertson  M. E. Sutter
Department of Emergency Medicine, University of California, elastic recoil and diminishes both alveoli and pulmonary
Davis, CA, USA vascular bed. The former adds to the obstructive
480 T. E. Albertson et al.

bronchiolitis and bronchospasm to limit the airway’s abil- dyspnea for a given degree of bronchoconstriction. The
ity to remain open during expiration thus generating air- reduction in the perception of dyspnea appears to be a
flow limitation [4]. Even patients with GOLD stage I specific feature of aging and delays diagnosing COPD in
COPD have significantly reduced ([20 %) peak oxygen this population [17]. A high index of suspicion for COPD is
consumption and power output with higher dyspnea ratings needed on the part of the clinician. Clues will become
for a given work and ventilation compared to controls. This evident when a detailed history of smoking and occupa-
is thought to be secondary to extensive small airway dys- tional/environmental exposures are revealed.
function, increased ventilation requirements, and increased Spirometry is required to confirm the clinical diagnosis
ventilation/perfusion abnormalities [5]. of COPD in the elderly patient. A post-bronchodilator
Patients diagnosed with COPD commonly suffer from forced expiratory volume in 1 s (FEV1) divided by forced
comorbid conditions associated with their COPD diagnoses. vital capacity (FVC) or (FEV1/FVC) of less than 0.70
The most common comorbidities include gastroesopha- identifies airway obstruction typical of COPD [18]. Con-
geal reflux, coronary artery disease, congestive heart fail- founding the use of this measure is ‘‘senile emphysema’’
ure, osteoporosis, obstructive sleep apnea, dementia, and where 35 % of healthy elderly who have never smoked
depression. Additional comorbidities seen in COPD patients aged over 70 years and 50 % of patients over 80 years
include skeletal muscle dysfunction, metabolic syndrome, have a FEV1/FVC ratio less than 0.7 [18].
and lung cancer [6, 7]. Older COPD patients commonly have The elderly are at some increased risk of being inad-
depression, particularly the patients with the greatest degree vertently classified as having airway obstruction because of
of disability [8]. Clusters of comorbidities have been the fixed 0.70 FEV1/FVC ratio criteria [15]. In the absence
reported in older COPD patients. These included cardio- of symptoms or risk factors, reliance solely on the FEV1/
vascular, cachectic, metabolic, psychological, and ‘‘less FVC ratio in the elderly patient to diagnose COPD is not
comorbidity’’ [9]. Many of these comorbidities may have a recommended [15]. Physical examination findings such as
link to the chronic inflammation associated with COPD distant breath sounds, wheezes, a prolonged expiratory
including atherosclerotic disease, depression, chronic kid- phase, clubbing, a displaced point of maximal impulse of
ney disease, cognitive impairment, obstructive sleep apnea, the heart, increased thoracic cage dimensions, and evidence
lung cancer, osteoporosis, diabetes, arrhythmias, heart fail- of right heart failure can suggest advanced COPD. Chest
ure, and pulmonary embolisms [10]. The overall disability of X-rays and chest computer tomography (CT) can have
the older COPD patient is mainly a function of the severity of findings suggesting COPD, though these may be normal in
comorbidities and significantly impacts treatment options patients with airflow obstruction. Complete pulmonary
[11]. Between 10 and 59 % of COPD patient have at least one functions tests (PFT) including spirometry, flow-volume
of these comorbid conditions [12–14]. These conditions are loops, lung volumes, and diffusion capacity of carbon
also more common in the elderly in general and must be monoxide are frequently needed in elderly patients to
considered when choosing therapy for COPD [11]. confirm the diagnosis of COPD, eliminate other lung dis-
This paper will review the approach to the diagnosis and eases, and further evaluate the severity of COPD. Osteo-
pharmacologic treatment of COPD in the elderly patient porosis and CHF can also alter the degree of airflow
(65 years and older). Special issues that relate to elderly limitation by lowering the FVC and thereby making the
COPD patients include comorbidities, smoking cessation, FEV1/FVC ratio appear less alarming.
potential difficulties of various medication delivery devi- The GOLD guidelines provide a COPD severity classi-
ces, medication issues including multiple adverse drug fication system based on the FEV1/FVC ratio coupled with
effects, and palliative care/end-of-life issues. the FEV1 expressed as a percent (%) of predicted values.
The post-bronchodilator spirometric GOLD classification
of COPD now starts with mild, grade 1, COPD with a
2 Diagnosis and Disease Severity FEV1/FVC less than 0.70 (or \70 %) and a FEV1 at least
80 % of predicted. Moderate, grade 2, COPD also has a
2.1 Pulmonary Lung Function Testing FEV1/FVC ratio less than 0.70, but a FEV1 at least 50 and
and the Classification of Severity less than 80 % of predicated values. Severe, grade 3,
COPD criteria include a FEV1/FVC ratio less than 0.70 and
COPD is often under-recognized in the elderly patient [15]. a FEV1 greater than or equal to 30 %, but less than 50 % of
The increased prevalence of comorbid conditions in the predicted values. The very severe, grade 4, group has a
elderly COPD patient can contribute to the difficulty of the FEV1/FVC ratio less than 0.70, a FEV1 less than 30 % of
diagnosis [16]. Symptoms of COPD and congestive heart predicted or a FEV1 less than 50 % of predicted coupled
failure (CHF) can significantly overlap. Age is as an with chronic respiratory failure. Chronic respiratory failure
independent variable predicting reduced sensation of is defined as arterial partial pressure of oxygen (PaO2) of
Treatment of the Elderly COPD Patient 481

less than 60 mmHg with or without arterial partial pressure hyperinflation measure of inspiratory capacity-to-total lung
of carbon dioxide (PaCO2) greater than 50 mmHg at sea capacity ratio (IC/TLC \25 %) is an independent predictor
level [4]. Increasing COPD severity is associated with of all-cause and respiratory mortality. FEV1, lower body
worsening mortality, morbidity, and health-related quality mass index, poor 6-min walk performance, patients with
of life scores. Three-year mortality for GOLD moderate or more dyspnea, and those with higher BODE index also
grade 2 is 11.4 %, and mortality increases to 24.3 % for predict mortality [24]. Age also is a risk factor. In a pro-
very severe or grade 4 COPD [19]. Grade 2 COPD patients spective study, patients at least 75 years of age with higher
tend not to die from COPD but rather from heart disease levels of dyspnea and FEV1 at most 50 % of predicted
and stroke. Grade 3 and grade 4 COPD patients more likely were found to have the highest 5-year mortality (0.74) and
die from COPD. Use of age-specific FEV1 and FEV1/FVC patients less than 55 years of age with FEV1 greater than
ratios have also been advocated to reduce the overdiagnosis 35 % of predicted and one or no recent COPD exacerbation
of COPD in the elderly [20]. Adjustments to the GOLD requiring hospitalization were found to have the lowest
spirometry criteria have been suggested to avoid this error. 5-year mortality (0.04) [25].
These include reducing the FEV1/FVC ratio to 65 % for
diagnosing COPD in patients aged 70 years or older [21]. 2.2 The 6-Min Walk Test
The most recent revision of the GOLD document continues
to require the use of spirometry to diagnose COPD using Because COPD is associated with increased airflow limi-
the FEV1/FVC ratio of less than 70 % criterion but now tation due to dynamic air trapping with exertion, a self-
also highlights the importance of assessing symptoms, paced walking test can be used to evaluate dyspnea in the
history of exacerbations, and comorbidities along with elderly. This is particularly helpful when dyspnea is out of
spirometry [7]. The Modified British Medical Research proportion to the degree of airflow obstruction and
Council (mMRC) questionnaire on breathlessness or the comorbid illnesses (e.g., CHF) are present. The 6-min walk
COPD Assessment Test (CAT) and a separate accounting is a simple, inexpensive, and safe test often conducted in a
of exacerbation risk provides a more clinically relevant corridor that has minimal traffic. The test has minimal
COPD assessment than FEV1 alone [7]. Integrating all requirements including a technician with a stopwatch, an
these metrics has resulted in several COPD patient oximeter, and known hallway distance. The 6-min walk
assessment groups: group A—low risk, less symptoms— test assesses disease severity, disease progression, and
GOLD 1–2, and 0–1 exacerbation per year and mMRC therapeutic effectiveness of medications and pulmonary
grade 0–1 or CAT score less than 10; group B—low risk, rehabilitation programs in elderly patients with COPD [26].
more symptoms—GOLD 1–2, and 0–1 exacerbation per When repeated over time, the distance walked provides
year and mMRC grade at least 2 or CAT score at least 10; increasingly useful information as to the progression and
group C—high risk, less symptoms—GOLD 3–4 and/or at increased severity of COPD [27]. Additionally, the distance
least 2 exacerbations per year and/or at least 1 exacerbation walked in 6 min is an important component of the BODE
resulting in a hospitalization per year, and mMRC grade index in COPD [23]. A recent report using the Evaluation
0–1 or CAT score less than 10; and group D—high risk, of COPD Longitudinally to Identify Predictive Surrogate
more symptoms—GOLD 3–4, and/or at least 2 exacerba- Endpoints (ECLIPSE) cohort determined that the minimum
tions per year and/or at least 1 exacerbation resulting in a clinically important difference (MCID) in the 6-min walk
hospitalization per year, and mMRC grade at least 2 or over a year was a reduction in walk distance of more than
CAT score at least 10. When this approach is combined 30 m. This conferred a hazard ratio of 1.93 (95 % CI
with an analysis of the comorbidities, the complexity of the 1.29–2.90, P = 0.001) [28].
COPD patient is better assessed than using the uni-
dimensional analysis of FEV1 alone [7]. This new GOLD
stratification system yielded surprising observations, e.g., 3 Treatment of COPD
group B, which is characterized by more severe dyspnea,
had significantly poorer survival than group C despite 3.1 Smoking Cessation
having higher FEV1 measures and fewer exacerbations
[22]. Although there has been a decrease in the prevalence of
Several metrics other than FEV1 alone can predict cigarette smoking from 2005 to 2010, it still is at 19.3 % in
mortality. One of the first developed was the BODE (Body the USA and higher in many other countries [29]. In the
mass index, airflow Obstruction, Dyspnea, Exercise per- recent Global Adult Tobacco Survey (GATS), 62.2 % of
formance) index. This simple multidimensional grading men in Russia and 52.9 % in China were found to smoke
system is better than FEV1 alone in predicting death in tobacco products, whereas the highest proportion of adult
COPD patients [23]. In a study from Spain, the lung females was in Poland (24.4 %) and in Russia (21.7 %) [30].
482 T. E. Albertson et al.

In men over 65 years, 40.7 % of Russians, 40.2 % of Chi- (CS) or b2-bronchodilators (b2Bs) in patients with COPD or
nese, and 12.6 % of Americans smoked. Lower rates are asthma, no difference in clinical effectiveness between
seen in women in this age group ranging from 1.4 % in nebulizers, alternative inhaler devices, and MDIs with or
Egypt, 7.4 % in the USA to 21.0 % in the Philippines [30]. without spacer devices were found [35]. Similarly, a sys-
A comprehensive smoking cessation approach requires tematic review and evidence-based guidelines by the
aspects of education, counseling, reinforcement, and phar- American College of Physicians and the American College
macotherapy [31]. In one study of elderly Korean smokers of Asthma, Allergy, and Immunology on the inhalation
(C65 years), alcohol use (social drinking), alcohol use dis- delivery of CS, b2Bs, and antimuscarinic agents concluded
order, and depression were characteristics rendering subjects that none of the delivery devices were superior and all
less likely to quit smoking [32]. It is likely that addressing provide similar outcomes in patients correctly using the
these comorbidities may improve smoking cessation rates in devices [36]. They recommend that the specific selection of
this age group. In a recent review, the importance of a brief the device should be based on device/drug availability,
intervention by physicians to prompt smokers to quit was clinical setting, patient age, ability to use the device, inter-
underscored [33]. Physicians actively linking patients to actions with other medications or devices being used, con-
behavioral support or counseling, nicotine replacement venience, cost/reimbursement, and drug administration time.
therapy (lozenge, gum, inhaler, or nasal spray), and bupro- Unfortunately, none of the studies or reviews focus
pion or varenicline when patients are trying to quit smoking exclusively on elderly patients. An example of the trials
doubles their odds of success. Addressing smoking as a used in reviews includes one by Turner et al. [37], where
chronic disease by giving it a high priority in health care patients with asthma or COPD exacerbations presenting to
systems like diabetes mellitus, coronary heart disease, and the emergency department were randomized to an MDI
hypertension allows the use of a chronic disease manage- with a spacer or a nebulizer. A total of 75 patients were
ment model in supporting the elderly patient’s efforts [33]. A included with age ranges from 18 to 73 years and no
recent evidence-based analysis concluded that moderate advantages were seen with either delivery device. Most
quality evidence supports significantly higher smoking clinical trials that focus on devices exclude subjects
abstinence rates in COPD patients receiving intensive deemed incapable of using the device properly, making it
counseling or a combination of intensive counseling plus hard to conclude on their relative merits [38]. Looking at
nicotine replacement therapy compared to the usual care. elderly patients, Chapman et al. [39] showed that subjects
Limited moderate-quality data supports nicotine replace- more successfully used breath-actuated inhalers than reg-
ment compared to placebo, and moderate quality evidence ular MDIs in a group with a mean age of 70.8 years. In a
exists for the antidepressant bupropion compared to placebo cross-sectional study of subjects 70 years and older, MDIs
in increasing smoking abstinence in COPD patients [34]. were the most common devices used and when used with a
There is an increased risk of seizures with bupropion over- spacer, they were used correctly by most subjects [40],
doses. Neuropsychiatric symptoms including behavior suggesting that slight modifications to routinely used
changes, hostility, agitation, depression, and increased risk devices may improve compliance in elderly COPD
of suicide have been reported with both the use of bupropion patients. A study of technique using two DPIs to deliver the
or varenicline in smoking cessation. The increased risk of anti-influenza drug zanamivir in the elderly found that most
suicide declines in patients treated with bupropion who are could not use the Relenza Diskhaler compared to the
older than 65 years. The continued risk of smoking must be Turbuhaler device [41]. The major difference between the
weighed against the risks of the drug therapy but even elderly inhalers was in the difficulty of loading and priming them.
COPD patients are likely to benefit from reduced airway A subjective component on the part of the individual
inflammation and further airway function decline. patient and or clinician exists that may influence decisions on
specific devices and their usage. Because of the 1987 Mon-
3.2 Inhalation Delivery Devices treal protocol, chlorofluorocarbon (CFC)-based propellants
are almost completely phased out and replaced by hydro-
The preferred route to deliver drug therapy in COPD patients fluoroalkane (HFA)-based propellants for MDIs [36]. A new
is by inhalation. Hand-held drug delivery options include SMI device is also shown in Fig. 1. This device is currently
pressurized metered-dose inhalers (MDIs), dry powder used in the USA to deliver albuterol and ipratropium bro-
inhalers (DPIs), spring-powered mist inhalers (SMIs), and mide combination therapy and is replacing the CFC-based
nebulizers. The main classes of medication delivered with MDI that delivered this combination of medications. The
these devices include bronchodilators and corticosteroids same SMI device is available in Europe to deliver tiotropium.
(Table 1). Figure 2 gives an example of an MDI with and without a
In a systematic review evaluating the clinical effective- spacer device. Both the MDI and the spacer require train-
ness of different inhaler devices delivering corticosteroids ing and retraining in many elderly patients to ensure proper
Treatment of the Elderly COPD Patient 483

Table 1 Current and emerging drug treatments for COPD

Smoking cessation aids
Nicotine replacement treatments (NRT)
Zyban = bupropion
Chantix = varenicline
Nicotine vaccines—experimental
SABA or short-acting b2-agonists (e.g., racemic albuterol, Xopenex = levalbuterol)
SAMA or short-acting muscarinic antagonists (e.g., Atrovent = ipratropium)
Combination SABA ? SAMA (e.g., Combivent = combination albuterol ? ipratropium)
LABA or long-acting b2-agonists (e.g., Serevent = salmeterol, Foradil = formoterol, Brovana = arformoterol inhalation solution,
Performist = formoterol inhalation solution, Arcapta = indacaterol, and experimental or not yet available in USA—vilanterol,
carmoterol, milveterol, BI-1744-CL, PF-00610355, LAS-1000977)
LAMA or long-acting muscarinic antagonists (e.g., Spiriva = tiotropium, Tudoraza or Eklira = aclidinium, and experimental or not
yet available in the USA—glycopyrronium, darotropium, dexpirronium, umeclidinium, QAT-370, TD-4208)
Emerging treatment (MABA) dual pharmacophore with long-acting muscarinic antagonist and b2-agonist pharmacology
GSK-961081 (GSK) formerly TD-5959
THRX-200495 (Theravance)
Inhaled corticosteroids (in order of increasing potency; equal efficacy when dose-adjusted)
Azmacort = triamcinolone
Qvar = beclometasone
Pulmicort = budesonide
Zetonna = ciclesonide
Asmanex = mometasone
Flovent = fluticasone propionate
Double therapy (CS ? LABA) in single delivery device
Seretide or Advair = fluticasone proprionate ? salmeterola
Relovair = fluticasone furoate ? vilanterol—not yet available in the USA
Symbicort = budesonide ? formoterola
Dulera = mometasone ? formoterolb
Mometasone ? indacaterol—not yet available in the USA
Double therapy (LABA ? LAMA) in single delivery device—not yet available
Carmoterol ? tiotropium
Formoterol ? aclidinium
Formoterol ? glycopyrronium
Indacaterol ? glycopyrronium
Vilanterol ? umeclidinium
Milveterol ? darotropium
Vilanterol ? darotropium
Triple therapy (CS ? LABA ?LAMA) in single delivery device—not yet available
Mometasone ? indacaterol ? glycopyrronium
Fluticasone furoate ? milveterol or vilanterol ? darotropium or umeclidinium
Ciclesonide ? formoterol ? tiotropium
Phosphodiesterase-4 inhibitor
Daliresp or Daxas = roflumilast
NTHi oral immunotherapeutic (HI-1640V) against Haemophilus influenzae
Pneumococcal vaccine (23 and 13 valencies)
484 T. E. Albertson et al.

Table 1 continued
Influenza vaccine (configured yearly)
Tetanus, diphtheria, and pertussis (TDaP)
Azithromycin—available, but not approved for COPD in USA
L-Carbocisteine—available, but not approved for COPD in USA
CS corticosteroid, SABA short-acting b2-agonist, SAMA short-acting muscarinic antagonist, LABA long-acting b2-agonist, LAMA long-acting
muscarinic antagonist, MABA combined effect muscarinic antagonist/b2-agonist
Only fluticasone 250 lg/salmeterol 40 lg fixed combination dry powder inhaler and budesonide 160 lg/formoterol 4.5 lg fixed combination
metered-dose inhaler are Food and Drug Administration (FDA)-approved for COPD in the USA
Approved in the USA only for asthma

use. Of interest, most of the HFA MDIs have little clinical coordination with a nebulizer is a real advantage in some
data supporting spacer use. The actuation of the MDI in elderly COPD patients and has been recently advocated [42].
synchrony with breath initiation is a common problem for DPIs are breath-actuated, but they do require a relatively
all ages and usually improves with a spacer. Currently at fast speed of inhalation (around 35 L/min inspiratory flow) to
least one MDI is actuated by inspiratory effort making it drive the delivery of the medication into the lungs. They may
unsuitable for spacer use. The currently available SMI also seem more complicated to some elderly patients, and the DPI
requires training and can be accidentally triggered which devices that require the elderly patient to open foil packages,
may prove difficult for some elderly patients. take out small capsules, and insert those capsules in the device
Nebulizer devices have small air compressors connected (Fig. 1) can be difficult for many elderly patients.
by tubing to the Acorn reservoir that holds the medication/ Combination medications seem to improve compliance
saline. Airflow through the tubing moving air generates a mist and are increasingly being used in the treatment of COPD
that is then inhaled through a mouthpiece. These have become patients (Table 1). Elderly COPD patients may not benefit
smaller, cheaper, and more mobile (rechargeable batteries) from being prescribed multiple types of delivery devices
over the years. Particular challenges to elderly patients that require consistent proficiency to deliver different
regarding nebulizers include the risk of contamination, limited bronchodilator and corticosteroids drugs. In the absence of
available types of medications, setup requirements, device outcome data, drug device availability, cost, and patient
cleaning, and opening and loading the sterile unit dose med- acceptance will often determine the optimal treatment
ications (Fig. 2). The lack of requiring actuation and breath options for each elderly COPD patient.

Fig. 1 Top row: left a spring-powered mist-generating inhaler called

Respimat; middle metered dose inhaler; right a dry powder inhaler
that requires each dose to be loaded with foil-covered capsules.
Bottom row: left dry powder inhaler with built in doses; middle Fig. 2 Top a metered dose inhaler attached to a spacer device; bottom
another dry powder inhaler with built in doses; right a dry powder left a sterile unit dose that is put into the Acorn to the right.
inhaler that requires each dose to be loaded with a capsule from a foil- Compressed air is inserted in bottom of Acorn and the mist of drug
covered packet and saline is inhaled from mouthpiece
Treatment of the Elderly COPD Patient 485

3.3 Classification of Bronchodilators Used in Treating Table 2 Bronchodilator classifications

COPD A. Beta2 (b2) adrenergic agonist (sympathomimetics)
1. Short-acting b2
Outside of the pharmacological therapies directed at
a. Albuterol/salbutamol
smoking cessation, drugs used in treating COPD are clas-
b. Levalbuterol
sified into two major groups. These include bronchodila-
c. Fenoterol
tors, which relax airways, opening airways, and reduce air
d. Terbutaline
trapping; and anti-inflammatory agents, which modify and
e. Bitolterol mesylate
modulate the inflammation associated with COPD.
f. Pirbuterol
Bronchodilators are further classified by route (either
g. Metaproterenol
oral or inhaled), by length of duration (either short- or
h. Isoetharine
long-acting), and by mechanism of action. Long-acting
2. Long-acting b2-agonists (LABA)
bronchodilators are given no more than twice a day, and
a. Salmeterol
short-acting agents require more frequent dosing. Table 2
offers a classification system that merges the three b. Formoterol
parameters. Similarly, the corticosteroid anti-inflammatory c. Arformoterol
agents can be classified into systemic (oral or parenteral), d. Indacaterol
and inhaled or topical. In an attempt to improve medication e. Clenbuterol
usage and compliance, many inhalers have combined B. Muscarinic antagonists (anticholinergics)
therapies that include a bronchodilator with a steroid or two 1. Short-acting muscarinic antagonists (SAMA)
types of bronchodilators. Combined therapy with two types a. Ipratropium
of bronchodilators and an inhaled corticosteroid (i.e., 2. Long-acting muscarinic antagonists (LAMA)
‘‘triple therapy’’) is being evaluated (Table 1). a. Tiotropium
b. Aclidinium
3.3.1 b2-Adrenergic Agonists c. Oxitropium
d. Glycopyrrolate bromide
The periodic use of an inhaled short-acting b2-adrenergic C. Oral agents
agonist (SABA) is recommended for treatment on an ‘‘as 1. Oral SABA
needed’’ basis in all stages of COPD ( a. Albuterol/salbutamol
). Acute testing with an inhaled SABA during spirometry does 2. Methylxanthine
not always predict a clinical response to these agents, and a. Theophylline
exercise symptom improvement is frequently seen in COPD b. Oxtriphylline
patients that failed to show acute spirometric improvement 3. Phosphodiesterase-4 inhibitor
following a SABA dose [43]. In addition to the use of SABAs a. Roflumilast
as rescue or ‘‘as needed’’ medication, inhaled long-acting b2-
adrenergic agonists (LABAs) are used in the treatment of
COPD as maintenance therapy. A LABA provides at least 12 h when it compared twice daily salmeterol 50 lg combined
of bronchodilation coverage (salmeterol, formoterol, and ar- with high dose fluticasone (500 lg) to either twice daily
formoterol) and newer ones such as indacaterol can provide a salmeterol, placebo, or fluticasone alone over a 3-year
24-h duration of action (Tables 1, 2). period. The hazard ratio for death in the combination
Most efficacy data for the use of SABAs and LABAs treated group compared to placebo was 0.825 (95 % CI
have focused on improvement in spirometry (FEV1), 0.681–1.002, P = 0.052) [47]. Even though this very high
improvement in health-related quality of life, and fre- standard of efficacy has not been reached for a broncho-
quency of adverse drug-associated events [44, 45]. Other dilator, an anti-inflammatory agent, or a combination
trials have assessed the speed of FEV1 change after LABA preparation, improvement in other outcomes are now rou-
use, in spite of the fact that LABAs should be used only for tinely reported. Table 3 reviews several large trials with
maintenance therapy [46]. Some SABAs are formulated as various treatment options and their effect on reducing the
an oral preparation, but these offer less bronchodilation and frequency of COPD exacerbations. In the TORCH trial, the
more frequent b2-adrenergic agonist side effects including combination of salmeterol plus fluticasone significantly
hypokalemia, hyperglycemia, muscle tremor, tachycardia, improved health status, spirometric values, and reduced
and restlessness compared to inhaled formulations. the annual rate of exacerbations compared to placebo
No bronchodilator has shown an improvement in the (P \ 0.001 for all comparisons). A similar magnitude
mortality of COPD patients. The TORCH trial came close reduction in exacerbations was seen with salmeterol alone
486 T. E. Albertson et al.

or fluticasone alone compared to placebo (P \ 0.001 for 3.3.2 Muscarinic Antagonists (Anticholinergics)
both comparisons) [47].
A recent systematic review of five randomized con- Large airways have muscarinic receptors, which result in
trolled trials explored the efficacy and safety of the once-a- increased airway tone and decrease airway diameter and
day LABA indacaterol evaluated in COPD patients with an flow when stimulated. These receptors are innervated by
average age of 63–64 years [48]. A total of 5,920 patients the vagus nerve. Three subtype muscarinic airway recep-
were included and showed statistically significant tors M1, M2, and M3 have been recognized [57, 58]. Use of
improvement and clinical reductions in the use of rescue muscarinic antagonists in COPD was pioneered with
medication and dyspnea index compared to the use of inhaled atropine and Datura stramonium that was smoked,
tiotropium. The once-a-day LABA indacaterol has been both of which are tertiary amines which cross biological
shown to improve FEV1 and health-related quality of life membranes to enter the brain, bladder, pupils, and other
compared to placebo and to be as effective as salmeterol, organs. The quaternary amine ipratropium bromide is
formoterol, and tiotropium [49–51]. Similarly, indacaterol classified as a short-acting muscarinic antagonist (SAMA)
showed a statistically significant improvement in dyspnea and does not easily cross biological membranes. It has been
index, health status, and trough FEV1 compared to twice-a- shown to be as effective as the SABA metaproterenol in a
day LABAs [48]. randomized, double-blind, 90-day study in COPD patients
In a small randomized crossover study of 44 previously [59]. Side effects with the SABA metaproterenol included
untreated elderly Japanese COPD patients, the 6-min walk tremors that were not seen with the SAMA ipratropium.
test and the health-related quality of life scores were both A randomized, double-blind, placebo-controlled, multi-
statistically better with the experimental transdermal center trial of 144 COPD patients with an average age of
LABA tulobuterol than inhaled twice-a-day salmeterol. 64 ± 7 years examined the LABA salmeterol twice a day,
The adherence rate was also statistically improved (90.3 % salmeterol plus the SAMA ipratropium four times a day, or
with the LABA patch versus a 75.5 % with the inhaled placebo alone for 12 weeks [60]. Symptom scores and
LABA) [52]. morning FEV1 determinations were statistically improved
Although long-acting antimuscarinic antagonists and greater with both the salmeterol and the salmeterol
(LAMAs) have been advocated as first-line therapy for with ipratropium group compared to placebo. Compared to
maintenance bronchodilators in COPD, recent guideline the group receiving salmeterol alone, the combined treat-
updates and current data support the early use of LABAs ment group had more improvement in FEV1 and airway
[4]. Specific trials focused on elderly patients and LABA conductance. The combined treatment of salmeterol and
therapy in COPD are lacking. Table 3 reviews the average ipratropium was associated with statistically less COPD
age of COPD patients in the trials that focus on the out- exacerbations than the placebo group (13 vs. 36 %,
comes of COPD exacerbation frequency. Most therapy P \ 0.01) [60]. In a study that evaluated the SABA albu-
trials use patients tested for their ability to use the device terol, the SAMA ipratropium, and a combination of albu-
being evaluated and studied patients who averaged terol and ipratropium all given as MDIs in a 12-week,
between 62 and 68 years and were predominately male. double-blind, prospective study of COPD patients, both the
Additional concerns about using beta-blockers in FEV1 and FVC were statistically improved with the com-
patients who have CHF or history of coronary disease in bination SABA/SAMA compared to each alone on all days
addition to COPD have been alleviated with multiple tested [61].
studies. Initial recommendation for COPD patients was for The SAMA ipratropium binds non-selectively to M1,
cardio-selective beta-blocker but more recently the safe use M2, and M3 receptors, whereas the quaternary amine
of non-selective beta-blockers has been confirmed [53–55]. LAMA tiotropium binds selectively to M1 and M3 recep-
A recent Swedish study examined the use of cardiovascular tors over M2 [58]. Tiotropium has a long half-life and is
drugs in 2,249 patients with COPD [56]. Using a time- administered once a day. The newer LAMA agent aclidi-
dependent model and controlling for important sources nium and the older agents oxitropium and glycopyrrolate
of bias, non-statistically significant reduced mortality bromide are all quaternary amines and are dosed twice a
was seen for the use of angiotensin-converting enzyme day [62, 63]. Tiotropium is available as a DPI and in
inhibitors/angiotensin receptor blockers and for statins Europe in an SMI [64]. A 28-day safety and tolerability
(HR = 0.88, 95 % CI 0.76–1.02 and HR = 0.86, 95 % CI study using the investigational LAMA umeclidinium in
0.71–1.03, respectively) but not for the use of beta-blockers combination with the experimental LABA vilanterol in a
(HR = 1.14, 95 % CI 0.99–1.30). Further study including once-a-day combination inhaler found marked improve-
randomized prospective trials is needed on the long-term ment in FEV1 on day 29 and no significantly different
use of cardiovascular drugs in elderly COPD patients. adverse effects [65].
Table 3 Important studies evaluating the prevention of acute exacerbations of COPD
Drug or treatment Trial Demography Results Comments

Budesonide/formoterol 320/9 lg vs. N = 1,219 180 research centers in USA, 34.6 and 25.9 % reduction in exacerbations for high Pneumonia rates 6.4, 4.7, and 2.7 % for
budesonide/formoterol 160/9 lg vs. RDBMC— South Africa, and South and low dose budesonide/formoterol compared to high dose, low dose, and formoterol
formoterol 9 lg metered dose inhaler twice 1 year America formoterol alone alone
daily [197] Mean age = 63.0 ± 9.3
62 % male
Fluticasone 500 lg ? salmeterol vs. TORCH 444 research centers in 42 25 % reduction in exacerbations vs. placebo 14 % reduction in exacerbations with
fluticasone alone vs. salmeterol alone vs. study countries salmeterol alone; 18 % reduction
placebo N = 6,184 Mean age = 65.0 ± 8.3 with fluticasone alone vs. placebo
Treatment of the Elderly COPD Patient

RDBMC— 75.5 % male

3 years
Fluticasone 500 lg or placebo twice daily ISOLDE 18 hospitals in UK 25 % reduction in exacerbations Delayed the onset of clinically
metered dose added to standard treatment study Mean age = 63.7 ± 7.1 important reduction in health status
N = 751 74.6 % male
3 years
Fluticasone/salmeterol 250/50 lg powder vs. N = 782 94 research sites in Canada 30.5 % reduction in moderate/severe exacerbations 40 % reduction in exacerbations
salmeterol 50 lg powder plus as needed RDBMC— and USA requiring oral corticosteroids
albuterol 52 weeks Mean age = 64.9 ± 9.0
[199] 55 % male
Fluticasone/salmeterol 250/50 lg or N = 797 98 research sites in USA and 30.4 % reduction in moderate/severe exacerbations Improvement in prn albuterol use,
salmeterol 50 lg as powder, twice daily RDBMC— Canada dyspnea scores, and nighttime
52 weeks Mean age = 65.4 ± 9.0 waking. Increased pneumonia (7 vs.
[200] 2 %)
54 % male
Mometasone furoate/formoterol 400/10 lg, N = 2,251 131 ? 164 research centers 21.4 % reduction in exacerbations with high dose High dose mometasone/formoterol had
mometasone/formoterol 200/10 lg, RDBMC— in Europe, USA, Central mometasone/formoterol group, compared to placebo 2 % pneumonia vs. 0.7 % placebo
mometasone 400 lg, formoterol 10 lg or 52 weeks and South America, Asia, group
placebo [97] and Africa
Mean age = 59.7 ± 8.8
76 % male
Azithromycin 250 mg orally vs. placebo N = 1,142 17 sites associated with 12 19.1 % reduction in exacerbations 125 % increase in hearing decrement
daily RPCMC— academic health centers (P = 0.04)
1 year USA
[133] Mean age = 65.5 ± 9
59 % male
Table 3 continued

Drug or treatment Trial Demography Results Comments

Azithromycin 500 mg orally vs. placebo EMBRACE 3 New Zealand centers 64.4 % reduction in exacerbations in the azithromycin No difference in FEV1 or health-related
daily 9 3/week study Mean age = 60.0 ± 13.2 group compared to placebo quality of life scores
N = 141
6 months
Tiotropium 18 lg vs. placebo powder daily MISTRAL 177 research centers in 35 % reduction in exacerbations 17 % reduction in number of patients
plus usual care, but no oral or inhaled study France experiencing more than one
LABA, any other inhaled anticholinergics N = 1,010 Mean age = 68.8 ± 9.3 exacerbation
or theophylline
RDBMC— 88 % male
1 year
Tiotropium 18 lg or placebo added to UPLIFT 37 countries 14 % reduction in exacerbations with tiotropium; mean 62 % pts on ICS
regular treatment study 490 investigation centers FEV1 elevated (P \ 0.001) compared to placebo 60 % pts on LABA
LABA ± ICS ± theophylline N = 5,993 Mean age = 65 ± 8 28 % pts on theophylline
RDBMC— 74.6 % male
44 years
Tiotropium 18 lg once daily vs. salmeterol POET study 25 countries at 725 research 11.1 % reduction in moderate/severe exacerbations 30.8 % reduction in severe
50 lg twice daily plus usual medications N = 7,376 centers exacerbations Increased time to first
except LABA and anticholinergic Mean age = 62.9 ± 9.0 exacerbation 187 vs. 145 days
DD— 74.6 % male
1 year
Roflumilast 500 lg once daily vs. placebo M2–124/ 10 countries at 246 research 17 % reduction in moderate/severe exacerbations A 2.17-kg weight decrease with
plus usual treatment 125 study centers roflumilast compared to placebo
N = 3,091 Mean age = 64 ± 9
RDBMC— 75.5 % male
1 year
Roflumilast 500 lg one daily plus either M2–127/ M2–127 study—10 38.9 % reduction in moderate/severe exacerbations Roflumilast was used to replace ICS;
salmeterol or plus tiotropium no other 128 study countries in 135 centers with salmeterol/roflumilast vs. salmeterol/placebo significant increase in FEV1 with
LAMA/LABA, ICS or theophylline N = 1,676 and M2–128 study—7 (P = 0.0015); 31.2 % reduction in moderate/severe either salmeterol or tiotropium
permitted countries in 85 centers exacerbations with tiotropium ? roflumilast vs. compared to placebo
Mean age = 64.6 ± 9 placebo/ ? tiotropium but N.S. (P = 0.0867)
24 weeks
[204] 68.4 % male
T. E. Albertson et al.
Treatment of the Elderly COPD Patient 489

double-blind, multicenter trial, RPCMC randomized, placebo-controlled, multicenter trial, FEV1 forced expiratory volume in 1 s, N number of patients (pts), RR relative risk, CI 95 %
N.S. no significant difference, prn as needed, DD double-dummy, LABA long-acting beta agonist, LAMA long-acting muscarinic antagonist, ICS inhaled corticosteroids, RDBMC randomized,
The use of LAMA inhalers is a first-line maintenance
therapy for moderate-to-severe COPD. Adding tiotropium
No difference in adverse events to COPD patients already treated with a LABA/cortico-
steroid (CS) resulted in significantly improved health-
related quality of life scores, FVC, FEV1, and inspiratory
capacity (IC) compared to treatment with LABA/CS alone
[66]. Combination inhaled therapy with tiotropium plus the
LABA formoterol with or without the CS budesonide also

resulted in improved lung function [67]. The addition of

the SABA fenoterol or the SAMA ipratropium to 60 COPD
patients on maintenance tiotropium therapy in a random-
ized, placebo-controlled study resulted in improved lung
function. Both drugs were effective in increasing FEV1
with the SABA improving the FEV1 statistically greater
24.5 % reduction in exacerbations (P = 0.004)

than the SAMA [68]. The addition of a SAMA onto

maintenance tiotropium in COPD patients has resulted in
small FEV1 improvement, but has not yet been shown to
significantly improve other clinically relevant parameters
[69]. A systematic review found a small improvement in
health-related quality of life with the addition of the
LAMA triotropium to an inhaled LABA compared to
tiotropium alone in COPD patients [70]. Looking at pre-
scription claims from the Ontario Drug Benefit Program
% = all listed reductions statistically significant at P B 0.05 except as noted. ± = ±1 standard deviation

over 12 months found that persistence with inhaled treat-

ment in COPD patients was low, but was highest with

tiotropium [71]. Table 3 summarizes significant studies

that generally demonstrate reduced rates of COPD exac-
erbations with LAMA use, but no reductions in mortality
rates have been demonstrated to date. The LAMA tiotro-
Mean age = 65.2 ± 8.9

pium is well tolerated with anticholinergic side effects such

22 centers in China

as dry mouth, constipation, gastrointestinal obstruction,

and dysuria being the most common. Dilated pupils and

78.5 % male

worsening of intraocular pressure in those patients with

glaucoma have also been noted. Men with lower urinary
tract symptoms or benign prostate hyperplasia may develop
acute urinary retention with the use of an inhaled SAMA or
LAMA, but the frequency of this happening is not known

despite widespread use of the agents [72]. Potential anti-

N = 709

1 year


cholinergic-related adverse events were reported to be


seen in at most 2.5 % of patients in large trials with ac-

lidinium [73].
Carbocisteine 1,500 mg orally or placebo

In systematic reviews of the cardiovascular risk of

inhaled SAMA/LAMAs in COPD patients that include the
large 4-year UPLIFT trial, no significant difference was
found between tiotropium and placebo in the risk of a
stroke. The risks of serious cardiac adverse events includ-
ing myocardial infarction and CHF were significantly
lower with tiotropium [67, 74]. This contrasts with the
confidence interval
Table 3 continued
Drug or treatment

recent UK general practitioner electronic medical record

database analysis of new users of tiotropium compared to
new users of LABA in patients with COPD. A small
increase in rates of stroke, angina, and myocardial infarc-
tion were seen with the new use of the LAMA compared to
490 T. E. Albertson et al.

the LABA [75]. Small increased risk of arrhythmias in seem to correlate with increased disease severity, exacer-
COPD patients treated particularly with the SAMA iprat- bation rates, and decline in lung function in COPD patients
ropium and the use of LABAs/SABAs has been suggested [83]. Increases in CRP in COPD patients are also associ-
in the Saskatchewan cohort study and in a reassessment of ated with poor health status and comorbidities such as
the larger Quebec cohort study [76]. Using Ontario Canada cardiovascular disease, cancer, and poor skeletal muscle
databases, Gershon et al. [77] evaluated mortality at function. The importance of inflammation in the patho-
6 months in elderly (C65 years) COPD patients treated genesis of COPD and associated comorbidities has resulted
with a LABA or the LAMA tiotropium. They found a 20 % in the use of topical and systemic CS in the treatment of
reduction in mortality with the use of the LAMA compared COPD.
to the LABA (HR = 0.80, 95 % CI 0.70–0.93). However, Although the acute treatment of COPD exacerbations is
when these same investigators looked at the use of LABA outside the focus of this review, randomized controlled,
versus LAMA in elderly (C65 years) COPD patients using double-blind, and cohort trials have demonstrated that
the same databases for up to 5.5 years, mortality was systemic CS contributes to moderate improvement in
higher in patients prescribed a LAMA compared to a clinical outcomes among patients experiencing COPD
LABA (adjusted HR = 1.14, 95 % CI 1.09–1.19) [78]. exacerbations [84–86]. This includes shorter duration of
Further trials are needed to evaluate this in other elderly symptoms, faster improvement of FEV1, and less chance of
patients, younger patients, and in more randomized con- relapse exacerbations. A number of reviews have also
trolled studies that focus on elderly COPD patients. concluded that short courses of oral or parenteral CS in
acute COPD exacerbations improve clinical outcomes [87,
3.3.3 Combination Inhaler Therapy 88]. At least one study has shown that oral CS is not
inferior to parenteral CS in hospitalized patients with acute
One of the first combination inhalers for COPD was the COPD exacerbations [89]. Short courses of less than
MDI that combined the SABA albuterol with the SAMA 2 weeks and maybe as short as 3 days of oral or parenteral
ipratropium bromide. Although the use of the combination followed by oral CS appear to be well-established treat-
of a SAMA/SABA in one inhaler has been shown to be ment approaches during COPD exacerbations [90].
more efficacious than each alone, no study has shown that a The use of oral or inhaled/topical CS in stable moderate-
combined inhaler is better than using the two drugs in severity COPD patients significantly reduced a number of
separate inhalers. One analysis of a large claims database selected systemic cytokines measured in a randomized trial
reported that the use of a single inhaler has better adher- [91]. It is recognized that the majority of COPD patients do
ence rates than those with multiple inhalers in COPD not benefit from long-term systemic CS [92].
patients [79]. In another analysis of the same database, the Those COPD patients with more atopic/asthmatic or
use of multiple inhalers was associated with a higher risk of bronchospastic symptoms appear to benefit the most from
exacerbations, higher health care resource utilization, and CS, and patients with irreversible airway obstructive
higher costs compared to single inhaler users in patients disease benefit the least from inhaled CS [92]. A recent
with COPD [80]. The use of the combination therapy of Cochrane review supports the use of inhaled LABA over
albuterol/ipratropium was approved for use in COPD inhaled CS with inhaled CS suggested as adjunct therapy
almost 20 years ago, but has been supplanted in most in COPD patients [93]. A randomized, double-blind,
COPD treatment guidelines by longer-acting inhalers placebo-controlled, crossover study compared fluticasone
containing a LAMA or LABA and newer combination propionate to placebo in COPD patients with an average
inhalers of CS/LABA in the treatment of COPD [81]. New age of 67.2 ± 6.9 years. The study underscores the
inhalers with once-a-day combinations of LAMA/LABA importance of topical CS when it found that the addition
are under investigation and the first triple inhaler contain- of the inhaled CS to patients already on a stable LABA
ing the CS ciclesonide, the LABA formoterol, and the improved FEV1, static lung volumes, dynamic lung vol-
LAMA tiotropium has already been released in India [82]. umes, and exercise endurance in moderate to severe
Combination inhalers appear to improve medication use COPD [94]. The experimental LABA vilanterol when
compliance and may be particularly useful in elderly combined with fluticasone furoate has been studied in a
COPD patients. once-a-day combination inhaler in a randomized, placebo-
controlled, three-way, crossover study in COPD patients.
3.4 Inhaled and Systemic Corticosteroids The once-a-day CS/LABA resulted in significantly
improved pulmonary function compared to placebo over
COPD involves significant airway inflammation in its path- the 28 days of this preliminary trial [95]. The addition of
ophysiology. Elevated levels of circulating interleukin-8, inhaled CS has been shown to improve FEV1 and quality
tumor necrosis factor alpha, and C-reactive protein (CRP) of life, and reduce COPD exacerbations in a meta-
Treatment of the Elderly COPD Patient 491

analysis, but with significantly increased risk of pneu- suggested [96, 103, 104]. In elderly COPD patients, the cli-
monia [96]. nician must balance the limited data on benefits against the
Many fixed combinations of inhaled CS/LABA have long-term risks of inhaled and systemic CS.
been studied in COPD patients. A 52-week study in 2,251
patients reported a lower incidence of COPD exacerba- 3.5 Methylxanthines, Phosphodiesterase-4 Inhibitors,
tions, improved FEV1, and improved quality of life with Antibiotics, and Mucolytics
inhaled mometasone furoate/formoterol combination ver-
sus mometasone, formoterol, or placebo alone [97]. Maintenance theophylline and the more water-soluble
Table 3 offers a summary of several clinical trials in COPD agent aminophylline (theophylline in an ethylenediamine
patients evaluating inhaled CS/LABA combination inhalers complex) have been controversial drugs used in COPD
in reducing the frequency of COPD exacerbations. The use management for more than 25 years [105]. Theophylline
of a combined inhaler of CS/LABA compared to a LABA causes bronchodilation, enhances diaphragmatic contrac-
alone in COPD patients has been systematically reviewed, tility and endurance, increases myocardial contractility,
though the review could not endorse the use of a combined and increases central respiratory drive [105–108]. The
CS/LABA over the LABA because of concerns regarding clinical significance of these effects is debated, however,
the analysis and data availability from the studies [98]. especially in light of theophylline’s notoriously narrow
Similarly, systematic reviews of combined CS/LABA therapeutic window and toxicity profile. In low concen-
use in COPD patients comparing inhaled CS/LABA to trations, theophylline appears to have anti-inflammatory
inhaled tiotropium have failed to conclude superiority of effects, but again the clinical significance has not been
either therapy because of data quality concerns. The clearly shown [109, 110].
reviewers noted that more high-quality data as seen in two A double-blind crossover study of 40 ambulatory COPD
large trials (TORCH and UPLIFT) is needed to appropri- patients compared theophylline to placebo and demon-
ately perform the systematic review [99]. Three trials strated a small, but statistically significant, increase in
evaluated adding combined inhaled CS/LABA to tiotropi- FEV1. Of the 40 patients, six were identified as theophyl-
um (LAMA) compared to tiotropium or combination CS/ line ‘‘responders’’, but theophylline was not beneficial to
LABA alone and found no statistically significant differ- most of the COPD patients [111]. Similarly, a significant
ence in mortality, rate of hospitalizations, episodes of improvement in lung function was seen when theophylline
pneumonia, or other adverse events between the groups. and an inhaled SABA were combined compared to each
Because of the heterogeneous nature of the exacerbation separately, though no improvement in symptoms was
data, the authors were unable to determine exacerbation reported [112]. When low dose theophylline (plasma levels
frequencies. However, benefit was seen in health-related of 8.8–12.4 mg/L) was added to inhaled CS, statistical
quality of life and lung function when the inhaled LAMA improvement in FEV1 was seen compared to the use of
was added to the inhaled CS/LABA compared to the inhaled CS by itself [113]. Using the results of randomized
LAMA or CS/LABA alone [100]. In contrast, a retro- controlled clinical trials totaling 2,087 patients, a meta-
spective cost-effective ‘‘real-world’’ study of COPD analysis concluded that compared to placebo, theophylline
patients suggests that the combination CS/LABA inhaler is can improve lung function, arterial blood gas exchange,
associated with significantly better clinical and economic and walking distance at the cost of higher drug-related
outcomes compared to the use of inhaled SAMA or LAMA adverse events [114]. A newer methylxanthine derivative,
therapy alone [101]. A single-center, double-blind ran- doxofylline, appears to have less drug-induced side effects
domized controlled trial evaluated the removal of the and still demonstrates a bronchodilator effect [115].
inhaled CS fluticasone propionate after 4 months in 244 Higher blood levels of theophylline are associated with
COPD patients (average age 64 years) on the rate of COPD greater bronchodilation but increased risk of toxicity. Sig-
exacerbations [102]. The placebo-treated group was found nificant variations in theophylline pharmacokinetics asso-
to have an increased risk of a first exacerbation compared ciated with age, active smoking, disease states, and drug
to the inhaled CS group (HR = 1.5, 95 % CI 1.05–2.1). interactions exist [116–119]. The large variations in serum
The mean time to the first exacerbation was 42.7 days for half-life and pharmacokinetics make theophylline a very
the placebo group and 75.2 days for the inhaled CS group challenging treatment in elderly COPD patients with little
[102]. Further randomized controlled trials are needed to convincing evidence of clinically meaningful improvement
better understand when inhaled CS can be withdrawn in in outcomes.
elderly COPD patients. The drug-associated side effects with theophylline
In addition to the increased risk of pneumonia with inhaled include diarrhea, tremor, nervousness, confusion, cardiac
CS in COPD patients, thrush, vertebral fractures, osteoporo- arrhythmias, myocardial infarctions, and seizures [120,
sis, and the risk of diabetes onset and progression have been 121]. COPD patients receiving treatment regimens that
492 T. E. Albertson et al.

include theophylline have slightly increased mortality, anti-inflammatory properties that will potentially improve
COPD exacerbations, and COPD hospitalization risk efficacy while minimizing the risks of long-term use.
compared to patients without theophylline [122]. In fact, Mucolytics are used in patients with COPD and chronic
some experts have called for an end to theophylline use in sputum production. A review of mucolytics in the man-
COPD management [123]. agement of COPD patients concluded that despite the poor
The oral phosphodiesterase-4 inhibitor roflumilast rep- quality of published evidence, small reductions in exacer-
resents a new class of medication approved for use in bation frequency were seen, but there were few additional
COPD. Although roflumilast has been shown to improve health benefits [136]. A systematic review of the use of
FEV1 by 40–60 mL compared to placebo, it has not been mucolytics in COPD and chronic bronchitis patients
classified as a bronchodilator [124]. Perhaps its greater included 28 trials and 7,042 patients. Oral mucolytics were
benefit has been its ability to reduce COPD exacerbations associated with a significant 21 % reduction in exacerba-
(Table 3). A post hoc pooled analysis of two studies with tions, but this was only seen in patients not taking inhaled
2,686 randomized patients evaluated roflumilast 500 lg or CS [137]. A large Chinese study found a significant 25 %
placebo daily for 52 weeks and found that the use of rof- reduction in COPD exacerbations and improvement in
lumilast significantly decreased exacerbations by 14.6 % health-related quality of life with daily carbocisteine
compared to placebo. Subjects most likely to benefit from compared to placebo for a year (Table 3). Carbocisteine is
roflumilast included those with cough, sputum production, a mucolytic and likely has antioxidant and anti-inflamma-
and concomitant inhaled CS use, suggesting that roflumi- tory properties [138]. The use of chronic oral mucolytics in
last affects inflammatory cascades to reduce exacerbations elderly COPD patients will likely be limited to those
[125]. Significant adverse effects, including diarrhea, patients with chronic mucus production who are not on
nausea, and weight loss, limit the use of roflumilast [125, inhaled corticosteroids.
126]. As a result, roflumilast is recommended as an adjunct
therapy in patients with severe or symptomatic COPD 3.6 Oxygen Therapy
associated with frequent exacerbations [127, 128].
The use of antibiotics in acute exacerbations of COPD, The use of long-term oxygen therapy (LTOT) for specific
particularly associated with acute exacerbation of chronic elderly patients with COPD is common and defined by
bronchitis (AECB), has a long history. Antibiotics such as the physiological criteria that vary little between the USA, UK,
fluoroquinolone moxifloxacin is as effective as amoxicillin/ Europe, and Australia [139]. Although slight variations in
clavulanic acid in the treatment of acute exacerbations of criteria exist, a PaO2 less than 55 mmHg or an arterial pulse
COPD associated with bacterial infections and AECB [129, oximetry (SaO2) of less than 88 % on room air at rest at sea
130]. The use of macrolide antibiotics to treat COPD exac- level will qualify most elderly COPD patients for LTOT.
erbations associated with AECB is also well documented Demonstrating these same parameters with exercise will
[131]. Long-term use of macrolide antibiotics for diffuse usually qualify a patient for LTOT during exercise. The
panbronchiolitis began in the 1980s with at least six ran- presence of pulmonary hypertension, cor pulmonale, elevated
domized controlled trials demonstrating evidence of benefit in hematocrit ([56 %), or a commitment to palliative care in a
cystic fibrosis [132]. A randomized controlled trial of daily patient with refractory dyspnea that does not otherwise meet
azithromycin compared to placebo in COPD patients given the LTOT criteria will often qualify. The goal of LTOT is
over a year demonstrated a significant reduction in the rate of correction of the hypoxemia, and this correction needs to be
COPD exacerbations (Table 3). Improved health-related documented [139]. Overall, the need for LTOT in elderly
quality of life scores were noted, but hearing decrements were COPD patients is a prognostic factor for markedly reduced
also statistically more common in the azithromycin-treated survival and poor quality of life [140–142].
group [133]. A smaller randomized, double-blind trial of Two major studies (MRC and the NOTT trials) have
COPD patients in three centers in New Zealand also tested reported mortality improvement in COPD patients on
azithromycin versus placebo each three times a week for LTOT who met criteria compared to controls [6, 143]. A
6 months. A significant reduction in COPD exacerbations and systematic review of six studies on the effect of LTOT in
improvement in health-related quality of life were seen COPD patients concluded that LTOT improved survival in
without any improvement in FEV1 [134]. The mechanism of a selected group of patients with severe hypoxemia [PaO2
action of the macrolide antibiotics in these lung diseases is \55 mmHg (8.0 kPa)] and did not improve survival with
possibly due to their antibiotic effects, their ability to restore mild to moderate hypoxemia or in those COPD patients
corticosteroid receptor sensitivity, and their direct anti- with only nocturnal desaturations [144]. A recent ‘‘mega-
inflammatory actions [135]. Newer macrolides are being analysis’’ has concluded, on the basis of a low quality of
developed that lack antibiotic effects and the ability to induce evidence, that LTOT of at least 15 h/day decreases all-
microbial resistance. Nevertheless, these agents still have cause mortality and improves health-related quality of life
Treatment of the Elderly COPD Patient 493

in COPD patients with severe hypoxemia, but does not Pneumococcal pneumonia is a disease associated with
reduce hospital readmission rates [145]. A small reduction meningitis, pneumonia, and sepsis in adults. It has been
of COPD-related pulmonary hypertension after the first shown to colonize the airway of COPD patients at a higher
2 years of LTOT followed by a return to initial values rate than healthy patients and to be associated with higher
occurs [146–148]. In selected elderly COPD patients, it rates of exacerbation in these patients [152]. Historically,
appears that LTOT can improve physiological parameters, the 23-valent pneumococcal/polysaccharide vaccine has
health-related quality of life, and mortality. been recommended and studied in COPD patients with
Picking the best LTOT source and delivery device for the mixed efficacy reported [152]. A recent evidence-based
elderly COPD patient is often a balance between insurance analysis of COPD patients concluded that the 23-valent
and expense issues and logistical issues concerning the pneumococcal vaccination significantly reduces the risk of
oxygen-supplying device (i.e., weight, portability, com- acquiring pneumococcal pneumonia [154]. The risk of
plexity, and comfort associated with using a device). Liquid acquiring pneumococcal pneumonia was significantly
oxygen, oxygen concentrators, and tank oxygen devices are reduced by 80 % in patients younger than 65 years
changing rapidly in the market place, often with little out- and also in those patients with severe airflow limitations
come data to support the changes [149, 150]. In evaluating (FEV1 \40 % of predicted), but the risk was not reduced in
the compliance of the elderly COPD patient with their COPD patients 65 years of age or older [154]. The GOLD
LTOT, it is important to reinforce with the patient and their guidelines stress the importance of pneumococcal vacci-
care support team the unacceptable risks of combining nations for all COPD patients. The CDC recommendations
oxygen therapy with flames. The simultaneous use of LTOT suggest a second vaccination 5 years after the original
and smoking cigarettes results in several fatal fires a year in [152]. The CDC Advisory Committee on Immunization
the USA [151]. The use of LTOT in elderly COPD patients Practices as of June 2012 is recommending the routine use
meeting hypoxemic criteria reduces mortality, pulmonary of the 13-valent pneumococcal conjugate vaccine in eli-
hypertension, dyspnea, and improves the health-related gible immunocompromised adults including COPD
quality of life, but it requires many practical considerations patients on long-term systemic steroids. This vaccination is
to ensure safety and patient compliance. in addition to the currently recommended 23-valent pneu-
mococcal polysaccharide vaccine [155]. The new 13-valent
3.7 Vaccinations pneumococcal conjugate vaccine succeeds the 7-valent
pneumococcal conjugate vaccine used in children between
The single-stranded RNA influenza virus A and B cause the ages of 6 weeks and 71 months in the USA. It includes
seasonal and pandemic disease in humans. Each year the the capsular polysaccharide antigens of serotypes 1, 3, 4, 5,
World Health Organization’s Global Influenza Surveillance 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F all individ-
Network in conjunction with the USA’s Center for Disease ually conjugated to a non-toxic diphtheria CRM 197 carrier
Control (CDC) develops a new injectable trivalent inactivated protein, which was used in the older 7-valent product
viral vaccine. Seasonal influenza annually leads to more than [156]. There is some evidence that in adults, the conjugated
200,000 hospitalizations, 36,000 deaths, and billions of dol- 7-valent or the 13-valent pneumococcal vaccine in com-
lars of direct and indirect health care costs in the USA [152]. bination with the 23-valent pneumococcal polysaccharide
Influenza infections are also associated with acute COPD vaccine is more effective in immunocompromised patients
exacerbations, increased hospitalizations, increased episodes of [155]. The use of this product combination has not been
pneumonia, and respiratory failure in COPD patients. Data on widespread and no trials to date in immunocompromised
the effectiveness of influenza vaccination in COPD patients is COPD patients have been reported. In pneumococcal
inconsistent with some studies reporting reductions in influ- vaccine-naive immunocompromised patients, the recom-
enza-related metrics, whereas other studies have reported no mendation is that the 13-valent product should be given
improvement [152]. In general, elderly patients ([65 years) first and then followed by the 23-valent vaccination at least
have been shown to have a 70 % reduction in mortality after 8 weeks later. If patients have previously been vaccinated
influenza vaccinations [153]. A recent evidence-based review with the 23-valent product, the 13-valent vaccination
concluded that influenza vaccination in COPD patients reduced should be done a year or more later. Elderly COPD patients
influenza-related acute respiratory tract infections and reduced who are not immunocompromised are still recommended
the rate of hospitalizations and episodes of mechanical venti- by the CDC only to be vaccinated with the 23-valent
lation. The patient’s age, sex, severity of COPD, smoking sta- pneumococcal vaccine [155]. Others have advocated
tus, and comorbid disease status did not modify its effectiveness for only the use of the conjugated 13-valent vaccine in
[154]. As a result, GOLD and other guidelines on the treatment older patients [157–159]. The Joint Committee on Vacci-
of COPD stress annual influenza vaccination in both elderly and nation and Immunization of the UK (JCVI) has recom-
younger patients with COPD. mended discontinuing the routine use of the 23-valent
494 T. E. Albertson et al.

pneumococcal vaccine in patients older than 65 years, but 3.9 Non-Invasive Ventilation
did not substitute it with the conjugated 13-valent vaccine
[160]. Non-invasive mechanical ventilation (NIMV) is a useful
Highly infectious pertussis-like illnesses caused by treatment in hypoxemic respiratory failure and reduces the
Bordetella pertussis and similar organisms (i.e., Bordetella need for endotracheal tube placement and invasive mechani-
holmesii/Bordetella parapertussis) are associated with a cal ventilation (IMV) [172]. In a series of elderly (mean age
persistent cough and may include the classic ‘‘whoop’’ 81 ± 4.8 years) patients with hypercapnia in which the
sound lasting up to 3 months. In recent outbreaks in the majority (50/62) had COPD, treatment with NIMV resulted in
states of Washington and Ohio, the vast majority of the successful avoidance of IMV in the majority of patients with a
cases were less than 20 years old [161, 162]. Pertussis 12.9 % failure rate (death or the need for IMV) [173]. A recent
clusters and outbreaks have been reported in adults randomized controlled study evaluated NIMV in 82 elderly
including recent outbreaks of B. pertussis among oncology (mean age 81 ± 3.5 years) patients with chronic pulmonary
nurse specialists in the UK [163]. A 71-year-old, unim- disease and hypercapnic respiratory failure against standard
munized social contact of one of the primary cases of medical therapy [174]. Both the mortality (OR = 0.40, 95 %
pertussis was infected. Although no specific trials of B. CI 0.19–0.83, P = 0.014) and the rate of patients meeting
pertussis vaccination have been reported in COPD patients, endotracheal tube intubation criteria (7.3 vs. 63.4 %,
there is evidence that pertussis can have a role in acute P \ 0.001) were significantly reduced in the NIMV treatment
asthma exacerbations [164]. On the basis of serologic group compared to the standard medical treatment group.
evidence, B. pertussis has also been associated with exac- NIMV should be considered an alternative to early endotra-
erbation of chronic bronchitis [165]. cheal intubation and IMV in elderly COPD patients and in
A one-time (tetanus, diphtheria, and acellular pertussis) selected ‘‘do not intubate’’ elderly COPD patients.
TDaP vaccination is estimated to reduce the incidence of
pertussis by 44 % over a 10-year period [152]. A review of 3.10 Treatment Guidelines
vaccinations in adult asthma and COPD patients endorsed
by the CDC recommends that adults between the ages of 19 The diagnosis and treatment of the COPD patient are out-
and 64 years should have one dose of TDaP [152]. lined in several national, regional, and global guidelines
[1, 4, 175, 176]. A review of new inhalational therapies
3.8 Pulmonary Rehabilitation notes that prescribing aerosol treatment to the elderly
patient has many similar problems to prescribing to children
The use of pulmonary rehabilitation in older elderly [177]. Cognitive and dexterity limitations should be taken
patients with COPD has been shown to improve their into account and more complex maneuvers that may be
exercise capacity [166, 167]. In a recent Cochrane meta- challenging to the elderly should be avoided. The clinician
analysis of nine trials including 432 COPD patients should only prescribe a delivery system that the elderly
undergoing pulmonary rehabilitation of variable durations patient can and will use effectively. A stepwise or pyramid
compared to usual care, there was a significant mortality approach is common to all the treatment guidelines. As the
reduction over 107 weeks in those patients enrolled in severity of the physiological alterations and symptoms in
pulmonary rehabilitation (OR 0.28, 95 % CI 0.10–0.84; COPD increase, the more the interventions and medications
number needed to treat 6, 95 % CI 5–30) [168]. There still are layered in for the patient [178]. Figure 3 offers a hybrid
exists some controversy about the utility of pulmonary pyramid of current recommendations for the treatment of
rehabilitation in the elderly COPD patient, but its use the COPD patient with increasing interventions as the dis-
remains generally accepted in those elderly patients capa- ease severity increases.
ble of participating in a program [169, 170]. An evidence-
based analysis of pulmonary rehabilitation in COPD
patients included 17 randomized controlled trials of mod- 4 Palliative Care and End-of-Life Issues
erate quality of evidence and concluded that programs of at
least 4 weeks of exercise training lead to clinically and In a retrospective study of the last year of life of 209
statistically significant improvement in health-related Londoners who died from COPD, the average age was
quality of life, functional exercise capacity, and hospital 76.8 years, 98 % were breathless all or some of the year,
readmission rates [171]. Pulmonary rehabilitation should 96 % noted fatigue or weakness, 77 % had low mood, and
be considered for every COPD patient without regard to 70 % reported pain [179]. These investigators concluded
age. Comorbidities including both physical and mental that patients who died from COPD lacked surveillance,
limitations should be evaluated in the elderly COPD patient care coordination, and received inadequate services in the
before committing them to a program. year before their death.
Treatment of the Elderly COPD Patient 495

nebulized opioids used morphine. The meta-analysis

showed a statistical reduction (P = 0.0068) in breathless-
ness with the use of opioids. The meta-regression revealed
a greater effect (P = 0.02) with oral/parenteral opioids
than with nebulized opioids [187]. A specific subgroup
analysis also failed to show improvement in breathlessness
after nebulized opioid treatment in severe COPD patients.
A recent small study of 16 patients with COPD (average
age 70.5 ± 7.3 years) demonstrated that a single inhaled
dose of fentanyl citrate improved exercise endurance without
changing dyspnea or measured spirometric or plyethysmo-
graphic lung volumes [188]. Side effects of oral/parenteral
opioid treatment include constipation, drowsiness, nausea,
and anorexia. Bitter taste, cough, and a ‘‘pricking’’ sensation
Fig. 3 The COPD pyramid of treatment. Adapted from the Canadian
Thoracic Society and GOLD guidelines [4, 205]. LVRS lung volume in the throat have been reported with nebulized opioids.
reduction surgery including endobronchial approaches, LTS lung trans- Statistical increases in the partial pressure of arterial carbon
plant surgery, LABA long-acting b2-agonist, CS inhaled corticosteroid, dioxide (pCO2) were found in one study that measured it
LAMA long-acting muscarinic antagonist, SABA short-acting b2-agonist, after oral opioids, but these were not clinically concerning
SAMA short-acting muscarinic antagonist, Vaccinations annual influ-
enza, pneumococcal, and pertussis vaccinations, OCS oral corticoste- increases and none had elevated arterial pCO2 determina-
roids, Theo theophylline, Roflum roflumilast, Azith azithromycin tions at the beginning. Nine of the 18 studies reported oxygen
saturations and none reported a significant change during the
The need for coordinated and multidisciplinary palliative study [187]. The use of opioids in severe COPD patients with
care at the end-of-life of elderly COPD patients that addresses baseline pCO2 elevations comes with the risk of increasing
breathlessness is clearly needed [180]. In a prospective com- their narcotizing effect by encouraging further carbon
munity survey and interview study of 128 COPD patients dioxide retention. Potentially off-setting the central nervous
(mean age 72 years) in London, 57 % had severe breathless- system’s negative effects is the possible advantage of
ness, 92 % said breathlessness was their most important prob- slowing the respiratory rate in those patients reducing breath
lem, and 21 % felt they were on suboptimal treatment [181]. stacking and allowing more time for exhalation. The overall
Elderly patients with COPD have been shown to have worse effect of reducing dynamic hyperinflation may be improved
dyspnea and poorer quality of life than many patients with ventilation and exercise tolerance, but this can be difficult to
cancer [182, 183]. Early discussions with the elderly patient predict in a patient with severe COPD. As a result, routine
about end-of-life issues and palliative approaches are needed use of opioids for breathlessness in COPD patients is
before the terminal phase of COPD [184]. Standard approaches reserved for those in a palliative medicine program.
to dyspnea in the COPD patient include oxygen therapy, but A Cochrane systematic review has evaluated the use
may include opioids and anxiolytics. The last two are more of benzodiazepines in breathlessness associated with
generously and commonly used in conjunction with a palliative advanced stages of cancer, idiopathic fibrosis, chronic heart
medicine approach in treating severe COPD because of the risk failure, motor neuron disease, and COPD [189]. They only
of increasing carbon dioxide retention. The American Thoracic found seven studies with about 200 patients that had either
Society guidelines for treating end-stage respiratory disease and advanced cancer or COPD. In these patients, no beneficial
critically ill patients stress the importance of palliative care in effect was found in reducing breathlessness with benzodi-
COPD [185]. Integrating palliative care into the management of azepines or in preventing breakthrough dyspnea. To date,
the severe COPD patient is a realistic goal [186]. no evidence of routine relief of breathlessness exists in
patients with advanced cancer or COPD [189].
4.1 Opioids and Anxiolytics
4.2 Systemic Anticholinergics/Antimuscarinic Agents
As noted, breathlessness is a significant problem in elderly
patients with severe or end-stage cases of COPD. A sys- The use of tertiary amine antimuscarinic agents in the
tematic review of the use of opioids in 18 double-blind, treatment of COPD historically included nebulized or
randomized, placebo-controlled trials of the treatment of smoked atropine and Datura stramonium, but their use was
dyspnea in COPD patients were included in the analysis. limited by the systemic effects including dilated pupils,
Nine of the trials used oral or parenteral opioids including urinary retention, and tachycardia. This resulted in the
morphine subcutaneous, dihydrocodeine oral, diamorphine development of antimuscarinic quaternary amine agents
oral, and slow-release morphine oral. The nine studies on such as ipratropium bromide that is less likely to cross
496 T. E. Albertson et al.

biological membranes and manifest systemic symptoms. In from the American College of Physicians, American College of
the treatment of severely disabled and hospice patients, the Chest Physicians, American Thoracic Society, and European
Respiratory Society. Ann Intern Med. 2011;155(3):179–91.
tertiary amine scopolamine (hyoscine), often as a patch, 2. Menezes AM, Perez-Padilla R, Jardim JR, Muino A, Lopez MV,
has been used to decrease drooling and reduce noisy res- Valdivia G, et al. Chronic obstructive pulmonary disease in five
pirations (‘‘death rattle’’) in hospice patients [190–192]. Latin American cities (the PLATINO study): a prevalence study.
This noisy breathing is thought to be caused by inspiratory Lancet. 2005;366(9500):1875–81.
3. Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P,
and expiratory movement of respiratory secretions in the Mannino DM, et al. International variation in the prevalence of
upper and lower airway. The drying effects of antimu- COPD (the BOLD study): a population-based prevalence study.
scarinic agents seem to improve this situation and in the Lancet. 2007;370(9589):741–50.
dying COPD patient, they actually also provide a second- 4. Global Strategy for Diagnosis, Management, and Prevention
of COPD. 2011.
ary bronchodilation effect. The central nervous system strategy-for-diagnosis-management.html. Accessed 24 Oct
(CNS) complications of tertiary amine anticholinergic/ 2012.
antimuscarinic agents have led to evaluating glycopyrro- 5. Ofir D, Laveneziana P, Webb KA, Lam YM, O’Donnell DE.
late, which is another quaternary amine antimuscarinic Mechanisms of dyspnea during cycle exercise in symptomatic
patients with GOLD stage I chronic obstructive pulmonary
agent that is associated with less CNS effects. No consis- disease. Am J Respir Crit Care Med. 2008;177(6):622–9.
tent advantage was noted in its use in palliative care 6. Nocturnal Oxygen Therapy Trial Group. Continuous or noc-
patients [193–196]. Since the use of these agents is pri- turnal oxygen therapy in hypoxemic chronic obstructive lung
marily symptom control, the limited data in the palliative disease: a clinical trial. Ann Intern Med. 1980;93(3):391–8.
7. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C,
care patients does not focus on their secondary broncho- Anzueto A, et al. Global strategy for the diagnosis, management,
dilator effects nor does it justify their use in this patient and prevention of chronic obstructive pulmonary disease:
population as bronchodilators. GOLD executive summary. Am J Respir Crit Care Med.
8. Yohannes AM, Roomi J, Baldwin RC, Connolly MJ. Depression
in elderly outpatients with disabling chronic obstructive pul-
5 Conclusion monary disease. Age Ageing. 1998;27(2):155–60.
9. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel
The elderly COPD patient represents an increasingly pre- VP, Bruijnzeel PL, et al. Clusters of comorbidities based on
validated objective measurements and systemic inflammation in
valent challenge, particularly in diagnosis and pharmaco- patients with chronic obstructive pulmonary disease. Am J
therapy to help reduce symptoms and decrease the risk of Respir Crit Care Med. 2013;187(7):728–35.
acute exacerbations from their disease and associated 10. Corsonello A, Antonelli Incalzi R, Pistelli R, Pedone C, Bu-
comorbidities. New and improved drug delivery devices and stacchini S, Lattanzio F. Comorbidities of chronic obstructive
pulmonary disease. Curr Opin Pulm Med. 2011;17(Suppl
medications have increased therapeutic options for the elderly 1):S21–8.
patient. Smoking cessation remains a cornerstone therapy and 11. Landi F, Pistelli R, Abbatecola AM, Barillaro C, Brandi V,
should be initiated as soon as possible. New oral medication Lattanzio F. Common geriatric conditions and disabilities in
options now exist and adjunctive approaches such as LTOT older persons with chronic obstructive pulmonary disease. Curr
Opin Pulm Med. 2011;17(Suppl 1):S29–34.
and pulmonary rehabilitation remain important. Infection 12. Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone
control with timely vaccinations can help reduce morbidity metabolism, and osteoporosis. Chest. 2011;139(3):648–57.
and mortality from influenza and pneumococcal pneumonia. 13. Sidney S, Sorel M, Quesenberry CP Jr, DeLuise C, Lanes S,
Palliative approaches that focus on symptom improvement Eisner MD. COPD and incident cardiovascular disease hospi-
talizations and mortality: Kaiser Permanente Medical Care
should be considered early in the course of COPD manage- Program. Chest. 2005;128(4):2068–75.
ment in concert with appropriate pharmacotherapy and defi- 14. van Ede L, Yzermans CJ, Brouwer HJ. Prevalence of depression
nitely for the end-stage elderly COPD patient. in patients with chronic obstructive pulmonary disease: a sys-
tematic review. Thorax. 1999;54(8):688–92.
Acknowledgments S. Louie has received payment for lectures and 15. Bhatt NY, Wood KL. What defines abnormal lung function in
is on the Speaker’s Bureaus for AstraZeneca, Boehringer-Ingelheim, older adults with chronic obstructive pulmonary disease? Drugs
Forest, GlaxoSmithKline, and Pfizer. M. Avdalovic is a paid speaker Aging. 2008;25(9):717–28.
for Novartis. T. Albertson is a paid speaker for GlaxoSmithKline. 16. Mannino DM, Watt G, Hole D, Gillis C, Hart C, McConnachie
A. Chan is a paid speaker for Forest, Intermune, Gilead, and Boeh- A, et al. The natural history of chronic obstructive pulmonary
ringer-Ingelheim. The other authors have nothing to disclose. disease. Eur Respir J. 2006;27(3):627–43.
17. Ottanelli R, Rosi E, Ronchi MC, Grazzini M, Lanini B, Sten-
dardi L, et al. Perception of bronchoconstriction in smokers with
airflow limitation. Clin Sci (Lond). 2001;101(5):515–22.
References 18. Gelberg J, McIvor RA. Overcoming gaps in the management of
chronic obstructive pulmonary disease in older patients: new
1. Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der insights. Drugs Aging. 2010;27(5):367–75.
Molen T, et al. Diagnosis and management of stable chronic 19. Jenkins CR, Jones PW, Calverley PM, Celli B, Anderson JA,
obstructive pulmonary disease: a clinical practice guideline update Ferguson GT, et al. Efficacy of salmeterol/fluticasone propionate
Treatment of the Elderly COPD Patient 497

by GOLD stage of chronic obstructive pulmonary disease: 37. Turner JR, Corkery KJ, Eckman D, Gelb AM, Lipavsky A,
analysis from the randomised, placebo-controlled TORCH Sheppard D. Equivalence of continuous flow nebulizer and
study. Respir Res. 2009;10:59. metered-dose inhaler with reservoir bag for treatment of acute
20. Hardie JA, Buist AS, Vollmer WM, Ellingsen I, Bakke PS, airflow obstruction. Chest. 1988;93(3):476–81.
Morkve O. Risk of over-diagnosis of COPD in asymptomatic 38. Sims MW. Aerosol therapy for obstructive lung diseases: device
elderly never-smokers. Eur Respir J. 2002;20(5):1117–22. selection and practice management issues. Chest. 2011;140(3):
21. Medbo A, Melbye H. Lung function testing in the elderly—can 781–8.
we still use FEV1/FVC \70% as a criterion of COPD? Respir 39. Chapman KR, Love L, Brubaker H. A comparison of breath-
Med. 2007;101(6):1097–105. actuated and conventional metered-dose inhaler inhalation
22. Lange P, Marott JL, Vestbo J, Olsen KR, Ingebrigtsen TS, Dahl techniques in elderly subjects. Chest. 1993;104(5):1332–7.
M, et al. Prediction of the clinical course of chronic obstructive 40. Ho SF, O’Mahony MS, Steward JA, Breay P, Burr ML. Inhaler
pulmonary disease, using the new GOLD classification: a study technique in older people in the community. Age Ageing.
of the general population. Am J Respir Crit Care Med. 2004;33(2):185–8.
2012;186(10):975–81. 41. Diggory P, Fernandez C, Humphrey A, Jones V, Murphy M.
23. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Comparison of elderly people’s technique in using two dry
Mendez RA, et al. The body-mass index, airflow obstruction, powder inhalers to deliver zanamivir: randomised controlled
dyspnea, and exercise capacity index in chronic obstructive trial. BMJ. 2001;322(7286):577–9.
pulmonary disease. N Engl J Med. 2004;350(10):1005–12. 42. Dhand R, Dolovich M, Chipps B, Myers TR, Restrepo R, Farrar
24. Casanova C, Cote C, de Torres JP, Aguirre-Jaime A, Marin JM, JR. The role of nebulized therapy in the management of COPD:
Pinto-Plata V, et al. Inspiratory-to-total lung capacity ratio evidence and recommendations. COPD. 2012;9(1):58–72.
predicts mortality in patients with chronic obstructive pulmon- 43. Guyatt GH, Townsend M, Nogradi S, Pugsley SO, Keller JL,
ary disease. Am J Respir Crit Care Med. 2005;171(6):591–7. Newhouse MT. Acute response to bronchodilator. An imperfect
25. Esteban C, Arostegui I, Moraza J, Aburto M, Quintana JM, guide for bronchodilator therapy in chronic airflow limitation.
Perez-Izquierdo J, et al. Development of a decision tree to assess Arch Intern Med. 1988;148(9):1949–52.
the severity and prognosis of stable COPD. Eur Respir J. 44. Hanrahan JP, Hanania NA, Calhoun WJ, Sahn SA, Sciarappa K,
2011;38(6):1294–300. Baumgartner RA. Effect of nebulized arformoterol on airway
26. Baumann HJ, Kluge S, Rummel K, Klose H, Hennigs JK, function in COPD: results from two randomized trials. COPD.
Schmoller T, et al. Low intensity, long-term outpatient reha- 2008;5(1):25–34.
bilitation in COPD: a randomised controlled trial. Respir Res. 45. Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne AM,
2012;13:86. Thomson MH, et al. Inhaled formoterol dry powder versus
27. Casanova C, Cote CG, Marin JM, de Torres JP, Aguirre-Jaime A, ipratropium bromide in chronic obstructive pulmonary disease.
Mendez R, et al. The 6-min walking distance: long-term follow up Am J Respir Crit Care Med. 2001;164(5):778–84.
in patients with COPD. Eur Respir J. 2007;29(3):535–40. 46. Kottakis J, Cioppa GD, Creemers J, Greefhorst L, Lecler V,
28. Polkey MI, Spruit MA, Edwards LD, Watkins ML, Pinto-Plata Pistelli R, et al. Faster onset of bronchodilation with formoterol
V, Vestbo J, et al. Six-minute-walk test in chronic obstructive than with salmeterol in patients with stable, moderate to severe
pulmonary disease: minimal clinically important difference for COPD: results of a randomized, double-blind clinical study. Can
death or hospitalization. Am J Respir Crit Care Med. 2013; Respir J. 2002;9(2):107–15.
187(4):382–6. 47. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C,
29. Centers for Disease Control and Prevention (CDC).Vital signs: Jones PW, et al. Salmeterol and fluticasone propionate and
current cigarette smoking among adults aged C18 years–United survival in chronic obstructive pulmonary disease. N Engl J
States, 2005–2010. MMWR Morb Mortal Wkly Rep. 2011; Med. 2007;356(8):775–89.
60(35):1207–12. 48. Rodrigo GJ, Neffen H. Comparison of indacaterol with tiotro-
30. Giovino GA, Mirza SA, Samet JM, Gupta PC, Jarvis MJ, Bhala pium or twice-daily long-acting b-agonists for stable COPD: a
N, et al. Tobacco use in 3 billion individuals from 16 countries: systematic review. Chest J. 2012;142(5):1104–10.
an analysis of nationally representative cross-sectional house- 49. Cope S, Capkun-Niggli G, Gale R, Lassen C, Owen R, Ouwens
hold surveys. Lancet. 2012;380(9842):668–79. MJ, et al. Efficacy of once-daily indacaterol relative to alter-
31. Schroeder SA. How clinicians can help smokers to quit. JAMA. native bronchodilators in COPD: a patient-level mixed treatment
2012;308(15):1586–7. comparison. Value Health. 2012;15(3):524–33.
32. Kim SK, Park JH, Lee JJ, Lee SB, Kim TH, Han JW, et al. Smoking 50. Donohue JF, Fogarty C, Lotvall J, Mahler DA, Worth H, Yor-
in elderly Koreans: prevalence and factors associated with smoking gancioglu A, et al. Once-daily bronchodilators for chronic
cessation. Arch Gerontol Geriatr. 2013;56(1):214–9. obstructive pulmonary disease: indacaterol versus tiotropium.
33. Rigotti NA. Strategies to help a smoker who is struggling to Am J Respir Crit Care Med. 2010;182(2):155–62.
quit. JAMA. 2012;308(15):1573–80. 51. Vogelmeier C, Magnussen H, LaForce C, Owen R, Kramer B.
34. Thabane M, COPD Working Group.Smoking cessation for Profiling the bronchodilator effects of the novel ultra-long-act-
patients with chronic obstructive pulmonary disease (COPD): an ing beta2-agonist indacaterol against established treatments in
evidence-based analysis. Ont Health Technol Assess Ser. chronic obstructive pulmonary disease. Ther Adv Respir Dis.
2012;12(4):1–50. 2011;5(5):345–57.
35. Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al. 52. Mochizuki H, Nanjo Y, Takahashi H. Better adherence to a
Comparison of the effectiveness of inhaler devices in asthma and transdermal tulobuterol patch than inhaled salmeterol in elderly
chronic obstructive airways disease: a systematic review of the chronic obstructive pulmonary disease patients. Geriatr Gerontol
literature. Health Technol Assess. 2001;5(26):1–149. Int. 2013;13(2):398–404.
36. Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau 53. Stefan MS, Rothberg MB, Priya A, Pekow PS, Au DH, Lindenauer
JL, et al. Device selection and outcomes of aerosol therapy: PK. Association between beta-blocker therapy and outcomes in
evidence-based guidelines: American College of Chest Physi- patients hospitalised with acute exacerbations of chronic
cians/American College of Asthma, Allergy, and Immunology. obstructive lung disease with underlying ischaemic heart disease,
Chest. 2005;127(1):335–71. heart failure or hypertension. Thorax. 2012;67(11):977–84.
498 T. E. Albertson et al.

54. Mentz RJ, Wojdyla D, Fiuzat M, Chiswell K, Fonarow GC, 72. VandeGriend JP, Linnebur SA. Inhaled anticholinergic agents
O’Connor CM. Association of beta-blocker use and selectivity and acute urinary retention in men with lower urinary tract
with outcomes in patients with heart failure and chronic symptoms or benign prostatic hyperplasia. Ann Pharmacother.
obstructive pulmonary disease (from OPTIMIZE-HF). Am J 2012;46(9):1245–9.
Cardiol. 2013;111:582–7. 73. Maltais F, Milot J. The potential for aclidinium bromide, a new
55. Hawkins NM, Petrie MC, Macdonald MR, Jhund PS, Fabbri anticholinergic, in the management of chronic obstructive pul-
LM, Wikstrand J, et al. Heart failure and chronic obstructive monary disease. Ther Adv Respir Dis. 2012;6(6):345–61.
pulmonary disease the quandary of beta-blockers and beta- 74. Hilleman DE, Malesker MA, Morrow LE, Schuller D. A sys-
agonists. J Am Coll Cardiol. 2011;57(21):2127–38. tematic review of the cardiovascular risk of inhaled anticholin-
56. Ekström MP, Hermansson AB, Ström KE. Effects of cardio- ergics in patients with COPD. Int J Chron Obstruct Pulmon Dis.
vascular drugs on mortality in severe COPD: a time-dependent 2009;4:253–63.
analysis. Am J Respir Crit Care Med. 2013;187(7):715–20. 75. Jara M, Wentworth C 3rd, Lanes S. A new user cohort study
57. Barnes PJ. The pharmacological properties of tiotropium. Chest. comparing the safety of long-acting inhaled bronchodilators in
2000;117(2 Suppl):63S–6S. COPD. BMJ Open. 2012;2(3):e000841.
58. Keam SJ, Keating GM. Tiotropium bromide. A review of its use 76. Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. Broncho-
as maintenance therapy in patients with COPD. Treat Respir dilator use and the risk of arrhythmia in COPD: part 2: reassessment
Med. 2004;3(4):247–68. in the larger Quebec cohort. Chest. 2012;142(2):305–11.
59. Tashkin DP, Ashutosh K, Bleecker ER, Britt EJ, Cugell DW, 77. Gershon AS, Wang L, To T, Luo J, Upshur RE. Survival with
Cummiskey JM, et al. Comparison of the anticholinergic bron- tiotropium compared to long-acting beta-2-agonists in chronic
chodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. COPD. 2008;5(4):229–34.
obstructive pulmonary disease. A 90-day multi-center study. Am 78. Gershon A, Croxford R, To T, Stanbrook MB, Upshur R, San-
J Med. 1986;81(5A):81–90. chez-Romeu P, et al. Comparison of inhaled long-acting beta-
60. van Noord JA, de Munck DR, Bantje TA, Hop WC, Akveld ML, agonist and anticholinergic effectiveness in older patients with
Bommer AM. Long-term treatment of chronic obstructive pul- chronic obstructive pulmonary disease: a cohort study. Ann
monary disease with salmeterol and the additive effect of Intern Med. 2011;154(9):583–92.
ipratropium. Eur Respir J. 2000;15(5):878–85. 79. Yu AP, Guerin A, Ponce de Leon D, Ramakrishnan K, Wu EQ,
61. COMBIVENT Inhalation Aerosol Study Group. In chronic Mocarski M, et al. Therapy persistence and adherence in
obstructive pulmonary disease, a combination of ipratropium patients with chronic obstructive pulmonary disease: multiple
and albuterol is more effective than either agent alone. An versus single long-acting maintenance inhalers. J Med Econ.
85-day multicenter trial. Chest. 1994;105(5):1411–9. 2011;14(4):486–96.
62. Frith PA, Jenner B, Dangerfield R, Atkinson J, Drennan C. 80. Yu AP, Guerin A, de Leon DP, Ramakrishnan K, Wu EQ,
Oxitropium bromide. Dose-response and time-response study of Mocarski M, et al. Clinical and economic outcomes of multiple
a new anticholinergic bronchodilator drug. Chest. 1986;89(2): versus single long-acting inhalers in COPD. Respir Med.
249–53. 2011;105(12):1861–71.
63. Montuschi P, Macagno F, Valente S, Fuso L. Inhaled muscarinic 81. Gordon J, Panos RJ. Inhaled albuterol/salbutamol and ipratro-
acetylcholine receptor antagonists for treatment of COPD. Curr pium bromide and their combination in the treatment of chronic
Med Chem. 2012. obstructive pulmonary disease. Expert Opin Drug Metab Toxi-
64. Hodder R, Pavia D, Lee A, Bateman E. Lack of paradoxical col. 2010;6(3):381–92.
bronchoconstriction after administration of tiotropium via 82. Barnes PJ. Triple inhalers for obstructive airways disease: will
Respimat Soft MistTM Inhaler in COPD. Int J Chron Obstruct they be useful? Expert Rev Respir Med. 2011;5(3):297–300.
Pulmon Dis. 2011;6:245–51. 83. Stockley RA. Progression of chronic obstructive pulmonary
65. Feldman G, Walker RR, Brooks J, Mehta R, Crater G. 28-Day disease: impact of inflammation, comorbidities and therapeutic
safety and tolerability of umeclidinium in combination with intervention. Curr Med Res Opin. 2009;25(5):1235–45.
vilanterol in COPD: a randomized placebo-controlled trial. Pulm 84. Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross
Pharmacol Ther. 2012;25(6):465–71. NJ, Light RW, et al. Effect of systemic glucocorticoids on
66. Perng DW, Wu CC, Su KC, Lee YC, Perng RP, Tao CW. exacerbations of chronic obstructive pulmonary disease.
Additive benefits of tiotropium in COPD patients treated with Department of Veterans Affairs Cooperative Study Group.
long-acting beta agonists and corticosteroids. Respirology. N Engl J Med. 1999;340(25):1941–7.
2006;11(5):598–602. 85. Lindenauer PK, Pekow PS, Lahti MC, Lee Y, Benjamin EM,
67. Keating GM. Tiotropium bromide inhalation powder: a review Rothberg MB. Association of corticosteroid dose and route of
of its use in the management of chronic obstructive pulmonary administration with risk of treatment failure in acute exacerba-
disease. Drugs. 2012;72(2):273–300. tion of chronic obstructive pulmonary disease. JAMA. 2010;
68. Kerstjens HA, Bantje TA, Luursema PB, Sinninghe Damste HE, 303(23):2359–67.
de Jong JW, Lee A, et al. Effects of short-acting bronchodilators 86. Albert RK, Martin TR, Lewis SW. Controlled clinical trial of
added to maintenance tiotropium therapy. Chest. 2007;132(5): methylprednisolone in patients with chronic bronchitis and acute
1493–9. respiratory insufficiency. Ann Intern Med. 1980;92(6):753–8.
69. Cole JM, Sheehan AH, Jordan JK. Concomitant use of ipratro- 87. Singh JM, Palda VA, Stanbrook MB, Chapman KR. Cortico-
pium and tiotropium in chronic obstructive pulmonary disease. steroid therapy for patients with acute exacerbations of chronic
Ann Pharmacother. 2012;46(12):1717–21. obstructive pulmonary disease: a systematic review. Arch Intern
70. Karner C, Cates CJ. Long-acting beta(2)-agonist in addition to Med. 2002;162(22):2527–36.
tiotropium versus either tiotropium or long-acting beta(2)-ago- 88. Walters JA, Gibson PG, Wood-Baker R, Hannay M, Walters
nist alone for chronic obstructive pulmonary disease. Cochrane EH. Systemic corticosteroids for acute exacerbations of chronic
Database Syst Rev. 2012;4:CD008989. obstructive pulmonary disease. Cochrane Database Syst Rev.
71. Cramer JA, Bradley-Kennedy C, Scalera A. Treatment persis- 2009(1):CD001288.
tence and compliance with medications for chronic obstructive 89. de Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA,
pulmonary disease. Can Respir J. 2007;14(1):25–9. van den Berg JW. Oral or IV prednisolone in the treatment of
Treatment of the Elderly COPD Patient 499

COPD exacerbations: a randomized, controlled, double-blind 107. Jenne JW, Siever JR, Druz WS, Solano JV, Cohen SM, Sharp
study. Chest. 2007;132(6):1741–7. JT. The effect of maintenance theophylline therapy on lung
90. Stoller JK. Clinical practice. Acute exacerbations of chronic work in severe chronic obstructive pulmonary disease while
obstructive pulmonary disease. N Engl J Med. 2002;346(13): standing and walking. Am Rev Respir Dis. 1984;130(4):600–5.
988–94. 108. Murciano D, Aubier M, Lecocguic Y, Pariente R. Effects of
91. Man SF, Xuekui Z, Vessey R, Walker T, Lee K, Park D, et al. theophylline on diaphragmatic strength and fatigue in patients
The effects of inhaled and oral corticosteroids on serum with chronic obstructive pulmonary disease. N Engl J Med.
inflammatory biomarkers in COPD: an exploratory study. Ther 1984;311(6):349–53.
Adv Respir Dis. 2009;3(2):73–80. 109. Zhang J, Feng MX, Qu JM. Low dose theophylline showed an
92. O’Brien A, Ward NS. Steroid therapy in chronic obstructive inhibitory effect on the production of IL-6 and IL-8 in primary
pulmonary disease. Med Health R I. 2002;85(2):52–5. lung fibroblast from patients with COPD. Mediators Inflamm.
93. Spencer S, Karner C, Cates CJ, Evans DJ. Inhaled corticoste- 2012;2012:492901.
roids versus long-acting beta(2)-agonists for chronic obstructive 110. Morfin Maciel BM, Castillo Morfin BM. Theophylline, a new
pulmonary disease. Cochrane Database Syst Rev. 2011(12): look to an old drug. Rev Alerg Mex. 2010;57(4):112–22.
CD007033. 111. Alexander MR, Dull WL, Kasik JE. Treatment of chronic
94. Guenette JA, Raghavan N, Harris-McAllister V, Preston ME, obstructive pulmonary disease with orally administered the-
Webb KA, O’Donnell DE. Effect of adjunct fluticasone propi- ophylline. A double-blind, controlled study. JAMA. 1980;
onate on airway physiology during rest and exercise in COPD. 244(20):2286–90.
Respir Med. 2011;105(12):1836–45. 112. Clark CJ, Boyd G. Combination of aminophylline (Phyllocontin
95. Boscia JA, Pudi KK, Zvarich MT, Sanford L, Siederer SK, Crim Continus tablets) and salbutamol in the management of chronic
C. Effect of once-daily fluticasone furoate/vilanterol on 24-hour obstructive airways disease. Br J Clin Pharmacol. 1980;9(4):
pulmonary function in patients with chronic obstructive pul- 359–64.
monary disease: a randomized, three-way, incomplete block, 113. Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM,
crossover study. Clin Ther. 2012;34(8):1655–66 e5. Barnes PJ. Treatment effects of low-dose theophylline combined
96. Singh S, Loke YK. An overview of the benefits and drawbacks with an inhaled corticosteroid in COPD. Chest. 2010;137(6):
of inhaled corticosteroids in chronic obstructive pulmonary 1338–44.
disease. Int J Chron Obstruct Pulmon Dis. 2010;5:189–95. 114. Wang CH, Zhang Q, Li M, Fu PF, Yan ZM, Peng AM, et al.
97. Tashkin DP, Doherty DE, Kerwin E, Matiz-Bueno CE, Knorr B, Meta-analysis of efficacy and safety of oral theophylline in
Shekar T, et al. Efficacy and safety characteristics of mometa- chronic obstructive pulmonary disease. Zhonghua Yi Xue Za
sone furoate/formoterol fumarate fixed-dose combination in Zhi. 2010;90(8):540–6.
subjects with moderate to very severe COPD: findings from 115. Shukla D, Chakraborty S, Singh S, Mishra B. Doxofylline: a
pooled analysis of two randomized, 52-week placebo-controlled promising methylxanthine derivative for the treatment of asthma
trials. Int J Chron Obstruct Pulmon Dis. 2012;7:73–86. and chronic obstructive pulmonary disease. Expert Opin Phar-
98. Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and macother. 2009;10(14):2343–56.
long-acting beta(2)-agonist in one inhaler versus long-acting 116. Rizzo A, Mirabella A, Ferrara G, Pipitone P, Bellia V, Bonsi-
beta(2)-agonists for chronic obstructive pulmonary disease. gnore G. Theophylline pharmacokinetics in patients with mild or
Cochrane Database Syst Rev. 2012;9:CD006829. severe airway obstruction. Bull Eur Physiopathol Respir. 1982;
99. Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and 18(6):811–8.
long-acting beta2-agonist versus tiotropium for chronic 117. Au WY, Dutt AK, DeSoyza N. Theophylline kinetics in chronic
obstructive pulmonary disease. Cochrane Database Syst Rev. obstructive airway disease in the elderly. Clin Pharmacol Ther.
2010(5):CD007891. 1985;37(4):472–8.
100. Karner C, Cates CJ. Combination inhaled steroid and long-act- 118. Jenne JW. Effect of disease states on theophylline elimination.
ing beta(2)-agonist in addition to tiotropium versus tiotropium J Allergy Clin Immunol. 1986;78(4 Pt 2):727–35.
or combination alone for chronic obstructive pulmonary disease. 119. Vestal RE, Thummel KE, Musser B, Mercer GD. Cimetidine
Cochrane Database Syst Rev. 2011(3):CD008532. inhibits theophylline clearance in patients with chronic
101. Dalal AA, Roberts MH, Petersen HV, Blanchette CM, Mapel obstructive pulmonary disease: a study using stable isotope
DW. Comparative cost-effectiveness of a fluticasone-propio- methodology during multiple oral dose administration. Br J Clin
nate/salmeterol combination versus anticholinergics as initial Pharmacol. 1983;15(4):411–8.
maintenance therapy for chronic obstructive pulmonary disease. 120. Patel AK, Skatrud JB, Thomsen JH. Cardiac arrhythmias due to
Int J Chron Obstruct Pulmon Dis. 2011;6:13–22. oral aminophylline in patients with chronic obstructive pul-
102. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van monary disease. Chest. 1981;80(6):661–5.
Herwaarden C. Effect of discontinuation of inhaled corticosteroids 121. Gupta P, O’Mahony MS. Potential adverse effects of bron-
in patients with chronic obstructive pulmonary disease: the COPE chodilators in the treatment of airways obstruction in older
study. Am J Respir Crit Care Med. 2002;166(10):1358–63. people: recommendations for prescribing. Drugs Aging. 2008;
103. McEvoy CE, Ensrud KE, Bender E, Genant HK, Yu W, Griffith 25(5):415–43.
JM, et al. Association between corticosteroid use and vertebral 122. Lee TA, Schumock GT, Bartle B, Pickard AS. Mortality risk in
fractures in older men with chronic obstructive pulmonary dis- patients receiving drug regimens with theophylline for chronic
ease. Am J Respir Crit Care Med. 1998;157(3 Pt 1):704–9. obstructive pulmonary disease. Pharmacotherapy. 2009;29(9):
104. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the 1039–53.
risks of diabetes onset and progression. Am J Med. 2010; 123. Rabe KF, Hiemstra PS. Theophylline for chronic obstructive
123(11):1001–6. pulmonary disease?….Time to move on. Am J Respir Crit Care
105. Sharp JT. Theophylline in chronic obstructive pulmonary dis- Med. 2010;182(7):868–9.
ease. J Allergy Clin Immunol. 1986;78(4 Pt 2):800–5. 124. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri
106. Aubier M. Effect of theophylline on diaphragmatic and other LM, Martinez FJ. Roflumilast in symptomatic chronic obstruc-
skeletal muscle function. J Allergy Clin Immunol. 1986;78(4 Pt tive pulmonary disease: two randomised clinical trials. Lancet.
2):787–92. 2009;374(9691):685–94.
500 T. E. Albertson et al.

125. Rennard SI, Calverley PM, Goehring UM, Bredenbroker D, 144. Cranston JM, Crockett AJ, Moss JR, Alpers JH. Domiciliary
Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor oxygen for chronic obstructive pulmonary disease. Cochrane
roflumilast—the importance of defining different subsets of Database Syst Rev. 2005(4):CD001744.
patients with COPD. Respir Res. 2011;12:18. 145. COPD Working Group.Long-term oxygen therapy for patients
126. Gross NJ, Giembycz MA, Rennard SI. Treatment of chronic with chronic obstructive pulmonary disease (COPD): an evi-
obstructive pulmonary disease with roflumilast, a new phos- dence-based analysis. Ont Health Technol Assess Ser. 2012;
phodiesterase 4 inhibitor. COPD. 2010;7(2):141–53. 12(7):1–64.
127. Cazzola M, Picciolo S, Matera MG. Roflumilast in chronic 146. Zielinski J, Tobiasz M, Hawrylkiewicz I, Sliwinski P, Palas-
obstructive pulmonary disease: evidence from large trials. iewicz G. Effects of long-term oxygen therapy on pulmonary
Expert Opin Pharmacother. 2010;11(3):441–9. hemodynamics in COPD patients: a 6-year prospective study.
128. Ulrik CS, Calverley PM. Roflumilast: clinical benefit in patients Chest. 1998;113(1):65–70.
suffering from COPD. Clin Respir J. 2010;4(4):197–201. 147. Weitzenblum E, Apprill M, Oswald M. Benefit from long-term
129. Wilson R, Anzueto A, Miravitlles M, Arvis P, Alder J, Haver- O2 therapy in chronic obstructive pulmonary disease patients.
stock D, et al. Moxifloxacin versus amoxicillin/clavulanic acid Respiration. 1992;59(Suppl 2):14–7.
in outpatient acute exacerbations of COPD: MAESTRAL 148. Shujaat A, Bajwa AA, Cury JD. Pulmonary hypertension sec-
results. Eur Respir J. 2012;40(1):17–27. ondary to COPD. Pulm Med. 2012;2012:203952.
130. Wilson R, Macklin-Doherty A. The use of moxifloxacin for 149. Paul J, Otvos T. Comparison of nasal cannulas and the OxyArm
acute exacerbations of chronic obstructive pulmonary disease in patients requiring chronic domiciliary oxygen therapy. Can
and chronic bronchitis. Expert Rev Respir Med. 2012;6(5): Respir J. 2006;13(8):421–6.
481–92. 150. Eaton T, Fergusson W, Kolbe J, Lewis CA, West T. Short-burst
131. Castaldo RS, Celli BR, Gomez F, LaVallee N, Souhrada J, oxygen therapy for COPD patients: a 6-month randomised,
Hanrahan JP. A comparison of 5-day courses of dirithromycin controlled study. Eur Respir J. 2006;27(4):697–704.
and azithromycin in the treatment of acute exacerbations of 151. Centers for Disease Control and Prevention (CDC).Fatal fires
chronic obstructive pulmonary disease. Clin Ther. 2003;25(2): associated with smoking during long-term oxygen therapy—
542–57. Maine, Massachusetts, New Hampshire, and Oklahoma, 2000–
132. Spagnolo P, Fabbri LM, Bush A. Long-term macrolide treat- 2007. MMWR Morb Mortal Wkly Rep. 2008;57(31):852–4.
ment for chronic respiratory disease. Eur Respir J. 2012. doi: 152. Pesek R, Lockey R. Vaccination of adults with asthma and
10.1183/09031936.00136712. COPD. Allergy. 2011;66(1):25–31.
133. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, 153. Nichol KL, Baken L, Nelson A. Relation between influenza
Criner GJ, et al. Azithromycin for prevention of exacerbations vaccination and outpatient visits, hospitalization, and mortality
of COPD. N Engl J Med. 2011;365(8):689–98. in elderly persons with chronic lung disease. Ann Intern Med.
134. Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, 1999;130(5):397–403.
et al. Azithromycin for prevention of exacerbations in non-cystic 154. Sehatzadeh S. Influenza and pneumococcal vaccinations for
fibrosis bronchiectasis (EMBRACE): a randomised, double- patients with chronic obstructive pulmonary disease (COPD): an
blind, placebo-controlled trial. Lancet. 2012;380(9842):660–7. evidence-based review. Ont Health Technol Assess Ser.
135. Cameron EJ, McSharry C, Chaudhuri R, Farrow S, Thomson 2012;12(3):1–64.
NC. Long-term macrolide treatment of chronic inflammatory 155. Centers for Disease Control and Prevention (CDC).Use of
airway diseases: risks, benefits and future developments. Clin 13-valent pneumococcal conjugate vaccine and 23-valent
Exp Allergy. 2012;42(9):1302–12. pneumococcal polysaccharide vaccine for adults with immuno-
136. Davies L, Calverley PM. The evidence for the use of oral compromising conditions: recommendations of the Advisory
mucolytic agents in chronic obstructive pulmonary disease Committee on Immunization Practices (ACIP). MMWR Morb
(COPD). Br Med Bull. 2010;93:217–27. Mortal Wkly Rep. 2012;61(40):816–9.
137. Poole P, Black PN. Mucolytic agents for chronic bronchitis or 156. Grijalva CG, Pelton SI. A second-generation pneumococcal
chronic obstructive pulmonary disease. Cochrane Database Syst conjugate vaccine for prevention of pneumococcal diseases in
Rev. 2010(2):CD001287. children. Curr Opin Pediatr. 2011;23(1):98–104.
138. Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, et al. 157. Scott LJ, Sanford M. Pneumococcal polysaccharide conjugate
Effect of carbocisteine on acute exacerbation of chronic vaccine (13-valent, adsorbed): a guide to its use in older adults.
obstructive pulmonary disease (PEACE study): a randomised Drugs Aging. 2012;29(10):847–55.
placebo-controlled study. Lancet. 2008;371(9629):2013–8. 158. Paradiso PR. Pneumococcal conjugate vaccine for adults: a new
139. Guell Rous R. Long-term oxygen therapy: are we prescribing paradigm. Clin Infect Dis. 2012;55(2):259–64.
appropriately? Int J Chron Obstruct Pulmon Dis. 2008;3(2): 159. Ridda I, Musher DM. Is there a potential role for protein-con-
231–7. jugate pneumococcal vaccine in older adults? Austral Med J.
140. Katsura H, Ogata M, Kida K. Factors determining outcome in 2012;5(4):231–5.
elderly patients with severe COPD on long-term domiciliary 160. JCVI. JCVI statement on the routine pneumococcal vaccination
oxygen therapy. Monaldi Arch Chest Dis. 2001;56(3):195–201. programme for adults aged 65 years and older. 2011. http://
141. Crockett AJ, Cranston JM, Moss JR, Alpers JH. Survival on
long-term oxygen therapy in chronic airflow limitation: from @ab/documents/digitalasset/dh_128704.pdf. Accessed 24 Oct
evidence to outcomes in the routine clinical setting. Intern Med 2012.
J. 2001;31(8):448–54. 161. Centers for Disease Control and Prevention (CDC).Pertussis
142. Dubois P, Jamart J, Machiels J, Smeets F, Lulling J. Prognosis epidemic—Washington, 2012. MMWR Morb Mortal Wkly Rep.
of severely hypoxemic patients receiving long-term oxygen 2012;61(28):517–22.
therapy. Chest. 1994;105(2):469–74. 162. Rodgers L, Martin SW, Cohn A, Budd J, Marcon M, Terranella A,
143. Long term domiciliary oxygen therapy in chronic hypoxic cor et al. Epidemiologic and laboratory features of a large outbreak of
pulmonale complicating chronic bronchitis and emphysema. pertussis-like illnesses associated with co-circulating Bordetella
Report of the Medical Research Council Working Party. Lancet. holmesii and Bordetella pertussis—Ohio, 2010–2011. Clin Infect
1981;1(8222):681–6. Dis. 2013;56:322–31.
Treatment of the Elderly COPD Patient 501

163. Baugh V, McCarthy N. Outbreak of Bordetella pertussis among obstructive pulmonary disease: a prospective community sur-
oncology nurse specialists. Occup Med (Lond). 2010;60(5):401–5. vey. Br J Gen Pract. 2011;61(587):e362–70.
164. Harju TH, Leinonen M, Nokso-Koivisto J, Korhonen T, Raty R, 182. Edmonds P, Karlsen S, Khan S, Addington-Hall J. A compari-
He Q, et al. Pathogenic bacteria and viruses in induced sputum son of the palliative care needs of patients dying from chronic
or pharyngeal secretions of adults with stable asthma. Thorax. respiratory diseases and lung cancer. Palliat Med. 2001;15(4):
2006;61(7):579–84. 287–95.
165. Bonhoeffer J, Bar G, Riffelmann M, Soler M, Heininger U. The 183. Gore JM, Brophy CJ, Greenstone MA. How well do we care for
role of Bordetella infections in patients with acute exacerbation patients with end stage chronic obstructive pulmonary disease
of chronic bronchitis. Infection. 2005;33(1):13–7. (COPD)? A comparison of palliative care and quality of life in
166. Couser JI Jr, Guthmann R, Hamadeh MA, Kane CS. Pulmonary COPD and lung cancer. Thorax. 2000;55(12):1000–6.
rehabilitation improves exercise capacity in older elderly 184. Nazir SA, Erbland ML. Chronic obstructive pulmonary disease:
patients with COPD. Chest. 1995;107(3):730–4. an update on diagnosis and management issues in older adults.
167. O’Donnell DE, Webb KA, McGuire MA. Older patients with Drugs Aging. 2009;26(10):813–31.
COPD: benefits of exercise training. Geriatrics. 1993;48(1): 185. Lanken PN, Terry PB, Delisser HM, Fahy BF, Hansen-Flaschen
59–62, 65–6. J, Heffner JE, et al. An official American Thoracic Society
168. Puhan MA, Gimeno-Santos E, Scharplatz M, Troosters T, clinical policy statement: palliative care for patients with
Walters EH, Steurer J. Pulmonary rehabilitation following respiratory diseases and critical illnesses. Am J Respir Crit Care
exacerbations of chronic obstructive pulmonary disease. Coch- Med. 2008;177(8):912–27.
rane Database Syst Rev. 2011(10):CD005305. 186. Hardin KA, Meyers F, Louie S. Integrating palliative care in severe
169. McDonald VM, Higgins I, Simpson JL, Gibson PG. The chronic obstructive lung disease. COPD. 2008;5(4):207–20.
importance of clinical management problems in older people 187. Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A
with COPD and asthma: do patients and physicians agree? Prim systematic review of the use of opioids in the management of
Care Respir J. 2011;20(4):389–95. dyspnoea. Thorax. 2002;57(11):939–44.
170. Corhay JL, Nguyen D, Duysinx B, Graas C, Pirnay F, Bury T, 188. Jensen D, Alsuhail A, Viola R, Dudgeon DJ, Webb KA,
et al. Should we exclude elderly patients with chronic obstruc- O’Donnell DE. Inhaled fentanyl citrate improves exercise
tive pulmonary disease from a long-time ambulatory pulmonary endurance during high-intensity constant work rate cycle exer-
rehabilitation programme? J Rehabil Med. 2012;44(5):466–72. cise in chronic obstructive pulmonary disease. J Pain Symptom
171. Pulmonary rehabilitation for patients with chronic pulmonary Manage. 2012;43(4):706–19.
disease (COPD): an evidence-based analysis. Ont Health 189. Simon ST, Higginson IJ, Booth S, Harding R, Bausewein C.
Technol Assess Ser. 2012;12(6):1–75. Benzodiazepines for the relief of breathlessness in advanced
172. Wysocki M, Antonelli M. Noninvasive mechanical ventilation malignant and non-malignant diseases in adults. Cochrane
in acute hypoxaemic respiratory failure. Eur Respir J. 2001; Database Syst Rev. 2010(1):CD007354.
18(1):209–20. 190. Kintzel PE, Chase SL, Thomas W, Vancamp DM, Clements EA.
173. Scarpazza P, Incorvaia C, di Franco G, Raschi S, Usai P, Ber- Anticholinergic medications for managing noisy respirations in
nareggi M, et al. Effect of noninvasive mechanical ventilation in adult hospice patients. Am J Health Syst Pharm. 2009;66(5):
elderly patients with hypercapnic acute-on-chronic respiratory 458–64.
failure and a do-not-intubate order. Int J Chron Obstruct Pulmon 191. Mato A, Limeres J, Tomas I, Munoz M, Abuin C, Feijoo JF,
Dis. 2008;3(4):797–801. et al. Management of drooling in disabled patients with sco-
174. Nava S, Grassi M, Fanfulla F, Domenighetti G, Carlucci A, polamine patches. Br J Clin Pharmacol. 2010;69(6):684–8.
Perren A, et al. Non-invasive ventilation in elderly patients with 192. Bennett MI. Death rattle: an audit of hyoscine (scopolamine) use
acute hypercapnic respiratory failure: a randomised controlled and review of management. J Pain Symptom Manage.
trial. Age Ageing. 2011;40(4):444–50. 1996;12(4):229–33.
175. O’Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk 193. Back IN, Jenkins K, Blower A, Beckhelling J. A study com-
DD, Balter M, et al. Canadian Thoracic Society recommenda- paring hyoscine hydrobromide and glycopyrrolate in the treat-
tions for management of chronic obstructive pulmonary dis- ment of death rattle. Palliat Med. 2001;15(4):329–36.
ease—2007 update. Can Respir J. 2007;14(Suppl B):5B–32B. 194. Hugel H, Ellershaw J, Gambles M. Respiratory tract secretions
176. Miravitlles M, Soler-Cataluna JJ, Calle M, Molina J, Almagro P, in the dying patient: a comparison between glycopyrronium and
Quintano JA, et al. Spanish COPD Guidelines (GesEPOC): hyoscine hydrobromide. J Palliat Med. 2006;9(2):279–84.
pharmacological treatment of stable COPD. Spanish Society of 195. Likar R, Rupacher E, Kager H, Molnar M, Pipam W, Sittl R.
Pulmonology and Thoracic Surgery. Arch Bronconeumol. Efficacy of glycopyrronium bromide and scopolamine hydro-
2012;48(7):247–57. bromide in patients with death rattle: a randomized controlled
177. Laube BL, Janssens HM, de Jongh FH, Devadason SG, Dhand study. Wiener klinische Wochenschrift. 2008;120(21–22):679.
R, Diot P, et al. What the pulmonary specialist should know 196. Wildiers H, Dhaenekint C, Demeulenaere P, Clement PM,
about the new inhalation therapies. Eur Respir J. 2011;37(6): Desmet M, Van Nuffelen R, et al. Atropine, hyoscine butylbr-
1308–31. omide, or scopolamine are equally effective for the treatment of
178. Tashkin DP. Is a long-acting inhaled bronchodilator the first death rattle in terminal care. J Pain Symptom Manage.
agent to use in stable chronic obstructive pulmonary disease? 2009;38(1):124–33.
Curr Opin Pulm Med. 2005;11(2):121–8. 197. Sharafkhaneh A, Southard JG, Goldman M, Uryniak T, Martin
179. Elkington H, White P, Addington-Hall J, Higgs R, Edmonds P. UJ. Effect of budesonide/formoterol pMDI on COPD exacer-
The healthcare needs of chronic obstructive pulmonary disease bations: a double-blind, randomized study. Respir Med. 2012;
patients in the last year of life. Palliat Med. 2005;19(6):485–91. 106(2):257–68.
180. Seamark DA, Seamark CJ, Halpin DM. Palliative care in 198. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA,
chronic obstructive pulmonary disease: a review for clinicians. Maslen TK. Randomised, double blind, placebo controlled study
J R Soc Med. 2007;100(5):225–33. of fluticasone propionate in patients with moderate to severe
181. White P, White S, Edmonds P, Gysels M, Moxham J, Seed P, chronic obstructive pulmonary disease: the ISOLDE trial. BMJ.
et al. Palliative care or end-of-life care in advanced chronic 2000;320(7245):1297–303.
502 T. E. Albertson et al.

199. Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg 203. Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van
C. Effect of fluticasone propionate/salmeterol (250/50 microg) Molken MP, Beeh KM, et al. Tiotropium versus salmeterol for
or salmeterol (50 microg) on COPD exacerbations. Respir Med. the prevention of exacerbations of COPD. N Engl J Med.
2008;102(8):1099–108. 2011;364(12):1093–103.
200. Anzueto A, Ferguson GT, Feldman G, Chinsky K, Seibert A, 204. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS,
Emmett A, et al. Effect of fluticasone propionate/salmeterol Brose M, Martinez FJ, et al. Roflumilast in moderate-to-severe
(250/50) on COPD exacerbations and impact on patient out- chronic obstructive pulmonary disease treated with longacting
comes. COPD. 2009;6(5):320–9. bronchodilators: two randomised clinical trials. Lancet.
201. Dusser D, Bravo ML, Iacono P. The effect of tiotropium on 2009;374(9691):695–703.
exacerbations and airflow in patients with COPD. Eur Respir J. 205. O’Donnell DE, Hernandez P, Kaplan A, Aaron S, Bourbeau J,
2006;27(3):547–55. Marciniuk D, et al. Canadian Thoracic Society recommenda-
202. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, tions for management of chronic obstructive pulmonary dis-
et al. A 4-year trial of tiotropium in chronic obstructive pul- ease—2008 update—highlights for primary care. Can Respir J.
monary disease. N Engl J Med. 2008;359(15):1543–54. 2008;15(Suppl A):1A–8A.
Reproduced with permission of the copyright owner. Further reproduction prohibited without