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Drugs Aging (2013) 30:479–502

DOI 10.1007/s40266-013-0080-1

REVIEW ARTICLE

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
e-mail: tealbertson@ucdavis.edu
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
Bronchodilators
Short-acting
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)
Long-acting
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
Methylxanthine
Theophylline
Vaccines
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)
Antibiotics
Azithromycin—available, but not approved for COPD in USA
Mucoregulators
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
a
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
b
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 (http://www.goldcopd.org 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
[47]
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
RDBMC—
3 years
[198]
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
487
Table 3 continued
488

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
RDBMC—
6 months
[134]
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
Add
MISTAL
[201]
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
[202]
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
RDBMC–
medications
DD— 74.6 % male
1 year
[203]
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
[124]
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
RDBMC—
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
Comments

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
Results

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
Demography

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
RDBMC—

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


N = 709

1 year
PEACE

[138]
study

cholinergic-related adverse events were reported to be


Trial

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
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