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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 PBL--EBM臨床問題分析單 問題敘述(problem describe): Is antitussives beneficial to COPD patients with cough? 關鍵字(key word): antitussives, Expectorants ,COPD, Chronic cough 查詢之資料庫(Journal search) 至少需查詢此四個實證資料庫: Medline 、Cochrane、ACP、DARE other database: 文獻等級、主要內容(Main results): Level 1:RCT Level 2:cohort study Level 3:case control Level 4:case series Level 5: expert opinion 與臨床狀況之比較分析(Reviewers' conclusions): 何明霖 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 何明霖 Oxford center for EBM (May 2001) The type of question is important and can help lead you to the best study design Type of Question 何明霖 Suggested best type of Study Therapy RCT>cohort > case control > case series Diagnosis prospective, blind comparison to a gold standard Etiology/Harm RCT > cohort > case control > case series Prognosis cohort study > case control > case series Prevention RCT>cohort study > case control > case series Clinical Exam prospective, blind comparison to gold standard Cost economic analysis Oxford Center for Evidence-based Medicine Levels of Evidence (May 2001) Level 何明霖 Therapy 1a 系統性回顧 Systematic review (分析數個隨機臨床對照試驗, 其結果均類似) 1b 設計良好, 結果精確 之隨機臨床對照試驗 1c All or none 2a 系統性回顧 (分析數個世代研究, 其結果均類似) 2b 世代研究 Cohort study; 設計粗糙之隨機臨床對照試驗 2c "Outcomes" Research; Ecological studies 3a 系統性回顧 (分析數個病例-對照研究, 其結果均類似) 3b 病例 - 對照研究 Case-control study 4 某家醫院的十年經驗; 設計不良之世代研究 及病例 - 對照研究 5 未經考證之專家個人意見, 基礎研究, 細胞實驗, 生理實驗, 動物實 驗…的結果 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 何明霖 Systemic Signs of Pulmonary Disease 何明霖 Component of COPD Emphysema Emphysema but no obstructive pulmonary disease Chronic bronchitis Simple bronchitis Airflow limitation by spirometry Asthma Asthma with no airflow limitation 何明霖 Obstructive airway diseases Chronic. Bronchitis Asthma ? Chronic Bronchiolitis Emphysema IRREVERSABLE 何明霖 REVERSABLE (Adapted from Jeffery PJ. Thorax 1999;53:129) 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) 何明霖 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 何明霖 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?” 何明霖 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 何明霖 何明霖 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. 何明霖 何明霖 Evidence-based problem solving 何明霖 “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。 PICO (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? 何明霖 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 何明霖 檢索途徑 EBM review Pubmed Limitation: randomized control, meta-analysis, controlled clinical trial, guideline 何明霖 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 何明霖 Users’ Guides to the Medical Literature Using 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 何明霖 何明霖 何明霖 何明霖 何明霖 何明霖 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, placebocontrolled 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) 何明霖 Dr. P.J. Poole, University of Auckland, Auckland, New Zealand. ACP J Club, Volume 136(2).March/April 2002.54 何明霖 何明霖 何明霖 何明霖 何明霖 何明霖 何明霖 何明霖 何明霖 何明霖 何明霖 Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airway obstructionBritish Thoracic Society Research committee Thorax 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” 何明霖 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 何明霖 Number of exacerbations per patient per month From: Poole: The Cochrane Library, Volume (4).2004. 何明霖 何明霖 Patients with no exacerbations in study period From: Poole: The Cochrane Library, Volume (4).2004. 何明霖 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 何明霖 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? 何明霖 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 bronchitisACP J club 1999; 131: 14 The Cochrane database of systematic reviews: Mucolytic agents for chronic bronchitis (Date of most recent update:12-5-2004) 何明霖 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 何明霖 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 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 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 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 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 何明霖 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. 何明霖 Number of exacerbations per patient per month From: Poole: The Cochrane Library, Volume (4).2004. 何明霖 Patients with no exacerbations in study period From: Poole: The Cochrane Library, Volume (4).2004. 何明霖 Mucolytic drugs v placebo for chronic bronchitis or chronic obstructive pulmonary disease* Evidence-Based Medicine 2002; 7:53 何明霖 Details of studies included in systematic review Study Country # pt Clinical Criteria Mean age % smoker Length of study Intervention Quality Allegra 1996 Italy 662 Chronic bronchitis (FEV1 65% pred) 60.1 73 current 6m Carbocisteine lysine 2.7g/d 5 Babolin i 1980 Italy 744 Chronic bronchitis (FEV1 2.18 l) NA 64.3 6 Acetylcysteine 200mg bid 4 Boman 1983 Sweden 259 Chronic bronchitis (FEV1 80% pred) 51.9 100 6 Acetylcysteine 200mg bid 2 McGavi 1985 UK 181 Chronic bronchitis (FEV1 0.86 l) 63.4 99 5 Acetylcysteine 200mg tid 4 : : : : : : : : : : : : : : : : : : Nowak 1999 Europe 313 COPD (FEV1 60% pred) 57 NA 8 Acetylcysteine 600mg bid 2 何明霖 onth, weighted mean difference, and 95% C.I. 何明霖 end of study period 何明霖 Are the results clinically significant? P value: 比較兩組是否有顯著差異 – 只要樣本數夠大, 就算是 只有些微差異, 也會變得顯著; 統計上的顯著不一定 代表臨床上有重要意義 Confidence interval 何明霖 真正的療效 (RR) 我們無從得知, 故我們以“95%信 賴區間”來表示該範圍有95%的機會會涵蓋真正的 療效; 區間的寬度代表該研究的精確度 (precision); 愈精確的研究結果代表我們愈有信心評估治療的療 效 Mucolytic drugs vs placebo for chronic bronchitis or chronic obstructive pulmonary disease Dr. P.J. Poole, University of Auckland, Auckland, New Zealand. ACP J Club, Volume 136(2).March/April 2002.54 何明霖 NNT (number needed to treat) 避免一位病患罹患某種疾病所需治療人數 (number needed to treat, NNT)」這項評估方 式佔據極重要的地位. NNT 是「絕對危險度減少百分比(absolute risk reduction, ARR)」的倒數, 亦即 NNT = 1/ARR. 若NNT愈大,表示其成本效益較差。 何明霖 當有了一個可信的結果,接下來要去評估 這結果的臨床意義 觀察 COPD No exacerbation 安慰劑組 42% 改善 58% 未改善 Mucolytic組 60%改善 40 % 未改善 P值 < 0.05 RRR(relative risk reduction)= (58%-40%)/58%= 31% ARR(absolutre risk reduction)= 58%-40%=18% NNT(number needed to treat to prevent one failure) = 1/ (ARR)= 5.5.. 科學上的文章常以RRR來代表療效,但對療效的感受上不如NNT 來的直接。假設有100位COPD患者未接受mucolytic治療,其中 有58位治療失敗,若這100位患者都接受mucolytic治療,則只有 40位治療失敗,故以mucolytic治療,每治療100位COPD患者可 避免其中18位治療失敗,換言之,每治療5.5位可拯救其中一人, 這就是NNT的概念。 何明霖 COPD: mucolytics reduce exacerbations and days of disability 何明霖 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 何明霖 Can the results be applied to my patients? Meet all the inclusion criteria Not violate any of the exclusion criteria Is your patient so different from those in the trial that its results should not be applied? Differences in the illness Patient differences in drug metabolism, immune response, environmental factors… Compliance Comorbid condition 何明霖 Will the results help me in caring for my patients? Can the results be applied to my patient care? How great would the benefit actually be for your individual patient? Were all clinically important outcomes considered? Are the likely treatment benefits worth the potential harms and costs? Do your patient and you have a clear assessment of their values and preferences? Are they satisfied by this therapy and its consequences? 何明霖 Will You Prescribe Mucolytics to Your Patient? Compared with placebo, # of exacerbations was significantly reduced by 29% in subjects taking mucolytics; NNT for one subject to have no exacerbation in the study period was 6 The typical patient with 2~3 exacerbations/yr could expect 1 less attack by taking the drug daily for 2 yrs The reduction in sick days from an average of 4 to 3.4 d/mo No effect was observed for FEV1 Adverse effects were mainly mild GI complaints; no difference between Tx and placebo group 何明霖 何明霖 Antitussives Regular use of antitussives is not recommended in COPD since cough can have a significant protective effect. Mucolytics There may be isolated circumstances (especially in the presence of copious, thick secretions) in which an individual with COPD might benefit from a mucolytic or mucoactive agent. Evidence supporting this recommendation is of classes: A In general, however, drugs from this class have not been shown to be effective and are not recommended as treatment for COPD. 何明霖 Take Home Message Regular use of mucolytics for at least 2 months significantly reduces exacerbations and days of illness in patients with chronic bronchitis and COPD The effect of mucolytics on days of illness was greater then the effect on # of exacerbations; The benefit from oral mucolytic agents is too small to justify routine use; Treatment may be not costeffective Clinicians should manage chronic bronchitis by encourage smoking cessation, exercise rehabilitation, and treating airway obstruction 何明霖 謝謝您的聆聽! 何明霖 Step 3---嚴格評估證據 (critical appraisal of evidence) 1、 Are the results of this individual study valid ? (1)Was the assignment of patients to treatment randomized ? And was the randomization list concealed ? (2)Was follow-up of patients sufficiently long and complete? (3)Were all patients analyzed in the groups to which they randomized? (4)Were patients and clinician kept “blind” to treatment? (5)Were the groups treated equally , apart from the experimental treatment? 6) Were the groups similar at the start of the trial? 何明霖 2. Are the valid results of this randomized trial important ? CER= Control Event Rate , 控制組(對照組)某種病況的 發生率 ERR=Experimental Event Rate , 實驗組某種病況的發 生率 ARR= Absolute Risk Reduction=|CER-EER| ARI= Absolute Risk Increase =|CER-EER| NNT= Number needed to be treat=1/ARR 避免一個病患發生某種病況所須治療的病人數 NNH= Number needed to be harmed=1/ARI 給予治療多少病人數發生一位病患受副作用所害 何明霖 See Table III , 把〝cough〞擬 人化 CER baseline = EER = placebo 13.8 cs/h x100h 2x1000 =69% = 0.69 11.1 cs/h x 100h =55.5% = 0.555 2x1000 ARR=|CER-EER|=0.135 NNT=1/ARR=7.4=8 解讀:在stable COPD病人,在100個小時內每1000個觀察次數中, 用placebo治療每8次cough可避免掉1次cough的發生 何明霖 Again see Table III CER = 13.8 cs/h x 100h 2 x 1000 = 10.7 cs/h x 100h =53.5% = 0.535 2 x 1000 baseline EER codeine =69% = 0.69 ARR=|CER-EER|=0.155 NNT=1/ARR=6.45=7 解讀:在stable COPD病人,在100個小時內每1000個觀察次數 中,用 codeine治療每7次cough可避免掉1次cough的發生 何明霖 2. Are the valid results of this randomized trial important ? 3. Can you apply this valid , important evidence about therapy in caring for your patients? 何明霖 何明霖