Transcript 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?
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
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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
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Systemic Signs of Pulmonary Disease
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Component of COPD
Emphysema
Emphysema but no
obstructive pulmonary
disease
Chronic bronchitis
Simple bronchitis
Airflow limitation
by spirometry
Asthma
Asthma with no airflow limitation
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Obstructive airway diseases
Chronic.
Bronchitis
Asthma
?
Chronic
Bronchiolitis
Emphysema
IRREVERSABLE
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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
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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?”
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
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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。
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
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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, 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
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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.
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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.
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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
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onth, weighted mean difference, and 95% C.I.
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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
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
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 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