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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):
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Levels of EvidenceLevel 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)
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Type of
Question 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
The type of question is important and can help lead you to the best study design
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Oxford Center for Evidence-based Medicine Levels of Evidence (May
2001)
Level 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
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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 bronchitisEmphysema
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Systemic Signs of Pulmonary Disease
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EmphysemaEmphysema but no
obstructive pulmonary disease
Chronic bronchitis
Simple bronchitis
Asthma
Asthma with no airflow limitation
Airflow limitationby spirometry
Component of COPD
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Obstructive airway diseases
AsthmaChronic.Bronchitis ?
ChronicBronchiolitis
Emphysema
IRREVERSABLE REVERSABLE
(Adapted from Jeffery PJ. Thorax 1999;53:129)
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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)
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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
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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 ?”
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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
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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.
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Evidence-based problem solving
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“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
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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
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檢索途徑
EBM reviewPubmed
Limitation: randomized control, meta-analysis, controlled clinical trial, guideline
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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
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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
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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
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Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airway obstruction- Britis
h 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, sp
utum 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”
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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
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Number of exacerbations per patient per month From: Poole: The Cochrane Library, Volume (4).2004.
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Patients with no exacerbations in study period From: Poole: The Cochrane Library, Volume (4).2004.
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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
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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?
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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)
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COPD: mucolytics reduce exacerbations and days of disability
Clinical bottom line (level 1a) Patients with chronic bronchitis who are given mucolytics, a
re 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
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Review: mucolytic drugs reduce exacerbations, illness days, and antibiotic use in chronic bronchitis and chronic obstructi
ve 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
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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 chr
onic 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 exace
rbations 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.
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Number of exacerbations per patient per month From: Poole: The Cochrane Library, Volume (4).2004.
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Patients with no exacerbations in study period From: Poole: The Cochrane Library, Volume (4).2004.
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Mucolytic drugs v placebo for chronic bronchitis or chronic obstructive pulmonary disease*
Evidence-Based Medicine 2002; 7:53
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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% pre
d)
60.1 73 current
6 m Carbocisteine lysine 2.7g/d
5
Babolini 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% pre
d)
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
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:
:
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Nowak 1999
Europe 313 COPD
(FEV1 60% pred)
57 NA 8 Acetylcysteine 600mg bid
2
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Mean (SD) # of exacerbations /subject/ month, weighted mean difference, and 95% C.I.
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Lung function at end of study period
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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 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
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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
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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。
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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
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 N
NT 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。
觀察 COPDNo exacerbation
安慰劑組 Mucolytic 組 P值42% 改善 60% 改善 < 0.05
58% 未改善 40 % 未改善
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COPD: mucolytics reduce exacerbations and days of disability
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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
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Can the results be applied to my patients?
Meet all the inclusion criteriaNot violate any of the exclusion criteriaIs your patient so different from those in the tri
al that its results should not be applied?Differences in the illnessPatient differences in drug metabolism, immune re
sponse, environmental factors…ComplianceComorbid condition
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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?
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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 dif
ference between Tx and placebo group
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Antitussives Regular use of antitussives is not recommended in COPD since coug
h can have a significant protective effect.
Mucolytics There may be isolated circumstances (especially in the presence o
f 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.
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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 cost-effective
Clinicians should manage chronic bronchitis by encourage smoking cessation, exercise rehabilitation, and treating airway obstruction
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謝謝您的聆聽！
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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 randomizat
ion 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？
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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
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See Table III , 把〝 cough〞擬人化
CER = =69% = 0.69
EER = =55.5% = 0.555
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
baseline13.8 cs/h x100h 2x1000
placebo
11.1 cs/h x 100h2x1000
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Again see Table III
CER = =69% = 0.69 EER = =53.5% = 0.535
ARR=|CER-EER|=0.155NNT=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
baseline
13.8 cs/h x 100h2 x 1000
codeine
10.7 cs/h x 100h2 x 1000
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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?
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