CHAPTER 5 PHARMACOLOGIC MANAGEMENT OF STABLE COPD Nicholas Anthonisen and Martin Boulé OBJECTIVESThe general objective of this chapter is to help the allied health care professionals and physicians becomemore familiar with the drug therapy commonly employed in patients with stable, symptomatic chronicobstructive pulmonary disease (COPD). Pharmacologic management is often based on an individualizedassessment of the disease and patient response to various medications.After reading this chapter, the physician and allied health care professional will be able to• identify the different classes of drugs used in COPD: bronchodilators, corticosteroids, and antibiotics;• appropriately use these drugs according to their beneﬁts and potential adverse effects;• recognize that, at this time, there are few other pharmacologic considerations;• recognize that there are many guidelines with differing recommendations; however, most recommenda- tions for pharmacologic management are empiric because of a lack of scientiﬁc information;• recognize that patients can be noncompliant with drug therapy; and• refer to speciﬁc professionals from the health care team when needed.P harmacologic therapy is an important part of managing COPD. However, it must be noted atthe outset that no drug therapy has been shown to the health status of patients with COPD is usually reﬂected by improvements in these areas. Although the management strategy is based on the patient’schange the course of the disease or to alter its long- symptoms and response to various therapies, it mayterm outlook and/or prognosis. Therefore, the ratio- also depend on adverse drug effects, patient skills innale for the use of these drugs is that they relieve using a speciﬁc inhalation device, and availability ofsymptoms and improve quality of life.1 medications. Since most patients with COPD seen in clinical In this chapter, we will review the accepted formspractice have less than optimal quality of life, this is of drug therapy for COPD and discuss their use.an important objective that is best assessed by care- Recommendations from national and internationalfully interviewing the patient. Such interviews must guidelines will be reviewed. Finally, issues related tobe structured to some extent to ascertain the sever- drug compliance will be discussed. Since exacerba-ity of symptoms such as dyspnea, cough, sputum, tions are covered elsewhere in this textbook and hos-and wheeze and the degree of exercise tolerance. pital management is beyond the textbook’s scope,Questions should be aimed at determining the pos- the main focus of the discussion will be on the treat-sibility of recent changes because improvement in ment of stable outpatients with COPD. 65
66 Comprehensive Management of Chronic Obstructive Pulmonary Disease BRONCHODILATOR THERAPY and greater bronchodilation8 simply because there are higher fractions of the total dosage in the lungsBronchodilators are the most important agents in and airways. For this reason, β2 agonists are verythe pharmacologic treatment of COPD.2 Bron- commonly administered by inhalation and shouldchodilator agents dilate the intrapulmonary airways, rarely be prescribed by other methods. The usualthereby decreasing airway resistance and improving short-acting β2 agonists speciﬁed above have a rela-ﬂow rates in and out of the lungs.3 Essentially, they tively short onset of action with noticeable effects inact as relaxants of the airway smooth muscle,4 which 15 minutes that can last 2 to 6 hours (Table 5–1).9is arranged so that its constriction, or even a normal Recently, long-acting β2 agonists such as salmeterolamount of muscle tone, tends to decrease the caliber xinafoate and formoterol fumarate have becomeof the airway and increase the resistance of airﬂow available. These agents induce bronchodilation thatthrough it. It should not be assumed that patients lasts 8 to 12 hours (Table 5–2).10with COPD have a poor response to bronchodila- Beta2 agonists have minor side effects such as ﬁnetors, even in those appearing to have essentially ﬁxed tremor, which is usually apparent only after largeairﬂow obstruction; several studies have demon- doses. With a conventional dose, the risk of sidestrated improvement in airﬂow following the use of effects is uncommon in patients with COPD (seeregularly dosed bronchodilators in most patients Table 5–1). Larger than conventional doses of β2with COPD, albeit to a lesser degree than in patients agonists may produce additional bronchodilation,with asthma.5,6 but further functional or symptomatic beneﬁt from There are essentially three types of bronchodila- such increased doses is limited to a small group oftor drugs: β2 agonists like salbutamol, anticholiner- patients with COPD with a lack of reproducibilitygic agents like ipratropium bromide, and methyl- for any given patient.11 Larger than conventionalxanthines like theophylline. There is excellent doses also increase the risk of side effects.evidence that ipratropium does not change theunderlying course of COPD7 and little reason to Anticholinergic Agentsbelieve that the other types of drugs differ from ipra- Anticholinergic drugs block receptors for acetyl-tropium in this respect. However, all of these drugs choline, a widely distributed substance that trans-are widely used because they tend to increase expi- mits impulses from one nerve to another and fromratory ﬂow rates such as the forced expiratory vol- nerve to muscle, including airway smooth muscle.4ume in 1 second (FEV1), tend to relieve dyspnea, As might be expected, anticholinergic agents thatand, ﬁnally, increase exercise tolerance.1 By optimiz- gain access to the circulation, like atropine sulfate,ing bronchodilator treatment, it may be possible to have a wide variety of effects, some of which aresufﬁciently reduce symptoms to permit patients to unpleasant. One effect is the blocking of impulsegradually increase their levels of activity as a form of transmission from the vagus nerve to the airwayself-directed pulmonary rehabilitation. smooth muscle; this produces bronchodilation since vagal impulses tend to increase the tone or tension in β2 Agonists airway smooth muscle. Ipratropium is an agent thatBeta agonists directly stimulate receptors on airway is poorly absorbed from the lungs and gastrointesti-smooth muscle, thus causing it to relax. There are nal tract but does gain access to smooth muscle whenseveral types of beta receptors in the body, including inhaled. Therefore, it produces bronchodilation bythe heart and blood vessels and the airways. Airway blocking vagal transmission to airway smooth mus-smooth muscle contains type 2 beta receptors, and cle. The onset of ipratropium action is slower thanprescribed agents that are speciﬁc to these types of that of the short-acting β2 agonists; furthermore, itsreceptors have fewer side effects than others. The duration is longer, lasting more than 4 hours (Tableprototypical short-acting β2-receptor agonist, or 5–3).12 Inhaled ipratropium has been shown to havestimulant, is salbutamol; other similar drugs include virtually no systemic side effects, with the only well-fenoterol hydrobromide and terbutaline sulfate. established risk of the drug occurring when it is mis-These agents cause bronchodilation when adminis- takenly squirted into the eyes (see Table 5–3).tered systemically, orally, or intravenously and when A longer-acting version of ipratropium, tiotropium,inhaled. Inhaled agents produce fewer side effects is currently undergoing clinical testing. Tiotropium
Pharmacologic Management of Stable COPD 67 TABLE 5–1 Pharmacology of Short-Acting β2 AgonistsAdrenergic Administration Route Adverse EffectsAgents and Dosage* Pharmacodynamics Monitoring, and InteractionsFenoterol hydrobromide Most frequent side effects (Berotec®) MDI Tremor 100 µg/inh Onset: 5–10 min Headache Sig: (dose)1–2 inh tid–qid Nervousness prn/regularly Peak: 30–60 min Hypotension Max: 8–12 inh/d Flushing Duration: 3–6 h Hypokalemia Nebulization Tachycardia/palpitations Nebules: 0.5 mg/2 mL Dizziness 1.25 mg/2 mL Solution: 1 mg/mL Sig: 0.5–1.25 mg qid prn/regularlyPirbuterol acetate MDI Onset: 5–10 min Monitoring (Maxair®) 250 µg/inh Blood pressure Sig: 1–2 inh tid–qid Peak: 30–60 min Heart rate prn/regularly Ion values Max: 8–12 inh/d Duration: 3–5 h Physical signsSalbutamol (Ventolin®) MDI Onset: 5–15 min 100 µg/inh Sig: 1–2 inh tid–qid Peak: 30–90 min prn/regularly Interactions Max: 8–12 inh/d Duration: 3–6 h β-blockersDiskus MDI Choose cardioselective 200 µg/inh • Atenolol (Tenormin®) Sig: 1 inh tid–qid prn/regularly • Acebutolol (Sectral®) Max: 6 inh/d Nebulization Rotahaler • Metoprolol tartrate Nebules 200 and 400 µg/capsule (Lopressor®) 1.25 mg/2.5 mL Sig: 1–2 capsules tid–qid • Bisoprolol (Monocor®) 2.5 mg/2.5 mL prn/regularly 5 mg/2.5 mL Max: 1,600 µg/d Solution: 5 mg/mL Sig: 2.5–5 mg tid–qid Oral solution 0.4 mg/mL Attention: potential prn/regularly Sig: 2–4 mg (5–10 mL) cardiac toxicity tid–qid MonoamineDiskhaler MDI prn/ regularly oxidase inhibitors 200 and 400 µg/blister Max: 16 mg/d Tricyclic antidepressants Sig:1–2 blisters tid–qid Diuretics prn/regularly Digoxin Max: 1,600 µg/d Systemic corticosteroidsSalbutamol (Airomir®) MDI (Hydroﬂuroalkane-134a) Onset: 5–15 min Methylxanthines 100 µg/inh Sig: 1–2 inh tid–qid Peak: 60–90 min prn/regularly Max: 8–12 inh/d Duration: 3–6 hTerbutaline sulfate Turbuhaler Onset: 5–15 min (Bricanyl®) 500 µg/inh Sig: 1–2 inh tid–qid Peak: 30–90 min prn/regularly Max: 8–12 inh/d Duration: 3–6 h*Dosage in clinical practice can be higher than those recommended in this table.MDI = metered dose inhaler.
68 Comprehensive Management of Chronic Obstructive Pulmonary Disease TABLE 5–2 Pharmacology of Long-Acting β2 AgonistsAdrenergic Administration Route Adverse Effects,Agents and Dosage* Pharmacodynamics Monitoring, and InteractionsSalmeterol xinafoate MDI (Serevent®) 25 µg/inh Onset: 10–20 min See short-acting β2 Sig: 1–2 inh id–bid agonists regularly Duration: 12 h Max: 100 µg/d Diskhaler 50 µg/blister Sig: 1 blister id–bid regularly Diskus 50 µg/inh Sig: 1 inh id–bid regularlyFormoterol fumarate Aerolizer Onset: 3 min (Foradil®) 12 µg/capsule Duration: 12 h Sig: 1 inh id–bid regularly Max: 2 inh bid regularly (48 µg/d) Oxeze® Turbuhaler 612 µg/inh Sig: 1 inh id–bid regularly Max: 48 µg/d*Dosage in clinical practice can be higher than those recommended in this table.MDI = metered-dose inhaler.will be suitable for once-daily dosing.13 It is undeter- convulsions and other serious central nervous systemmined whether its kinetic selectivity for M1 and M3 abnormalities. The most common side effects are gas-receptors over M2 receptors will be clinically useful. trointestinal and include nausea, vomiting, poor appetite, and even diarrhea (see Table 5–4). The side Methylxanthines effects are dose related, as is the degree of bronchodi-Methylxanthines such as theophylline are chemically lation achieved with these agents. A problem with therelated to caffeine and cause a variety of effects that are use of this drug is difﬁculty in predicting its clearanceof interest in patients with COPD. Alhough its mech- and therefore in establishing the dose that does notanism of action is uncertain, theophylline is a well- cause adverse effects. Theophylline clearance may bedocumented bronchodilator. It is also a central ner- modiﬁed by factors such as age, cigarette smoking,vous system stimulant that causes hyperventilation cardiac failure, liver disease, respiratory failure withand has been reported to strengthen the diaphragm.14 cor pulmonale, and drug interactions. TheophyllineThe clinical signiﬁcance of these latter effects has not levels can be measured in the blood; signiﬁcant bron-been well demonstrated,15 and thus far, theophylline chodilation is obtained at levels approximatingis employed in COPD largely as a bronchodilator, 10 µg/mL, whereas greater bronchodilation, but fre-although it might also elicit improvements in breath- quent side effects, is present at levels approximatinglessness.16,17 Theophyllines are administered orally and 15 µg/mL or more. Generally speaking, levels of aboutare available in long-acting preparations given twice 10 µg/mL are obtained when standard doses of theo-daily (Table 5–4). As might be expected, theophyllines phyllines are given, that is, 300 mg twice a day ofhave signiﬁcant potential for side effects including long-acting generic theophylline.16
Pharmacologic Management of Stable COPD 69 TABLE 5–3 Pharmacology of Anticholinergic Agents Administration Route Adverse EffectsAnticholinergics and Dosage* Pharmacodynamics MonitoringIpratropium (Atrovent®) MDI Most frequent side effects 20 µg/inh Onset: 5–15 min Dry mouth Sig: 2–4 inh tid–qid Bad taste regularly Peak: 60–120 min Headache Max: 8–12 inh/d Irritation of upper Duration: 4–8 h respiratory airways Nebulization Nebules: 0.25 mg/2 mL Monitoring 0.50 mg/2 mL Hydration Solution: 0.25 mg/mL Oral hygiene Sig: 250–500 µg qid regularlyIpratropium/salbutamol MDI Onset: 5–15 min Side effects (Combivent®) 20 µg/inh ipratropium Good tolerance 100 µg/inh salbutamol Peak: 60–120 min Side effects of both Sig: 2 inh qid drugs prn/regularly Duration: 6–8 h Contraindications Max: 12 inh/d Hypersensitivity to soya, lecithin or Nebulization similar food products 0.5 mg/UDV ipratropium (soybean, peanut) 2.5 mg/UDV salbutamol Sig: 1 nebul. tid–qid prn/regularlyIpratropium/fenoterol Nebulization Onset: 5–15 min (Duovent® UDV) 0.125 mg/mL ipratropium 0.3125 mg/mL fenoterol Peak: 60–120 min Sig: 4 mL qid prn/regularly Duration: 6–8 h*Dosage in clinical practice can be higher than those recommended in this table.MDI = metered-dose inhaler; UDV = unique dose vial. Choosing Bronchodilator Therapy absolute guide to therapy; the response to bron-Given this armamentarium, how should bron- chodilators on a particular occasion may not accu-chodilator therapy be used in patients with COPD? rately reﬂect responses at other times.5 It is better toInhaled bronchodilators should have preference over offer a trial of inhaled bronchodilators to all patientsoral bronchodilators. They should be given to all with COPD and discontinue them in the rare indi-patients with COPD who obtain symptomatic ben- vidual who does not derive any symptomatic bene-eﬁt from this treatment, which, in our experience, ﬁt. It is important to listen to patients because theyapplies to virtually all of them. In general, a metered- can describe how they feel better than any given test,dose inhaler or powder is used; nebulized therapy that is, if there is any reduction in symptoms allow-for stable patients is usually not necessary unless it ing for an increase in the daily level of activities.has been shown to be more effective than conven-tional devices. The response to inhaled bronchodila- Inhaled Bronchodilators: β2 Agoniststors can be assessed by measuring lung function, usu- versus Anticholinergic Agentsally FEV1, before and after drug administration. This Considerable energy has been expended by investi-may be a useful test but should not be used as an gators to determine which inhaled bronchodilator
70 Comprehensive Management of Chronic Obstructive Pulmonary Disease TABLE 5–4 Pharmacology of Methylxanthines Administration Route Adverse EffectsMethylxanthines and Dosage Monitoring Pharmacology InteractionsTheophylline Adult dose Mechanisim of action Most frequent side effects Theo-Dur® Caution re: purity of Nonspeciﬁc PDE* inhibitor Nausea/vomiting Quibron-T/SR® the molecule Anti-inﬂammatory and Headache Uniphyl® immunoregulatory Anxiety Theolair-SRTM Theophylline = 100% properties Irritability Slo-Bid® Aminophylline = 80% Insomnia Theochron SR® Oxtriphylline = 65% Tremor DiarrheaAminophylline Oral route Metabolism Gastroesophageal Phyllocontin® Theophylline 200 mg/d or Cytochrome P-4501A2 reﬂux Phyllocontin-350® 6–8 mg/kg/d Diuresis up to 900 mg/d or Metabolic clearance Tachycardia 13 mg/kg/d or inﬂuenced by Arrhythmia equivalent conversion Age Cigarette smoking InteractionsOxtriphylline Monitoring Diet (a few examples) Choledyl® Therapeutic deviation Drugs Choledyl SA® 10–20 µg/mL Cardiac disease ⇑Serum concentrations Aim: 10–15 µg/mL (congestive heart Allopurinol Dosing: every 6–12 mo failure) Cimetidine when stable Liver disease Ciproﬂoxacin Samples (cirrhosis ) Clarithromycin Long-acting preparation Viral infection Erythromycin measure peak concentration Inﬂuenza vaccine Propranolol 12 h preparation: 4–8 h after Ticlopidine the dose Absorption inﬂuenced by 24 h preparation: 12 h after Food ⇓Serum concentrations the dose Time of day Rifampin Short-acting preparation (slower at night) Phenobarbital measure through Drugs (antacids) Phenytoin concentration Tobacco 6 hours preparation: before Activated charcoal next dose If toxicity suspected, any time*PDE = phosphodiesterase.should be “ﬁrst-line therapy.” However, the results 2. Patients with asthma respond better to β2 ago-have not been entirely clear, and there is a general nists than to anticholinergic agents, implying thatconsensus on several issues: bronchoconstriction in asthma is not entirely1. Although they are probably not much larger,18 attributable to vagal inﬂuences.19 the responses to ipratropium in patients with 3. The onset of the effect of short-acting β2 agonists COPD are at least as important, if not more so, is more rapid than ipratropium so that the former than those to short-acting β2 agonists. This are considered better “rescue” drugs. implies that bronchodilator response in COPD 4. Concerning the utility of long-term treatment of is essentially owing to the blocking of vagal COPD with β2 agonists and anticholinergic impulses, which, although an interesting obser- agents, Colice demonstrated that the acute vation, remains of unknown clinical signiﬁcance. bronchodilator response to salbutamol on FEV1
Pharmacologic Management of Stable COPD 71 decreased over time but not to ipratropium after agents might also be indicated in patients who expe- an 85-day treatment.20 As well, there are studies rience nocturnal symptoms that disturb their sleep, showing that the acute bronchodilator response but this is less common in COPD than in asthma. to salbutamol does not decrease over time. Long-acting anticholinergic agents will soon be Anthonisen and Wright demonstrated that the available, as well. Tiotropium causes an early im- bronchodilator response to salbutamol did not provement in FEV1, which is well maintained23 and decrease over a 3-year period.5 Therefore, a signiﬁcantly superior to ipratropium at 6 hours.24 patient should take his or her bronchodilator as Less salbutamol was used by patients receiving regularly as needed; since COPD is a chronic tiotropium, suggesting that the control of COPD progressive disease, it usually means that the was improved. Adverse effects do not appear to be patient will need to use the bronchodilator for a problem with doses that are clinically useful. To the rest of his/her life. date, there are no published data on direct com-5. Finally, in many patients with COPD, conven- parison with long-acting β2 agonists, measurements tional doses of either ipratropium or short-acting of exercise tolerance, symptoms and health status, β2 agonists do not achieve the maximal bron- and effects on acute exacerbations. Tiotropium is chodilation obtainable. Many patients with an inhaled long-acting anticholinergic drug with a COPD are treated with both ipratropium and simple treatment regimen of being taken once daily. short-acting β2 agonists,18 with the former being It may prove to be a more convenient and consis- used on a regular, four-times-a-day basis and the tent bronchodilator than the currently recom- latter sometimes regularly or simply as a rescue mended four times daily needed for ipratropium. medication.12 Of the two agents, combinations are also available that can be used both in regular Methylxanthines: An Add-On Therapy maintenance and as rescue medication, but there Theophyllines are not routinely recommended in is no evidence that these combinations are more patients with COPD. However, they may provide effective than larger doses of either of their indi- distinct beneﬁt to some individuals whose symptoms vidual components. Larger doses of both iprat- are not controlled by inhaled bronchodilators.16 ropium and short-acting β2 agonists are generally Theophyllines can cause further bronchodilation in well tolerated, with the latter commonly limited patients with COPD who are on maximum inhaled by its adverse effects. It is probably safe to say that therapy,25 because as systemically administered drugs, either type of drug is effective and to allow they likely have access to more peripheral airways patients to increase the dose above conventional than inhaled agents. It has also been shown in clini- levels if they perceive added beneﬁts; moreover, in cal trials using validated instruments of quality of patients with COPD there is little to choose from life, that theophylline does indeed improve dyspnea between ipratropium, short-acting β2 agonists, and health status.26–28 A recent randomized trial and/or combinations of the two. showed that 21% of 34 patients with COPD had improvements in dyspnea as measured by theLong-Acting Inhaled Bronchodilators Chronic Respiratory Questionnaire during theo-Long-acting β2 agonists are now available. They are phylline treatment.17 Thus, there is a rationale for aeffective in COPD,21,22 although not consistently trial of theophylline in patients with COPD whomore effective than the shorter-acting variety. Stud- remain symptomatic and limited in their activitiesies have shown that long-acting β2 agonists improve despite having inhaled bronchodilators. It is seldomFEV1, attenuate daytime and nighttime symptoms, necessary or advisable to use theophylline dosesdecrease the use of rescue salbutamol,10 and improve larger than the standard of 300 mg twice a day or tohealth-related quality of life.22 Since the long-act- try to increase serum theophylline levels beyonding agents are expensive, their cost-effective use about 15 µg/mL. It is advisable to check serum theo-requires that the patient’s symptoms or activities of phylline levels in patients who are taking the drug,daily living improve and that they are comfortable especially when patients are still symptomatic orusing smaller amounts of the short-acting drugs, other drugs are given that might inﬂuence the rate ofwhich may not always be the case. Long-acting theophylline metabolism.
72 Comprehensive Management of Chronic Obstructive Pulmonary Disease CORTICOSTEROID THERAPY conﬁned to patients who demonstrated little response to oral corticosteroids and/or an inhaled Oral Corticosteroids bronchodilator, which, in other words, refers to peo-The question of whether anti-inﬂammatory cortico- ple who were unlikely to be “steroid responders.” Atsteroids have a useful role in COPD has a long and the present time, it seems clear that in such patientscontroversial history. They are of undoubted beneﬁt with COPD, substantial doses of inhaled cortico-in the airway obstruction of asthma, thus making it steroids do not have a worthwhile effect on the ratetempting to think that they might have a comparable of change of lung function, which is often thoughteffect in the similar airway obstruction of COPD. to represent the course of the disease.34Until very recently, most studies of corticosteroids in On the other hand, there are at least two trialsCOPD have involved short-term trials of high-dose that indicate that in severely ill patients withoral therapy. Most of these studies have shown that a COPD, high-dose inhaled corticosteroids reducesigniﬁcant minority of patients with COPD, about the number and severity of exacerbations such as15%, show a distinct decrease in obstruction with episodes of increased dyspnea, cough, sputum, andimprovement of FEV1 on such therapy.29 It is not wheeze.33 Exacerbations can have major negativeknown how reproducible these responses are or effects on the quality of life and health care costs inwhether oral corticosteroids are effective in longer-term such patients, so that decreasing the number and/ortherapy. Nevertheless, the results of these short-term severity of such episodes is a worthy goal of ther-trials are such that most COPD guidelines recommend apy. However, it remains uncertain if using high-that patients who do poorly on bronchodilator therapy dose inhaled corticosteroids for long periods of timebe given a therapeutic trial of high-dose oral cortico- is associated with favorable beneﬁt-to-risk ratios. Atsteroids, such as prednisone 40 mg per day for 2 weeks. present, one could consider the use of relativelyIf the trial produces an improvement in the FEV1 that high-dose inhaled corticosteroids (500 µg ﬂuticas-is greater than 20%, the patient is considered a “steroid one propionate, 800 µg budesonide, or 1,000 µgresponder.” In such individuals, long-term cortico- beclomethasone dipropionate per day) in patientssteroid therapy is considered using either low-dose oral with severe COPD who have frequent exacerbationsprednisone (10 mg/day) or higher-dose inhaled corti- (Table 5–5). However, it is difﬁcult to determine incosteroids (see below). However, there is mounting evi- a given patient if inhaled corticosteroids actuallydence that this approach poorly predicts long-term have an impact on acute exacerbations since thebeneﬁts. There is also evidence that there are undesir- exacerbations are very hard to predict. In addition,able side effects with either long-term choice.30 In spite since the original studies were done with highof this, most experts still regard the identiﬁcation of doses of inhaled corticosteroids, beclomethasone“steroid responders” and their subsequent treatment equivalent to 2,000 µg per day,33,36 further conﬁr-with corticosteroids to be justiﬁable. mation of this approach is needed using lower doses As a general rule, chronic treatment with systemic of inhaled corticosteroids. Such high doses maycorticosteroids should be avoided, considering their cause signiﬁcant adverse effects, such as osteoporo-modest beneﬁcial effects, if any, and their well- sis in some patients. Moreover, inhaled cortico-established long-term adverse effects. It has recently steroids in COPD need to be re-examined whilebeen shown that daily oral corticosteroids can be suc- taking into account relevant complications of acutecessfully discontinued in many “steroid-dependent” exacerbations such as hospitalizations and mortality.patients without apparent harm, thereby reducingcumulative corticosteroid exposure.31 ANTIBIOTICS Inhaled CorticosteroidsIn asthma, inhaled corticosteroids have become the Antibiotic therapy of patients with COPD shouldcornerstones of therapy because they are of unques- be reserved for the therapy of exacerbations; theretionable beneﬁt and are believed to cause no serious is no evidence that regular antibiotic therapy is ofside effects. This experience has led to a number of any beneﬁt. This will be covered in more detail else-large inhaled corticosteroid trials in patients with where in this textbook (Chapter 8, “ManagingCOPD.32–37 For the most part, these trials have been Acute Exacerbation”).
Pharmacologic Management of Stable COPD 73 TABLE 5–5 Pharmacology of Oral and Inhaled Corticosteroids Administration Route Adverse EffectsCorticosteroids and Dosage* Pharmacodynamics MonitoringOral route Prednisone (Deltasone®) 40–60 mg once a day in Onset: a few hours Most frequent side effects morning and weaning until ⇑ Appetite and weight minimum effective dose or Maximal response: after Mood swing discontinuation several days of treatment Dyspepsia Hyperglycemia Fluid retention Acne Inhibition of hypophy- seal-pituitary adrenal (HPA)-axis Osteoporosis Infection Muscle wastingInhaled MDI Beclomethasone 50 µg/inh (Beclovent®, Vanceril®, Sig: 100–1,000 µg/d Mechanism action Most frequent side effects QVAR®) bid–qid regularly Hoarseness Max: 2,000 µg/d Throat irritation Prophylactic and Oropharyngeal Diskhaler inhibitory action candidiasis 100 and 200 µg/blister Interferes with the Dysphonia Rotahaler metabolism and synthesis Increased bruising 100 and 200 µg/capsule of mediators involved in Long term the inﬂammatory process Inhibition of HPA axis Osteoporosis MDI (HFA134-a)/QVAR® Prevents their migration Sig: 100–400 µg/d and activation bid regularly Max: 800 µg/d Decreases vascular permeability caused by Budesonide (Pulmicort®) Turbuhaler inﬂammatory mediators 100–200–400 µg/inh Sig: 200–1,200 µg/d Increases reactivity of bid–qid regularly β2 receptors located in Max: 2,400 µg/d bronchial smooth muscle Nebulization Nebules Monitoring 0.25 mg/2 mL Oral hygiene 0.5 mg/2 mL Adrenal function 1.0 mg/2 mL Bone loss Sig: 1–2 mg bid Fluticasone (Flovent®) MDI HFA 134-a 25–50–125–250 µg/inh Diskus 50–100–250–500 µg/inh Sig: 100–500 µg bid Max: 2,000 µg/d (continues over...)
74 Comprehensive Management of Chronic Obstructive Pulmonary Disease TABLE 5–5 Pharmacology of Oral and Inhaled Corticosteroids (continued) Administration Route Adverse EffectsCorticosteroids and Dosage* Pharmacodynamics Monitoring Triamcinolone (Azmacort®) MDI 200 µg/inh Sig: 400–600 µg/d bid–qid regularly Max: 3,200 µg/d Fluticasone/salmeterol Diskus (Advair®) 250 µg/50µg/inh 500 µg/50µg/inh Sig: 1 inh bid regularly MDI HFA 134-a 125/250 µg/50µg Sig: 2 inh bid regularly*Dosage in clinical practice can be higher than those recommended in this table.MDI = metered-dose inhaler. OTHER PHARMACOLOGIC tum more liquid, but it does not produce improve- CONSIDERATIONS ments in lung function or quality of life in patients with COPD; furthermore, it is expensive and difﬁ-The other essentials of COPD management are cov- cult to administer. Because many patients complainered elsewhere in this textbook; this section will pri- of difﬁculty in raising pulmonary secretions, there ismarily focus on the newer but not yet proven meth- still considerable interest in the development of anyods of treatment. agents that will effectively resolve this problem. Other Anti-inﬂammatory Therapy Sedatives and Anxiolytic DrugsThere is a need for the development of new anti- A variety of sedatives, tranquilizers, and even nar-inflammatory drugs as evidence shows that the cotics have been used to treat patients with COPDinﬂammatory process initiated by smoking is not who have severe dyspnea. There is little evidence toresponsive to corticosteroids and may continue suggest that these approaches are helpful; thus, theyeven when smoking has ceased. Several new drugs should be attempted only in special circumstancesare under development such as leukotriene B4 and under the supervision of specialists.inhibitors, 5-lipoxygenase inhibitors, PDE4 inhi-bitors (phosphodiesterase inhibitors), new antiox- Proteinase Inhibitorsidants, neutrophil elastase, and matrix metallo- A small minority of patients with COPD have aproteinase inhibitors. However, more studies and genetic deﬁciency of α1-antitrypsin, which is a sub-large trials will be needed to establish the effect stance that tends to prevent digestion of lung pro-of any of these drugs on the rate of decline in teins. It is believed that these patients developlung function. emphysema because their lungs are incapable of cop- ing with protein-cleaving enzymes from inﬂamma- Mucolytic Therapy tory cells, recruited to the lungs by smoke inhala-Mucolytic therapy has a long history in the treat- tion. This mechanism may apply to patients withoutment of COPD. Acetylcysteine (Mucomyst) is α1-antitrypsin deﬁciency, with emphysema develop-apparently used in Europe to help patients eliminate ing when the normal defenses against protein diges-secretions but is used very little in North America tion are overwhelmed.because it has not been proven beneﬁcial, and we do In patients with α1-antitrypsin deﬁciency, intra-not recommend its use.38 Similarly, there is a genet- venous augmentation therapy with naturally derivedically engineered enzyme that lyses deoxyribonucleic α1-antitrypsin has been demonstrated to have bio-acid (dornase alfa) and unquestionably makes spu- chemical efﬁcacy in achieving and maintaining ele-
Pharmacologic Management of Stable COPD 75vated serum and lung α1-antitrypsin levels.39 Pub- (3) in some cases, homeopathic remedies might evenlished results from registries have suggested that cause aggravation of symptoms. In addition to thesepatients with FEV1 35 to 49% of the predicted nor- adverse effects, safety issues are sometimes neglected,mal value who received replacement therapy had a such as advice against immunizations or conventionalslower rate of decline of lung function than those who drug therapies. Therefore, in light of the absence ofdid not receive replacement.40 However, these patients evidence-based alternative medicine, these therapieswere not randomly assigned to replacement therapy, cannot be recommended at this time.and the absence of randomized, placebo-controlledtrials precludes deﬁnitive conclusions regarding intra-venous replacement therapy in patients who have the RECOMMENDATIONSdeﬁciency. In patients without α1-antitrypsin deﬁ- FROM INTERNATIONAL ANDciency, such therapy is even harder to justify. NATIONAL GUIDELINES Leukotriene Antagonist Drugs Over the last several years, international and nationalThere is data to suggest that leukotriene (LT)B4 is a guidelines on the management of COPD have beenpotent chemoattractant of neutrophils and that its produced.38,41–44 Even though guideline recommen-concentrations are increased in the sputum of dations are based on scientiﬁc information as muchpatients with COPD. However, leukotriene antago- as possible, except for the Global Initiative fornist drugs that are available for the treatment of Chronic Obstructive Lung Disease (GOLD) guide-asthma (zaﬁrlukast, montelukast sodium) are not lines,44 none of the guidelines provide evidence-LTB4 antagonists but involve direct antagonism of based documentation; in many instances, the rec-the Cys LT1 receptor for LTC4 and LTD4. They will ommendations are essentially empiric because of aalmost certainly be tried in COPD, but, at present, lack of scientiﬁc data. There are many similitudesthere are essentially no data indicating whether they and some differences in the recommendations forare helpful. Several potent leukotriene B4 antagonists pharmacologic management of stable COPD.may be more promising, but they are now only in All guidelines recommend inhaled bronchodila-early development, and it is not known if they will tors as central to the symptomatic management of sta-have clinical signiﬁcance in COPD. ble COPD, with the GOLD guidelines44 and the European Respiratory Society (ERS)42,43 offering no Complementary/Alternative Medicine preference between β2 agonists and anticholinergicComplementary/alternative medicine has become an agents for intitial therapy. The Canadian Thoracicincreasingly topical theme in respiratory medicine. Society (CTS)41and the American Thoracic SocietyAlternative medicine comprises hundreds of different (ATS)38 suggest initial therapy with an anticholinergictherapies that vary in theory and in practice; the most drug if regular therapy is needed and a β2 agonist ifprevalent treatments are acupuncture, aromatherapy, therapy as needed is all that is required. All groupsphytotherapy, homeopathy, reﬂexology, and chiro- discuss the value of combination therapy with a β2practics. These alternative therapies are often perceived agonist and an anticholinergic drug compared withas effective by those who use them, but their speciﬁc increasing the dose of a single drug. The GOLDand nonspeciﬁc effects remain unclear. Nonspeciﬁc guidelines consider long-acting inhaled bronchodila-effects can undoubtedly be an important part of the tors as more convenient; the ERS and the ATS suggesttotal therapeutic effect of any treatment; however, a possible role in patients with nighttime or earlybecause safety is an essential precondition in any treat- morning symptoms, whereas the BTS recommendsment, it should be stressed that although alternative limited use until more information is available, andmedicine is often promoted as entirely risk free, in fact, the CTS does not provide any mention of it. It isthere is no therapy that is totally devoid of risk. We worth noticing that the CTS guidelines were pub-are uncertain about the beneﬁts of most alternative lished in 1992, the ERS and ATS in 1995, and thetherapies and ignorant of their potential risks. Some of BTS in 1997, well before published studies hadthe possible risks could be the following: (1) acupunc- reported information on the efﬁcacy and potentialture can cause trauma such as pneumothorax or infec- convenience of using long-acting bronchodilators. Alltions; (2) some herbal medicines are hepatotoxic; and guidelines place some value on the use of theo-
76 Comprehensive Management of Chronic Obstructive Pulmonary Diseasephylline, but owing to the high risk of drug interac- report at 1-year follow-up was slightly over 60%,tion and its potential toxicity, inhaled bronchodila- declining to less than 50% at 5 years. In the sametors are preferred. Theophylline is recommended study, compliance measured by canister weight waswhen patients are still symptomatic despite combined about 10% below patient-reported compliance.use of inhaled bronchodilators. However, these data may not be generalized since The GOLD guidelines recommend that chronic patients with COPD participating in the Lungtreatment with systemic corticosteroids should be Health Study were largely non symptomatic. Per-avoided because of an unfavorable beneﬁt-to-risk haps we should not worry about underuse of drugsratio. When considering regular treatment with that have only symptomatic beneﬁt.inhaled corticosteroids, it should be prescribed only Compliance issues do not refer only to underusefor symptomatic patients with COPD with a docu- but also to overuse and improper use of the drug ormented spirometric response to corticosteroids. It device. Improper use of the inhaled drug devices iscan also be given to those with FEV1 less than 50% an extremely common and important issue. Mostpredicted and with repeated exacerbations requiring commonly, improper patient techniques withantibiotic and/or oral corticosteroid therapy. It is inhaled medication result in a suboptimal level ofworth mentioning that it has also been stated that drug delivery.45,46 Overcompliance in COPD hasthe dose-response relationship and long-term safety also been observed.47 Overuse of inhaled drugs isof inhaled corticosteroids in COPD are not known. often a consequence of improper use of the drugOther guidelines emphasize the need to document delivery system and related drug inefﬁciency.corticosteroid responsiveness before long-term use. Patients with severe COPD who often experienceRegarding the recommendations on using inhaled breathlessness on exertion may make excessive usecorticosteroids, they are of limited value considering of their inhaled β2 agonist when it is more appro-that these national guidelines were produced prior to priate and efﬁcient to implement their breathingany real research on long-term treatment with techniques and appropriately pace their level ofinhaled corticosteroids.34–37 activity. It is also important to note that more than Other drugs are generally not recommended, such one type of noncompliance is possible in the sameas mucokinetic drugs or the routine use of antibiotics patient. In patients with unfavorable outcomes, non-and respiratory stimulants. The use of psychoactive compliance should always be considered before con-drugs is suggested for the appropriate patients. cluding that a speciﬁc drug therapy is ineffective.Alpha1-antitrypsin replacement therapy is recom-mended for appropriate patients by the ATS but notby the ERS and BTS. The GOLD guidelines suggest WHEN TO REFERthat young patients with severe hereditary α1-anti-trypsin deﬁciency and established emphysema might When to Refer to a Pharmacistbe candidates for replacement therapy. Advice from a pharmacist may be useful when ques- tions arise regarding adverse effects or compliance with drug treatment. Adverse effects are uncommon PATIENT NONCOMPLIANCE with most of the drugs used to treat COPD except WITH THERAPY for theophylline. Theophylline presents a special case whereby the patient’s metabolism and consequentSuccessful pharmacologic management of COPD blood levels are subject to many drug interactions,also involves monitoring and reinforcing effective including interactions with antibiotics (erythromycin,compliance with drug therapy. Compliance can be ciproﬂoxacin) that may be used to treat exacerbations.very poor and should be seen as a signiﬁcant barrier It is essential to carefully review the therapy and non-to improving clinical outcomes for those with pulmonary conditions of patients with COPD whoCOPD. Even in the context of clinical trials, which are considered for theophylline therapy; moreover,presumably involved more monitoring than standard consultation with a pharmacist may be of great valuecare settings, compliance has been reported as low in in indicating whether these conditions, or drugs tothe past. In the Lung Health Study,7 patient com- treat comorbid conditions, need to be considered inpliance with inhaled bronchodilator therapy by self- theophylline dosing and monitoring.
Pharmacologic Management of Stable COPD 77 Compliance with drug regimens should always changes in drug therapy are contemplated andbe a consideration in patients with chronic diseases. whenever a patient does not respond to treatmentA dangerous and difﬁcult scenario occurs when a as anticipated. Furthermore, they should be con-patient with severe disease overuses his/her drugs. sulted if a patient appears to be so ill that hospital-This can occur with bronchodilators, corticosteroids, ization or an emergency department visit may beor antibiotics and can cause problems with drug required. Indicators of this kind of severity includereimbursement plans. In such cases, the clinic and fever and extreme dyspnea, cyanosis, or alteredthe pharmacist should cooperate to make sure that mentation, but no list is completely comprehen-the appropriate inhaler technique is employed and sive. Physicians should also be consulted wheneverthat proper education is available to the patient in a patient with COPD is suspected of developing aterms of the expectations and effects of these agents. nonpulmonary disease.With this in mind, it must be acknowledged thatinhaled bronchodilators are given to relieve symp- When to Refer to a Respirologisttoms and that if they successfully accomplish this, This decision varies with the degree of comfort andoveruse may be occasionally tolerable. However, experience that the practitioner and health care teamoveruse of corticosteroids or antibiotics can also have have in dealing with COPD. Uncertain diagnosisserious consequences, and every effort should be should be an absolute indication for respirologistmade to prevent mistakes; the pharmacist can help referral. Although there is no concrete evidence toby providing the necessary information and educa- support this view, it has been suggested that alltion. On the one hand, patients with relatively mild patients with COPD should see a respirologist atCOPD can also fail to comply with drug regimens some point in their disease. It is certainly true thatby under using prescribed therapy. This case, how- patients with COPD should undergo periodicever, is considered less serious since most treatments (roughly annual) spirometric testing that is oftenare aimed at improving symptoms, and one can infer available only through specialists. Other indicationsthat if the patient chooses not to take a particular for referral could include patients with cor pul-drug, it is likely owing to the fact that the drug is monale, bullous disease, rapid decline in FEV1, orreducing symptoms. disease in relatively young people, such as those under 40 years, and patients who cannot be with- When to Refer to a Physician drawn from their oral corticosteroids. Essentially allGenerally speaking, physicians should always symptomatic patients with COPD should be givensupervise the care of patients with COPD. Super- the opportunity to undergo pulmonary rehabilita-vision does not always require direct contact tion under the supervision of established specialistsbetween the patient and the physician but does and their programs. Finally, many patients withrequire that the physician know what is going on. COPD have such severe symptoms and such aThus, groups of patients with COPD can receive restricted quality of life that consultation with a spe-their front-line health care from nonphysicians; this cialist may be beneﬁcial in serving to reassure bothis routine in most clinical research. However, peri- the patient and the person making the referral thatodic meetings with the responsible physicians and everything possible is being done. The vast majoritykey members of the team are essential so that of daily care plans for patients with COPD are suc-progress can be monitored. As is always the case in cessfully delivered by a team of health care workersmedicine, decisions regarding health care and per- that does not always include respirologists.sonal maintenance have to be individualized.Whereas some patients are stable and require littlephysician input, others need more guidance and SUMMARYsupervision. The most comprehensive rule ofthumb states that the physician be consulted when- All patients with COPD should be offered treatmentever other caregivers are uncomfortable with the using inhaled bronchodilators with the understand-status of a particular patient, which is something ing that the beneﬁts of these agents are conﬁned tothat varies according to the individuals involved. the relief of symptoms. The choice of the particularPhysicians should always be consulted whenever bronchodilator agent is less important than the ini-
78 Comprehensive Management of Chronic Obstructive Pulmonary Diseasetiation of inhaled therapy, which should be guided they may reduce the frequency and severity of exacer-by issues of symptom relief, adverse effects, and cost bations and should thus be considered only in patientsin individual patients. Combining bronchodilators with frequent exacerbations. It is important tomay improve efﬁcacy and decrease the risk of adverse remember, however, that COPD exacerbations areeffects as compared with increasing the dose of a sin- very difﬁcult to measure, and further validation of thisgle agent. Many symptomatic patients will derive approach is needed. Other than in treating infectiousfurther symptomatic beneﬁt from theophylline, but exacerbations of COPD and other bacterial infections,some care must be taken with these agents to avoid the use of antibiotics is not established.overdoses and toxicity. When a patient is not responding to pharmaco- Chronic treatment with oral corticosteroids should logic treatment, it is also essential to consider non-be avoided because of an unfavorable beneﬁt-to-risk compliance. This is especially a concern as improperratio. Inhaled corticosteroids do not modify the long- patient techniques with inhaled medication resultterm decline in FEV1 in patients with COPD, but in a suboptimal level of drug delivery. CASE STUDY chodilator and 5.00 L postbronchodilator, and the FEV1/FVC ratio is 63%.Mr. Cope, a 45-year-old male civil servant, arrivesfor a check-up. Questions and Discussion Mr. Copd has mild airway obstruction, which is Medical History, Physical Examination, most likely owing to his smoking habit. Alhough he and Test Results regards himself as asymptomatic, he does, in fact, have COPD. Bronchodilator medication mightMedical History improve his function, but he is unlikely to comply• Morning cough and phlegm production have with treatment. He must be convinced to stop been present for many years, but he has no smoking; ideally, his motivation to quit might be wheezing or breathlessness. increased with the reception of the news on his• He smoked approximately 20 cigarettes a day abnormal pulmonary function. Although this may for about 30 years. take several visits, considerable effort should be• He has “chest colds,” but not every winter, and made to persuade him that quitting smoking is he does not miss work because of them; they both necessary and urgent. Inﬂuenza vaccines can are characterized by increased cough and puru- also be recommended for administration in the lent sputum, which have been treated with autumn of every year. antibiotics. At each encounter, the practicalities of quit-• He has never been hospitalized for respiratory ting should be discussed; these include drug ther- disease and did not have childhood asthma. apy, group programs available in the community,• He is not known to have any medical or surgical modifying behaviors associated with cigarettes, condition. and dealing with smokers in the home and the workplace. It is very important that the patient feelPhysical Examination that the physician is genuinely interested and con-• Physical examination and chest radiography are cerned. The physician should offer to work with the normal. patient throughout the quitting process. But what if this same patient has already devel-Test Results oped symptoms such as breathlessness on activi-• He has spirometry compatible with mild airﬂow ties at work? A long period of asymptomatic airway obstruction without significant reversibility; obstruction is followed by a gradual worsening of spirometry pre- and postbronchodilators: FEV1 is symptoms, such as breathlessness on daily activ- 3.11 L (75% of predicted normal) prebron- ities. Mr. Copd’s FEV1 would be less than 70% of chodilator and 3.30 L postbronchodilator, (FVC) predicted normal, and he would be experiencing is 4.95 L (101% of predicted normal) prebron- dyspnea on exertion or perhaps even at rest if it is
Pharmacologic Management of Stable COPD 79more advanced. Besides making the commitment bronchodilator therapy for every patient should beto stop smoking and administering inﬂuenza vac- based on the overall assessment of beneﬁt, withcines in the autumn of every year, this patient the additional goals of achieving compliance withshould be treated with inhaled bronchodilators. the medication while maintaining a low or tolera-The usual regimen is a regular dose of ipratropium ble level of adverse effects and an acceptable cost.plus an as-needed short-acting β2 agonist. If the In addition to his chronic symptoms, the patientpatient regularly uses ipratropium plus a short- described acute exacerbation of COPD once or twiceacting β2 agonist to relieve symptoms, prescribing over the past 5 years. He has required antibiotics buta single metered-dose inhaler that produces both no oral corticosteroid therapy, and he has never beenanticholinergic and β 2 -agonist bronchodilating hospitalized for his respiratory condition. Knowingeffects could be more convenient. Patients could that treatment with inhaled corticosteroids does notsometimes beneﬁt from a long-acting β2 agonist modify the long-term decline in FEV1 in patients withcombined with ipratropium, although an as- COPD, the use of regular treatment with inhaled cor-needed short-acting β2 agonist should still be pro- ticosteroids would not be required for this patientvided as a rescue medication. In any case, and should, in fact, be considered inappropriate. KEY POINTS Advice for Patients and Their Families • Follow the inhalation technique as recommended. Pharmacologic Therapy • Encourage use of a spacing device (spacer) for• None of the existing medications for COPD have improved therapeutic effects and reduced inci- been shown to prevent further decline in lung dence of adverse effects. function; therefore, drug therapy should be used • Rinse mouth after use if tremors or palpitations to improve symptoms and/or decrease complica- occur (β2 agonists). tions. • Rinse mouth after use to prevent dry mouth and• Successful management of COPD also involves attenuate bad taste (anticholinergic agents). monitoring and reinforcing effective compliance • Advise patients of the maximum number of with therapy. inhalations in 1 day. Inhaled Bronchodilators Oral Bronchodilators• Inhaled therapy is preferred.• The choice depends on the availability and cost of Methylxanthines the medication, the patient’s response, and the • Methylxanthines may be indicated for severe adverse effects involved. pulmonary obstruction despite optimal use of inhaled bronchodilators.β2 Agonists • Methylxanthines may produce therapeutic bene-• β agonists are effective for reversal (short-acting ﬁts unrelated to bronchodilation. β2 agonists) and prevention of bronchospasm. • Dose adjustments may be necessary because• β agonists are the most commonly used rescue metabolic clearance is affected by several diseases, medication (short-acting β2 agonists). liver dysfunction, and drug interactions.Anticholinergic Agents (Ipratropium Bromide) Advice for Patients and Their Families• Anticholinergic agents have proven value for • Take theophylline-based preparations at the same patients with COPD with chronic symptoms. time every day with food.• Anticholinergic agents have at least an equal • Avoid taking the medication at bedtime. bronchodilation effect in patients with COPD • Advise the local pharmacist of any changes in versus β2 agonists. drug regimen (withdrawal or addition of a drug,• Anticholinergic agents have an excellent side- over-the-counter purchases, new lifestyle changes effect proﬁle regardless of dose administered. such as smoking cessation, etc) because of the
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82 Comprehensive Management of Chronic Obstructive Pulmonary Disease47. Dolce JJ, Crisp C, Manzolla B, et al. Medication adher- physician and health professional to understand, detect, ence patterns in chronic obstructive pulmonary dis- and improve compliance. A health decision model that ease. Chest 1991;99:837–41. combines decision analysis, behavioral decision theory, and health belief is proposed. Pauwels RA, Buist AS, Calverley PMA, et al., on behalf SUGGESTED READINGS of the GOLD Scientiﬁc Committee. National Heart, Lung, and Blood Institute/WHO Global InitiativeBarnes PJ. New therapies for chronic obstructive for Chronic Obstructive Lung Disease (GOLD) pulmonary disease. Thorax 1998;53:137–47. This workshop summary: global strategy for the diagnosis, is a review of new therapies for COPD: new bron- management, and prevention of chronic obstructive chodilators, anti-inﬂammatory treatments, antipro- lung disease. Am J Respir Crit Care Med 2001;163: teases, mediator antagonists, pulmonary vasodilators, 1256–76. The GOLD guidelines present a COPD mucoregulators, and drugs affecting remodeling. It management plan with four components: (1) assess and presents some recent advances in the therapy of COPD monitor disease, (2) reduce risk factors, (3) manage sta- and several new drugs now in development that may ble COPD, and (4) manage exacerbations. It has been be useful in preventing disease progression. developed by individuals with expertise in COPDEraker SA, Kirscht JP, Becker MH. Understanding and research and patient care and reviewed by many experts improving patient compliance. Ann Intern Med and national societies. Levels of evidence are assigned to 1984;100:258–68. This review article presents the statements, where appropriate, using a system developed problem of patient compliance and the ability of the by the NHLBI.