US Pharm. 2007:32(7):30-36.
Chronic obstructive pulmonary disease (COPD)
is a significant cause of morbidity and mortality in the United States. In
fact, 11.4 million Americans ages 18 and older were reported to suffer from
COPD in 2004; however, an estimated 24 million Americans have evidence of lung
dysfunction, indicating an underdiagnosis of the condition. Additionally, an
estimated 638,000 hospital discharges attributed to COPD were reported in
2004. Currently ranking as the fourth leading cause of death behind
cardiovascular disease, cancer, and stroke, COPD is expected to be the third
leading cause of death in 2020. COPD is also an expensive disease state to
manage, costing the U.S. a total of $37.2 billion in 2004 to treat COPD, with
$20.9 billion accounting for direct costs.1
Pathology and Clinical
Presentation
COPD is a condition
involving largely irreversible obstruction of the airways.2
Although other risk factors such as occupational exposures (e.g., chemicals,
dust, asbestos), genetics, and childhood illnesses have been identified,
tobacco smoking is responsible for 80% to 90% of deaths from COPD.1
Particles from cigarette smoke activate neutrophils and macrophages in the
lungs, which results in a cascade of events involving the release of proteases
that eventually break down the connective tissue in the lungs. The release of
chemical mediators such as interleukin-8, leukotriene-B4, and tumor
necrosis factor by the inflammatory cells is also linked to structural damage.
Increased oxidative stress arising from an elevation in oxidants due to
cigarette smoke has been implicated. Excessive mucus production and cough are
attributed to an increase in goblet cells and mucus-producing glands as part
of the inflammatory response by the bronchi.2,3
Specifically, COPD is a term
that encompasses both emphysema and chronic bronchitis. Emphysema is
characterized by alveolar wall destruction involving compression of the
airways during inspiration due to loss of elastic recoil. Gases become
trapped, and ventilation and perfusion are impaired. Patients with emphysema
are commonly referred to as pink puffers, as they are generally thin
and present with dyspnea, tachypnea, pursed-lip breathing, and a flushed
appearance. Airway inflammation and narrowing and excessive mucus secretion
are characteristic of chronic bronchitis. Patients with chronic bronchitis
typically report chronic or recurrent mucus hypersecretion and a cough that
occurs on most days during three months of the year for at least two
consecutive years. Additionally, the function of cilia in the lungs is
impaired and can trap bacteria and viruses under the thick mucus secretions,
leading to an increased susceptibility to respiratory infections. Patients
with predominant chronic bronchitis also tend to be overweight. They may
present with a "barrel chest," cyanosis occuring from an increase in the
partial pressure of carbon dioxide relative to a decrease in the partial
pressure of oxygen, and peripheral edema due to right ventricular failure in
the setting of chronic hypoxia and pulmonary hypertension. Thus, patients with
chronic bronchitis are often referred to as blue bloaters. Although
distinctions are made with regard to clinical presentations of the COPD
subtypes, patients commonly present with signs and symptoms of both emphysema
and chronic bronchitis.2-5
Staging and Treatment
Recommendations for COPD
A staging system
for COPD has been developed as part of the Global Initiative for Chronic
Obstructive Lung Disease (GOLD) guidelines to help establish disease severity
and appropriate treatment recommendations (Table 1). Staging a patient
with suspected COPD involves the use of spirometry, including the forced
expiratory volume in one second (FEV1) and the forced vital
capacity (FVC). The presence of an FEV1/FVC ratio of less than 0.70
indicates airflow obstruction, while postbronchodilator FEV1 values
further assist in establishing the severity of COPD. Based on this staging
system, all patients classified with any degree of COPD severity are
recommended to reduce exposure to modifiable risk factors.6
Since most deaths associated
with COPD are attributed to tobacco smoking, patients are highly encouraged to
stop smoking. The Lung Health Study has demonstrated that smoking cessation is
the only intervention to reduce the decline in FEV1 and slow COPD
progression.7 Patients should be asked about their interest in
smoking cessation and assured that help is readily available when they are
committed to stop smoking.
The GOLD guidelines also
recommend the annual influenza vaccine to lower the risk for acute
exacerbations of COPD. The pneumococcal vaccination is advised in patients
with COPD who are 65 and older and for those who are younger than 65 and have
an FEV1 of less than 40% predicted in order to lower the incidence
of community-acquired pneumonia. As both Haemophilus influenzae and
Staphylococcus pneumoniae have been implicated as predominant bacteria
involved in COPD exacerbations, vaccinations against these microorganisms can
help reduce the risk of infection.
The addition of a short-acting
bronchodilator, such as albuterol or ipratropium, is recommended during all
stages of COPD on an as-needed basis for the quick relief of symptoms. These
agents work in a matter of minutes to provide bronchodilation. As patients
progress to stage II or moderate COPD, the addition of a long-acting
bronchodilator such as a beta-2 agonist (e.g., salmeterol, formoterol), an
anticholinergic (e.g., tiotropium, scheduled ipratropium), or a methylxanthine
(e.g., aminophylline, theophylline) is advised. Initiation of inhaled
corticosteroids continues to be debated in COPD owing to minimal effects on
the deterioration of lung function; however, GOLD guidelines suggest potential
addition during stage III or severe COPD if patients experience repeated
exacerbations. Oxygen therapy is reserved typically for the later stages of
COPD when hypoxemia is present.6,7
Use of Anticholinergics in
COPD
Anticholinergics
are used in the management of COPD for their bronchodilatory effects. These
agents are antagonists of muscarinic receptors (i.e., M1, M2
, and M3 subtypes). Blockade of these receptors in the smooth
muscle of the airways inhibits the activity of acetylcholine, which reduces
cyclic guanosine monophosphate levels to yield bronchodilation.8,9
Data regarding improvement of lung function with anticholinergic therapy have
ranged from no effect on lung function to modest improvements that are equal
or superior in efficacy to beta-2 agonists.7,10,11 A recent
meta-analysis of 22 trials involving 15,276 patients was conducted involving
clinical trials that studied anticholinergics or beta-2 agonists compared with
each other or to placebo administered for at least three months.12
Pooled results indicated that anticholinergic use resulted in a reduction in
severe COPD exacerbations by 33% and in respiratory mortality by 73% (absolute
risk reduction, 0.36%; number needed to treat, 278) when compared to placebo.
However, compared to placebo, beta-2 agonists were associated with an increase
in the risk of death (relative risk [RR] 2.47, confidence interval [CI]
1.12-5.45). When compared to anticholinergics, the use of beta-2 agonists was
associated with higher rates of COPD exacerbations requiring hospitalizations
(RR 1.95, CI 1.06-3.59). Clinical outcomes were not improved with combination
therapy of an anticholinergic and a beta-2 agonist.12
Additionally, anticholinergics notably improve exercise tolerance in patients
with COPD.13,14 Two commonly used anticholinergics in patients with
COPD include ipratropium bromide (Atrovent) and tiotropium bromide (Spiriva).
The addition of tiotropium to the market in 2004 has led to further studies
assessing its role in the management of COPD.8,9
Ipratropium and
Tiotropium: Ipratropium is considered a short-acting anticholinergic
because its effects last for four to six hours, although it may be prescribed
on a scheduled basis to provide sustained effects. However, tiotropium can be
given once daily because it has a duration of action extending beyond 24
hours. This is related to the fact that tiotropium dissociates much more
slowly from the M1 and M3 receptors, compared to
ipratropium. Ipratropium's onset of action is slower (about 20 minutes) than
that of albuterol (about five minutes), but ipratropium is commonly used to
provide quick relief and is available in both a metered-dose inhaler (MDI),
alone and in combination with albuterol, and as a solution for inhalation.
Tiotropium is not recommended to be used acutely, as its onset of action is
approximately 30 minutes following inhalation. It is available for use in a
HandiHaler device. Appropriate use of this device involves several key steps (
Table 2) and requires significant manual dexterity. Thus, this device may
be challenging for some patients such as those with arthritis.2,3,8,9
Dahl and colleagues conducted
a single-blind study to assess patient performance of appropriate HandiHaler
and MDI techniques four weeks after providing instructions for use. Patients
were given ipratropium two puffs four times daily via MDI and one placebo
capsule daily in the HandiHaler device. In the total population, patients
using the HandiHaler device had fewer errors in their technique compared to
those using a MDI (P <.01). Similar findings were demonstrated when
evaluating the subgroup of patients classified as "MDI beginners," indicating
they had never used a MDI before. However, findings among patients classified
as "MDI experienced," indicating they had used a MDI before, were similar but
not statistically significant (P = .096).15
Ipratropium and tiotropium are
both quarternary compounds and are minimally absorbed into systemic
circulation upon inhalation, thereby reducing the incidence of adverse drug
reactions. The most commonly reported side effects associated with these two
agents include dry mouth, nausea, and metallic taste. Other potential side
effects are tachycardia, blurred vision, urinary retention, and constipation.
Although minimal absorption is predicted, cautious use is warranted in
patients with benign prostatic hyperplasia and glaucoma, as anticholinergics
may worsen these conditions.2,3,8,9,16
The effects of ipratropium and
tiotropium on lung function have been compared and reported in the medical
literature. Vincken and colleagues designed two identical, randomized,
double-dummy studies to assess the effects of ipratropium and tiotropium on
lung function and other clinical outcomes after one year of use.17
The results were included into one report. Five hundred thirty-five patients
with COPD were randomized to receive tiotropium 18 mcg once daily or
ipratropium 40 mcg four times a day. At the end of one year of treatment, the
FEV1 improved by 120 mL from baseline in the tiotropium group but
declined by 30 mL from baseline in the ipratropium group (P<.001). In
the tiotropium group, 31% experienced clinical improvement in the Transition
Dyspnea Index score compared to 18% in the ipratropium group (P =
.004). Hospitalizations and exacerbations were lower in patients receiving
tiotropium than in those receiving ipratropium (7.3% vs. 11.7%, P =
.014 and 35% vs. 46%, P= .11, respectively). The authors concluded that
tiotropium is beneficial in maintaining improvements in lung function and
dyspnea. The reduced effects noted with ipratropium may be explained by
frequent dosing that can lead to patient nonadherence.17
Combination Therapy
Typically, more
medications are added to the patient regimen as COPD progresses in order to
reduce the risk for hospitalizations due to exacerbations and to prevent
death. Patients with severe COPD frequently receive a combination of a
short-acting bronchodilator with a long-acting bronchodilator and perhaps an
inhaled corticosteroid depending on the frequency of exacerbations. Recently,
the results of a randomized, double-blind, placebo-controlled study of
combination therapy in COPD by Aaron and colleagues was reported.18
Patients with moderate to severe COPD were randomized to receive tiotropium
and placebo, tiotropium and salmeterol, or tiotropium, fluticasone, and
salmeterol for one year. Interestingly, the primary end point--the proportion
of patients who experienced exacerbations requiring the use of antibiotics or
hospitalizations--did not significantly differ among the groups (62.8% for
tiotropium and placebo, 64.8% for tiotropium and salmeterol, and 60% for
tiotropium, fluticasone, and salmeterol). However, patients receiving a
combination of the three drugs had a lower rate of severe COPD exacerbations
requiring hospitalizations (CI 0.33-0.86, P = 0.01) and improved lung
function (0.086 L vs. 0.027 L, P = .049) when compared to the
tiotropium and placebo group. Similar findings were not demonstrated when
comparing tiotropium and salmeterol to tiotropium and placebo. However,
cautious interpretation of the effects on lung function and severe COPD
exacerbations is warranted, as these clinical outcomes were secondary end
points. Additionally, the authors raise the issue of whether the lack of
finding a significant primary outcome is attributed to the fact that a true
clinical difference does not exist or if it was a lack of statistical power in
the study.18 Although this trial did not find any differences with
regard to treatment strategies affecting the primary outcome, the decision to
add medications to patients with worsening COPD should continue to be based on
sound clinical judgment, evidence-based recommendations, and patient-specific
parameters.
Formulary Considerations
Current treatment
modalities have minimal to modest impacts on the decline in pulmonary function
associated with COPD. However, they can improve patient quality of life. GOLD
guidelines recommend the addition of a long-acting bronchodilator for patients
with moderate COPD; however, the selection of bronchodilator is not specified.
Results from the recent meta-analysis indicate that anticholinergics may be
more beneficial to reduce COPD exacerbations and mortality, compared to beta-2
agonists. Until further head-to-head clinical studies can definitively
determine the superiority of a particular anticholinergic agent, the decision
of which anticholinergic to use should be based on patient-specific
parameters.
Tiotropium offers the
convenience of once-daily dosing and may increase patient adherence to
therapy. However, ipratropium can be effectively scheduled throughout the day
and may provide a more cost-effective treatment option for patients,
especially for those paying out of pocket. Patients requiring therapy with a
long-acting bronchodilator are likely receiving treatment with a short-acting
bronchodilator for quick relief based on GOLD guidelines. Thus, patients
prescribed tiotropium and a short-acting bronchodilator will receive two
devices that each require patient education for appropriate use. This may be
time intensive for some health care providers, who can simplify medication
regimens by having patients take both medications in MDI formulations.
Patients with significant limitations in manual dexterity may find the
HandiHaler device challenging and difficult to use; however, Dahl and
colleagues found that patients experienced fewer errors with the HandiHaler
device than with MDIs.15
Although different
anticholinergics are currently available, ensuring that the patient is
receiving the most appropriate therapy and optimizing the pharmacotherapy for
the patient based on disease severity are most important to reduce COPD
exacerbations, improve quality of life, and prevent mortality. As pharmacists
are considered among the most trusted health care providers, they are in an
ideal position to make appropriate, evidence-based recommendations to primary
care providers regarding the management of COPD on behalf of the patient.
Patient counseling about the role and importance of medications in COPD
treatment, appropriate device usage, and the importance of smoking cessation
is essential for pharmacist involvement in the management of patients with
COPD.
References
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