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實證醫學 題目: Is antitussives beneficial to COPD patients with cough?

實證醫學 題目: Is antitussives beneficial to COPD patients with cough?

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實證醫學 題目: Is antitussives beneficial to COPD patients with cough?

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  1. 實證醫學題目:Is antitussives beneficial to COPD patients with cough? 何明霖、李孟智 中山醫學大學醫學研究所

  2. PBL--EBM臨床問題分析單

  3. Levels of Evidence • Level Ⅰ:Randomized Controlled Trial ( RCT ) • Level Ⅱ:Cohort Study • Level Ⅲ:Case Control Study • Level Ⅳ:Case Series,Case Report • Level Ⅴ:Expert Opinion Oxford center for EBM (May 2001)

  4. The type of question is important and can help lead you to the best study design

  5. Oxford Center for Evidence-based Medicine Levels of Evidence (May 2001)

  6. 定義 • Antitussives 鎮咳藥 • 咳嗽抑制劑,作用在延腦的咳嗽中樞,或作用在支氣管分支的末稍,用來緩解無益處的乾咳 • COPD (Chronic obstructive pulmonary disease) • Chronic bronchitis • Emphysema

  7. Systemic Signs of Pulmonary Disease

  8. Component of COPD Emphysema Chronic bronchitis Emphysema but no obstructive pulmonary disease Simple bronchitis Airflow limitation by spirometry Asthma Asthma with no airflow limitation

  9. Obstructive airway diseases Asthma Chronic. Bronchitis ? Chronic Bronchiolitis Emphysema IRREVERSABLE REVERSABLE (Adapted from Jeffery PJ. Thorax 1999;53:129)

  10. Pharmacological treatments of COPD • Antibiotics: only for treating infectious exacerbations (A) • Mucolytic (mukoinetic, mucoregulator) agents (D) • Antioxidant agents (N-acetylcysteine) (B) • Immunomodulators (B) • Antitussives: regular use is contraindicated(D) • Vasodilators (NO): contraindicated in stable COPD • Respiratory stimulants: almitrine (B), doxapram (D) • Narcotics (morhphine)

  11. 常見之咳藥根據其作用可分為兩類 • A‧袪痰劑 (Expectorant) • 作用是使呼吸道之分泌增加,這些分泌液不但可以保護呼吸道的黏膜,而且會減低痰的黏性,使其流動性增加,易於排出,間接促成止咳的目的。常用的袪痰藥有氯化胺(Ammonium Chloride)、依必格酊(Tincture of Ipecacuanha)、遠志酊(Tincture of Senega)等。 • 化痰的,助咳的除痰劑 a medicine promoting expectoration • B‧鎮咳劑、止咳劑 (Antitussive) • 作用是抑制中樞神經,以達到止咳之目的,部份鎮咳劑含輕微麻醉成份之可待因(Codeine),會引起睡意,因此服用時要特別留意。 • any medicine used to suppress or relieve coughing • C. Mucolytic • 在呼吸道的作用,減少支氣管腺體分泌,使氣管內黏液減少並分解痰液中的黏多糖蛋白等黏性物質,使低黏度的唾液蛋白分泌增加而高黏度的岩藻黏蛋白產生減少,因而降低痰液黏滯度,使痰容易咳出

  12. Clinical Scenario • 林先生, a 60 y/o retired taxi driver suffered from chronic productive cough & D.O.E. for years • COPD, diagnosed for 3 years • FEV1 65% predicted, not respond to bronchodilator • Smoking: 1 PPD for 30 yrs, quitted for 1+ year • Rx: Atrovent 2 puff bid only • “醫生, 我痰不好咳, 可不可以開個化痰藥給我?”

  13. 實證醫學的五大步驟 • 步驟一:提出可回答的臨床問題 • 步驟二:搜尋最好實證 • 步驟三:探討證據的效度及重要性 • 步驟四:統合證據、專家意見及病人現況 • 步驟五:成效評值

  14. Background • Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume and/or purulence of sputum and any therapy that reduced the number of exacerbations would be useful. • There is a marked difference between countries in terms of prescribing of mucolytics depending on whether or not they are perceived to be effective.

  15. Evidence-based problem solving

  16. “Foreground” Questions如何明確的分析我們所面臨的臨床問題 • (1) Patient • 在慢性阻塞性肺疾的病患,久咳不癒、又有中度呼吸道阻塞、已戒菸、未曾使用過類固醇及無明顯的肺炎跡象。  • (2) Intervention • 止咳藥。  • (3) Comparison • 與安慰劑(placebo)比較。  • (4) Outcome • 減輕症狀? • 改善呼吸道的阻塞或肺功能(FEV1/PEFR)? • 降低治療的失敗率(死亡、插管或再住院)or 縮短住院日數? PICO

  17. 實證醫學的五大步驟 • 步驟一:提出可回答的臨床問題 • 步驟二:搜尋最好實證 • 步驟三:探討證據的效度及重要性 • 步驟四:統合證據、專家意見及病人現況 • 步驟五:成效評值

  18. 檢索途徑 • EBM review • Pubmed • Limitation: randomized control, meta-analysis, controlled clinical trial, guideline

  19. Are the results of the study valid? • Was the assignment of patients to treatments randomized? • Was the randomization list concealed? • Were the groups similar at the start of the trial? • Aside from the experimental intervention, were the groups treated equally? • Were patients, health workers, and study personnel “blind” to treatment? • Was follow-up complete? • Were patients analyzed in the groups to which they were randomized (intention-to-treat analysis)? JAMA 1993; 270(21): 2598-2601

  20. Users’ Guides to the Medical LiteratureUsing Electronic Health Information resources • Clinical Evidence: www.clinicalevidence.org • Best Evidence (ACP J club, Evidence-Based Medicine) • Cochrane Library • Cochrane Database of Systematic Reviews • Database of Abstract of Reviews of Effectiveness • Practice Guidelines: www.guideline.org • Other resources: www.uptodate.com, www.mdconsult.com JAMA 2000;283:1875-9

  21. Review: Mucolytic drugs reduce exacerbations, illness days, and antibiotic use in chronic bronchitis and COPD • Question: In patients with chronic bronchitis or chronic obstructive pulmonary disease (COPD), do mucolytic drugs reduce exacerbations or days of illness? • Data sources: Studies were identified by searching the Cochrane Airways Group register of studies (compiled by searching MEDLINE, EMBASE/Excerpta Medica, and CINAHL and hand searching respiratory journals and meeting abstracts). Reference lists of articles were scanned, and researchers in the field and pharmaceutical companies were contacted. • Study selection: Studies were selected if they were randomized, double-blind, placebo-controlled trials of oral mucolytic drugs taken regularly for >= 2 months by adults who were > 20 years of age and had chronic bronchitis or COPD. Studies on inhaled mucolytic drugs, combinations of mucolytic drugs with antibiotics or bronchodilators, deoxyribonucleases, and such proteases as trypsin were excluded, as were studies on patients with asthma or cystic fibrosis. • Data extraction: Data were extracted on study country and duration, clinical criteria, patient age, smoking, intervention, and quality of study methods. Summary statistics were used. Main outcomes were number of acute exacerbations, days of illness, and days taking antibiotics. • Main results: 23 of 27 studies that met selection criteria reported data on the main outcomes. Patients had chronic bronchitis in 21 studies and COPD in 2 studies. Follow-up ranged from 2 to 24 months (mean 6 mo). Studies were done in Italy (11 studies), the United Kingdom (4 studies), Sweden (2 studies), Europe (2 studies), Germany (2 studies), Denmark (1 study), and the United States (1 study). Mucolytic drugs were better than placebo for reducing exacerbations (P < 0.001), days of illness (P < 0.001), and days of antibiotic use (P < 0.001) Dr. P.J. Poole, University of Auckland, Auckland, New Zealand. ACP J Club, Volume 136(2).March/April 2002.54

  22. Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airway obstruction- British Thoracic Society Research committeeThorax 1985;40:832-5 • A RCT enrolled 181 patients with chronic bronchitis, FEV1<50% predicted • Oral acetylcysteine 200 mg tid vs. Placebo for 5 months • Detailed daily symptom diaries about breathlessness, sputum appearance, volume, cough, difficulty in expectoration, days in bed or in hospital , assessed monthly by clinician • Outcome: # of exacerbation, days in bed, days taking ABx, mean change in FEV1 • “The outcome in Tx group was a little better, but the differences did not reach statistical significance”

  23. Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis Respiratory Medicine 1994;88:531-5 • A RCT comparing acetylcysteine 600mg bid vs. placebo for 22 weeks in 105 chronic bronchitis patients with FEV1 > 50% predicted • Using an established psychiatric instrument General Health Questionnaire and visual analogue scales for subjective symptoms, functional capacity…etc. • # of observed exacerbations was unexpectedly low in both groups. • No significant difference in subjective symptom scores, FEV1, or in # or severity of exacerbations; significant beneficial effect on general well-being

  24. Number of exacerbations per patient per monthFrom:   Poole: The Cochrane Library, Volume (4).2004.

  25. Patients with no exacerbations in study periodFrom:   Poole: The Cochrane Library, Volume (4).2004.

  26. 實證醫學的五大步驟 • 步驟一:提出可回答的臨床問題 • 步驟二:搜尋最好實證 • 步驟三:探討證據的效度及重要性 • 步驟四:統合證據、專家意見及病人現況 • 步驟五:成效評值

  27. The specific, answerable clinical question: • In patients with stable COPD or chronic bronchitis • Do Mucolytics, as compared with placebo • Be able to: Relieve symptoms (cough frequency, severity, ease in bringing up sputum) Decrease exacerbations? Reduce days of illness? Attenuate declination in lung function? Improve quality of life?

  28. What we have now… • Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review BMJ 2001; 322:1-6 • Review: oral mucolytic agents reduce exacerbations and sick days in chronic bronchitis- ACP J club 1999; 131: 14 • The Cochrane database of systematic reviews: Mucolytic agents for chronic bronchitis (Date of most recent update:12-5-2004)

  29. COPD: mucolytics reduce exacerbations and days of disability • Clinical bottom line (level 1a) • Patients with chronic bronchitis who are given mucolytics, are more likely to have a greater reduction in exacerbations per month, than those given placebo. • Patients given mucolytics are more likely to have a greater reduction in days of disability per month than those given placebo. • Patients given mucolytics are less likely to have an improvement in FEV1 or FVC than those given placebo. • There is no clear difference in number of adverse effects. Poole and Black: The Cochrane Library 1999; 3: 1-10

  30. Review: mucolytic drugs reduce exacerbations, illness days, and antibiotic use in chronic bronchitis and chronic obstructive pulmonary disease Evidence-Based Medicine 2002; 7:53 • Data sourcesStudies were identified by searching the Cochrane Airways Group register of studies (compiled by searching Medline, EMBASE/Excerpta Medica, and CINAHL, and hand searching respiratory journals and meeting abstracts). Reference lists of articles were scanned, and researchers in the field and pharmaceutical companies were contacted. • Study selectionStudies were selected if they were randomised, double blind, placebo controlled trials of oral mucolytic drugs taken regularly for 2 months by adults who were > 20 years of age and had chronic bronchitis or COPD. Studies on inhaled mucolytic drugs, combinations of mucolytic drugs with antibiotics or bronchodilators, deoxyribonucleases, and such proteases as trypsin were excluded, as were studies on patients with asthma or cystic fibrosis. • Main results23 of 27 studies that met selection criteria reported data on the main outcomes. Patients had chronic bronchitis in 21 studies and COPD in 2 studies. Follow up ranged from 2 to 24 months (mean 6 mo). Studies were done in Italy (11 studies), the UK (4 studies), Sweden (2 studies), Europe (2 studies), Germany (2 studies), Denmark (1 study), and the USA (1 study). Mucolytic drugs were better than placebo for reducing exacerbations (p < 0.001), days of illness (p < 0.001), and days of antibiotic use (p < 0.001) (table). 圖

  31. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease (Cochrane Review)From The Cochrane Library, Issue 4, 2004. • Objectives: To assess the effects of oral mucolytics in adults with stable chronic bronchitis or COPD. • Selection criteria: Randomised trials that compared oral mucolytic therapy with placebo for at least two months in adults with chronic bronchitis or COPD. Studies of people with asthma and cystic fibrosis were excluded. • Main results: 23 trials were included. • Compared with placebo, there was a significant reduction in the number of exacerbations per patient with oral mucolytics (weighted mean difference (WMD) -0.066 per month, 95% confidence interval -0.077, -0.054, p<0.001). • Using the annualised rate of exacerbations in the control patients of 2.7 per year, this is a 29% reduction. • The number of days of disability also fell (WMD -0.56, 95% confidence interval -0.77, -0.35, p<0.001). • The number of patients who remained exacerbation-free was greater in the mucolytic group (OR 2.22, 95% confidence interval 1.93, 2.54, p<0.001). • There was no difference in lung function or in adverse effects reported between treatments. • Reviewers' conclusions: In subjects with chronic bronchitis or COPD, treatment with mucolytics was associated with a small reduction in acute exacerbations and a somewhat greater reduction in total number of days of disability.