Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease Search date March 2005 Huib Kerstjens, Dirkje Postma, and Nick ten Hacken QUESTIONS What are the effects of maintenance drug treatment in stable chronic obstructive pulmonary disorder? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 What are the effects of non-drug interventions in stable chronic obstructive pulmonary disease? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15 INTERVENTIONS DRUG TREATMENTS Beneficial Inhaled anticholinergics (improved exacerbation rate, symptoms, and FEV1 compared with placebo) . . . . . . . . . . . .3 Inhaled anticholinergics plus beta2 agonists (improved FEV1 compared with either drug alone) . . . . . . . . . . . . . . . . . . . . . . . .7 Inhaled beta2 agonists (improved FEV1 , quality of life and exacerbation rates compared with placebo) . . . . . . . . . . . .4 Inhaled corticosteroids plus long acting beta2 agonists (improved exacerbation rate, symptoms, quality of life, FEV1 compared with placebo) . . . . . . . . . . . . . . . . . . .11 Likely to be beneficial Inhaled anticholinergics compared with beta2 agonists (improved FEV1 compared with beta2 agonists in long term) . . . . . . . . . .7 Long term domiciliary oxygen (beneficial in people with severe hypoxaemia) . . . . . .14 Trade off between benefits and harms Inhaled corticosteroids (improved exacerbation rates, but may have long term harms) . . . . . . . . . . . . . . . . . . . . . . . .9 Theophyllines . . . . . . . . . . . . . . . . . . . . .8 Unknown effectiveness Alpha1 antitrypsin . . . . . . . . . . . . . . . . .14 Mucolytics . . . . . . . . . . . . . . . . . . . . . .12 Prophylactic antibiotics . . . . . . . . . . . . . .13 Unlikely to be beneficial Oral corticosteroids (evidence of harm but no evidence of long term benefits). . . . . . . .9 NON-DRUG INTERVENTIONS Beneficial Psychosocial plus pharmacological interventions for smoking cessation . . . .16 Pulmonary rehabilitation . . . . . . . . . . . . .17 Likely to be beneficial General physical activity . . . . . . . . . . . . .19 Inspiratory muscle training. . . . . . . . . . . .18 Peripheral muscle training . . . . . . . . . . . .18 Unknown effectiveness Pharmacological interventions alone for smoking cessation . . . . . . . . . . . . . . .15 Psychosocial interventions alone for smoking cessation . . . . . . . . . . . . . . . . . . . . .15 Unlikely to be beneficial Nutritional supplementation. . . . . . . . . . .20 To be covered in future updates Acute exacerbations of chronic obstructive pulmonary disease Vaccination against influenza and pneumococcus See glossary� Key Messages • The main risk factor for the development and deterioration of chronic obstructive pulmonary disease (COPD) is smoking. • Inhaled anticholinergics and beta2 agonists improve lung function and symptoms and reduce exacerbations compared with placebo in stable COPD. Long acting inhaled anticholinergic drugs may improve lung function compared with long acting beta2 agonists, but studies comparing the two classes of drug have given conflicting results. Combined treatment with inhaled anticholinergics and beta2 agonists may improve symptoms and lung function and reduce exacerbations compared with either treatment alone, although long term effects are unknown. main/1502_new 17/10/06 R espiratory disorders (acute) Clin Evid 2006;15:1–3. BMJ Publishing Group Ltd 2006 1 • Inhaled corticosteroids may reduce exacerbations, and oral corticosteroids may improve short term lung function, but have serious adverse effects. Combined inhaled corticosteroids plus long acting beta2 agonists improve lung function and symptoms and reduce exacerbations compared with placebo, andmay bemore effective than either treatment alone. Long term domiciliary oxygen treatment may improve survival in people with severe daytime hypoxaemia. Theophyllines may improve lung function compared with placebo, but adverse effects limit their usefulness in stable COPD. We don’t know whether mucolytic drugs, prophylactic antibiotics or alpha1 antitrypsin improve outcomes in people with COPD compared with placebo. • Combined psychosocial and pharmacological interventions for smoking cessation can slow the deterioration of lung function, but have not been shown to reduce long term mortality compared with usual care. Multi-modality pulmonary rehabilitation and exercises can improve exercise capacity in people with stable COPD, but nutritional supplementation has not been shown to be beneficial. DEFINITION Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.1 Classically, it has been thought to be a combination of emphysema and chronic bronchitis, although only one of these may be present in some people with COPD. Emphysema is abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. Chronic bronchitis is chronic cough or mucus production for at least 3 months in at least 2 successive years when other causes of chronic cough have been excluded.2 INCIDENCE/ PREVALENCE COPD mainly affects middle aged and elderly people. In 1998, the World Health Organization estimated that COPD was the fifth most common cause of death worldwide, responsible for 4.8% of all mortality (estimated 2 745 816 deaths in 2002),3 and morbidity is increasing. Estimated prevalence in the USA rose by 41% between 1982 and 1994 and age adjusted death rates rose by 71% between 1966 and 1985. All cause age adjusted mortality declined over the same period by 22% and mortality from cardiovascular diseases by 45%.2 In the UK, physician diagnosed prevalence was 2% in men and 1% in women between 1990 and 1997.4 AETIOLOGY/ RISK FACTORS COPD is largely preventable. The main cause in developed countries is exposure to tobacco smoke. In developed countries, 85–90% of people with COPD have smoked at some point.1 The disease is rare in lifelong non-smokers (estimated prevalence 5% in 3 large representative US surveys of non-smokers from 1971–1984), in whom “passive” exposure to environmental tobacco smoke has been proposed as a cause.5,6 Other proposed causes include bronchial hyperresponsiveness, indoor and outdoor air pollution, and allergy.7–9 PROGNOSIS Airway obstruction is usually progressive in those who continue to smoke, resulting in early disability and shortened survival. Smoking cessation reverts the rate of decline in lung function to that of non-smokers.10 Many people will need medication for the rest of their lives, with increased doses and additional drugs during exacerbations. AIMS OF INTERVENTION To alleviate symptoms; to prevent exacerbations; to preserve optimal lung function; and to improve activities of daily living, quality of life, and survival.11 OUTCOMES Short and long term changes in lung function, including changes in forced expiratory volume in 1 second (FEV1); peak expiratory flow�; exercise tolerance; frequency, severity, and duration of exacerbations; symptom scores for dyspnoea; quality of life; and survival. Symptom and quality of life scores include the St George’s Respiratory Questionnaire, which is rated on a scale from 0–100 (a 4 point change is considered clinically important); the Transitional Dyspnoea Index, which is rated from –9 to + 9 (a 1 point change is considered clinically important), and the Chronic Respiratory Disease Questionnaire (CRDQ), which is rated from 1–7 (a 0.5 point change is considered clinically important). METHODS Clinical Evidence search and appraisal March 2005. This review deals only with treatment of stable COPD and not with treatment of acute exacerbations. We were interested in the maintenance treatment of stable COPD; therefore, we did not include single dose or single day cumulative dose–response trials. In this review, short term treatment is defined as less than 6 months and long term as 6 months or over. There is consensus that 6 months is the absolute minimum duration of main/1502_new 17/10/06 Chronic obstructive pulmonary disease R es pi ra to ry di so rd er s (a cu te )  BMJ Publishing Group Ltd 20062 treatment required to assess effects on decline in lung function. Where RCTs were found, no systematic search for observational studies was performed. We had articles translated as necessary and included all studies of sufficient quality. If we retrieved multiple systematic reviews which identified the same RCTs, we reported only the most recent review. QUESTION What are the effects of maintenance drug treatment in stable chronic obstructive pulmonary disorder? OPTION INHALED ANTICHOLINERGICS RCTs found that inhaled anticholinergics improved forced expiratory volume in 1 second, exercise capacity, and symptoms compared with placebo. One large RCT found that adding ipratropium to a smoking cessation programme had no significant impact on decline in forced expiratory volume in 1 second over 5 years compared with the smoking cessation programme alone. RCTs identified by a systematic review found that inhaled tiotropium (a long acting anticholinergic drug) improved exacerbation rates, health related quality of life, and forced expiratory volume in 1 second compared with placebo or ipratropium. Benefits: Short term short acting anticholinergics: We found four small12–15 and four large16–19 RCTs assessing the effects of ipratropium on lung function. We also found one systematic review, which assessed the effects of any anticholinergic drug compared with placebo on exercise capacity.20 All of the RCTs compared three or four interventions: ipratropium (at different doses in one trial), placebo, and a beta2 agonist. Two of the small RCTs12,13 found a significant effect in favour of ipratropium, and the remaining two14,15 found no significant difference among treatments. The first two of the large RCTs (276 people16 and 405 people17) compared ipratropium (36 �g 4 times daily) versus placebo and salmeterol for 12 weeks. In both RCTs, ipratropium significantly improved baseline forced expiratory volume in 1 second (FEV1) compared with placebo (results presented graphically). The third large RCT (780 people) compared ipratropium (40 �g 4 times daily) versus placebo and versus formoterol (eformoterol) for 12 weeks.18 It found that ipratropium significantly improved FEV1 compared with placebo (improve- ment in average FEV1 over 12 hours after medication 137 mL, 95% CI 88 mL to 186 mL). It found no significant difference in morning premedication peak expiratory flow, symptoms, quality of life scores, or need for rescue bronchodilators. The fourth large RCT (183 people with moderate to severe chronic obstructive pulmonary disease, mean FEV1 40% predicted, mean age 64 years) compared three treatments: ipratro- pium (80 �g 3 times daily), formoterol (18 �g twice daily), and placebo.19 It found no significant difference between ipratropium and placebo in shuttle walking distance at 12 weeks (mean increase from baseline: 15.3 m with ipratropium v 6.1 m with placebo; P value not reported, baseline mean distance 325 m). The systematic review (search date 1999) assessed changes in exercise capacity with anticholinergic drugs compared with placebo.20 Meta-analysis was not performed because of heterogeneity in design and outcomes assessed among studies. Sixteen of the 17 RCTs found that any anticholinergic drug improved exercise capacity compared with placebo. Long term treatment with ipratropium or tiotropium:We found one systematic review21 and one additional RCT.10 The review found that tiotropium significantly reduced exacerbation rates compared with placebo or ipratropium at 13–52 weeks (search date 2002; placebo: 3 RCTs; 2751 people; RR 0.74, 95% CI 0.62 to 0.89; ipratropium: 2 RCTs; 823 people; RR 0.78, 95% CI 0.63 to 0.95). It found that tiotropium significantly improved health related quality of life compared with placebo at 13–52 weeks (3 RCTs; 2751 people; mean change in St George’s Respiratory Questionnaire: –2.9, 95% CI –4.3 to –1.5). One included RCT found that tiotropium significantly improved mean trough FEV1 compared with placebo and 24 hours after dosing (mean improvement compared with placebo at 3 hours: 140–220 mL; P value not reported; at 24 hours: 120–220 mL; P < 0.01).25 One included RCT found that tiotropium significantly improved trough FEV1 compared with ipratropium at 1 year (improvement in FEV1 with tiotropium v ipratropium: 150 mL: P <0.001).26 One of the references in the review22 reported results from two 6 month RCTs, one of which was also reported in another reference included in the review;23,24 however, the review used both references in the meta-analysis. The additional RCT compared three interventions over a 5 year period: an main/1502_new 17/10/06 Chronic obstructive pulmonary disease R espiratory disorders (acute)  BMJ Publishing Group Ltd 2006 3 intensive 12 session smoking cessation programme combining behaviour modification and use of nicotine gum; the same smoking intervention programme plus ipratropium three times daily; or usual care.10 For results of the smoking cessation programme, see benefits of psychosocial plus pharmacological interventions for smoking cessation, p 16. Although the decline in FEV1 was significantly slower in people in both smoking cessation groups compared with usual care, adding ipratropium had no significant effect (5887 smokers aged 35–60 years with spirometric signs of early chronic obstructive pulmonary disease; FEV1 75% predicted; 5 year mean cumulative decline in FEV1 before bron- chodilator: usual care 249 mL, 95% CI 236 mL to 262 mL; smoking programme plus ipratropium 188mL, 95% CI 175 mL to 200 mL; smoking programme plus placebo 172 mL, 95% CI 159 mL to 185 mL). Inhaled anticholinergics plus beta2 agonists: See benefits of inhaled anticholinergics plus beta2 agonists, p 7. Inhaled anticholinergics versus beta2 agonists: See benefits of inhaled anticholinergics versus beta2 agonists, p 7. Harms: Short term short acting anticholinergics: One RCT comparing ipratropium found similar rates of adverse effects with ipratropium and placebo.19 Long term treatment with ipratropium or tiotropium: The review did not report on adverse effects. The first included RCT comparing tiotropium versus placebo found similar rates of adverse effects, except for dry mouth (16.0% with tiotropium v 2.7% with placebo; P < 0.05).25 The second included RCT found that dry mouth was significantly more common with tiotropium compared with ipratropium (12.1% with tiotropium v 6.1% with ipratropium; P < 0.05).26 The third included paper of two RCTs found that tiotropium significantly increased the proportion of people who had dry mouth compared with placebo (8.2% with tiotropium v 2.3% with placebo; reported as significant, P value not reported).22,23 The fifth included RCT found that tiotropium increased the proportion of people who had dry mouth compared with ipratropium, but the difference was not significant (dry mouth: 28/191 [14.7%] v 10/97 [10.3%]; difference reported as non-significant).27 The additional RCT of long term treatment found no significant difference between ipratro- pium and placebo in serious adverse events (cardiac symptoms, hypertension, skin rashes, and urinary retention: 1.2% with ipratropium v 0.8% with placebo), and dry mouth was the most common mild adverse effect.10 Inhaled anticholinergics plus beta2 agonists: See harms of inhaled anticholinergics plus beta2 agonists, p 7. Inhaled anticholinergics versus beta2 agonists: See harms of inhaled anticholiner- gics versus beta2 agonists, p 8. Comment: RCTs of long term treatment found no evidence that people developed tachyphylaxis in response to the bronchodilating effect of ipratropium or tiotropium over a 1–5 year period.10,25 The review included any RCTs with treatment for over 3 months, whereas our inclusion criteria for long term treatment is over 6 months.21 However, we have presented the results of the review, because only one of the included RCTs was of a treatment duration significantly shorter than 6 months. OPTION INHALED BETA2 AGONISTS RCTs found that treatment with inhaled beta2 agonists for 1 week to 12 months improved forced expiratory volume in 1 second compared with placebo. A systematic review and RCTs found that long acting beta2 agonists for 12–52 weeks improved quality of life and exacerbation rates compared with placebo. Since the last update of this topic, a drug safety alert has been issued on increased chance of severe, including life threatening, asthma attacks with long acting beta2 agonists (www.fda.gov/medwatch). Benefits: Short term treatment with short acting beta2 agonists: We found one systematic review (search date 2002, 9 crossover RCTs, 264 people with stable chronic obstructive pulmonary disease [COPD]) comparing short acting beta2 agonists versus placebo for at least 1 week.28 It found that beta2 agonists delivered by metered dose inhaler slightly but significantly increased forced expiratory volume in 1 second� (FEV1) compared with placebo (WMD 0.14 L, 95% CI 0.04 L to 0.25 L), and significantly improved daily breathlessness score (results reported as SMD; P < 0.001). There was no significant difference between treatments in exercise tolerance (4 RCTs; SMD + 0.18, 95% CI –0.11 to + 0.47), although the trials were small and the results were heterogeneous. main/1502_new 17/10/06 Chronic obstructive pulmonary disease R es pi ra to ry di so rd er s (a cu te )  BMJ Publishing Group Ltd 20064 The meta-analysis used post-crossover results, but there is unlikely to be persistence of treatment effects after crossover because the treatment is short acting. Short term treatment with long acting beta2 agonists: We found one systematic review, 21 one additional RCT,29 and two subsequent RCTs.30,31 The review found that beta2 agonists significantly reduced COPD exacerbations and improved health related quality of life compared with placebo at 12–52 weeks (search date 2002, publication date of some studies 2003; exacerbations: 8 RCTs; 3872 people; RR 0.79, 95% CI 0.69 to 0.90; mean change in St George’s Respiratory Questionnaire: 5 RCTs; 2551 people; –2.8, 95% CI –4.1 to –1.6). The effect on FEV1 was variable (data not reported). The review did not investigate the effects of long acting beta2 agonists on exercise capacity; however, four RCTs reported on exercise capacity, using varying inclusion criteria and methodologies.19,29–31 One RCT included in the review compared three treatments: formoterol 18 �g twice daily, ipratropium, and placebo.19 It found no significant differ- ence between formoterol and placebo in the shuttle walking test after 12 weeks’ treatment (183 people with moderate to severe COPD; increase from baseline: 20.4 m with formoterol v 6.0 m with placebo; reported as non-significant, P value not reported, baseline mean distance 325 m). The additional RCT compared the effects of three interventions on exercise capacity: formoterol (4.5, 9, or 18 �g twice daily), ipratropium (80 �g 3 times daily), or placebo for 1 week.29 It found that formoterol and ipratropium slightly but significantly increased time to exhaustion compared with placebo (34 people; crossover design; 10.94 minutes with 4.5 �g formoterol; 10.20 minutes with placebo; P < 0.0001 v placebo; 10.78 minutes with 9 �g formoterol; P < 0.01 v placebo; 10.59 minutes with 18 �g formoterol; P < 0.05 v placebo; 10.98 minutes with ipratropium; P < 0.0001 v placebo).29 The first subsequent RCT compared 18 �g tiotropium versus placebo once daily for 42 days. It