???? ??:Is antitussives beneficial to COPD patients with cough?

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??????Is antitussives beneficial to COPD
patients with cough?

• ???????
• ???????????

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PBL--EBM???????
????(problem describe) Is antitussives beneficial to COPD patients with cough?
???(key word) antitussives, Expectorants ,COPD, Chronic cough
??????(Journal search) ????????????? Medline ?Cochrane?ACP?DARE other database
?????????(Main results) Level 1RCT Level 2cohort study Level 3case control Level 4case series Level 5 expert opinion
??????????(Reviewers' conclusions)
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Levels of Evidence

• Level ?Randomized Controlled Trial
• ( RCT )
• Level ?Cohort Study
• Level ?Case Control Study
• Level ?Case Series,Case Report
• Level ?Expert Opinion

Oxford center for EBM (May 2001)
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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 ????? Systematic review (????????????, ??????)
1b ????, ???? ?????????
1c All or none
2a ????? (????????, ??????)
2b ???? Cohort study ?????????????
2c "Outcomes" Research Ecological studies
3a ????? (??????-????, ??????)
3b ?? - ???? Case-control study
4 ????????? ????????? ??? - ????
5 ???????????, ????, ????, ????, ???????
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??

• Antitussives ???
• ?????,??????????,????????????,??????????
• 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
Chronic bronchitis
Emphysema but no obstructive pulmonary disease
Simple bronchitis
Airflow limitation by spirometry
Asthma
Asthma with no airflow limitation
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Obstructive airway diseases
Asthma
Chronic. Bronchitis
?
Chronic Bronchiolitis
Emphysema
IRREVERSABLE REVERSABLE
(Adapted from Jeffery PJ. Thorax 199953129)
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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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???????????????

• A???? (Expectorant)
• ????????????,?????????????????,?????????,???????,?
  ???,????????????????????(Ammonium
  Chloride)?????(Tincture of Ipecacuanha)????(Tinctu
  re of Senega)??
• ???,?????? a medicine promoting expectoration
• B???????? (Antitussive)
• ?????????,????????,????????????????(Codeine),?????
  ,???????????
• any medicine used to suppress or relieve coughing
  
• C. Mucolytic
• ???????,?????????,?????????????????????????,??????
  ?????????????????????,?????????,??????

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Clinical Scenario

• ???, 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
• ??, ?????, ????????????

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• ?????????????????
• ???????

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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?????????????????

• (1) Patient
• ???????????,????????????????????????????????????? 
  
• (2) Intervention
• ???? 
• (3) Comparison
• ????(placebo)??? 
• (4) Outcome
• ?????
• ????????????(FEV1/PEFR)?
• ????????(?????????)or ???????

PICO 
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?????????

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• ?????????
• ??????????????
• ?????????????????
• ???????

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????

• EBM review
• Pubmed
• 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 20002831875-9

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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 gt 2 months by adults who were gt 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 lt
  0.001), days of illness (P lt 0.001), and days of
  antibiotic use (P lt 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- British Thoracic Society
Research committeeThorax 198540832-5

• A RCT enrolled 181 patients with chronic
  bronchitis, FEV1lt50 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

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Orally administered N-acetylcysteine may improve
general well-being in patients with mild chronic
bronchitis Respiratory Medicine 199488531-5

• A RCT comparing acetylcysteine 600mg bid vs.
  placebo for 22 weeks in 105 chronic bronchitis
  patients with FEV1 gt 50 predicted
• Using an established psychiatric instrument
  General Health Questionnaire and visual analogue
  scales for subjective symptoms, functional
  capacityetc.
• 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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• ?????????????????
• ???????

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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 update12-5-2004)

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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, 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
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Review mucolytic drugs reduce exacerbations,
illness days, and antibiotic use in chronic
bronchitis and chronic obstructive pulmonary
disease Evidence-Based Medicine 2002 753

• 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 gt 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 lt 0.001), days of
  illness (p lt 0.001), and days of antibiotic use
  (p lt 0.001) (table ).

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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 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, plt0.001).
• 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,
  plt0.001).
• The number of patients who remained
  exacerbation-free was greater in the mucolytic
  group (OR 2.22, 95 confidence interval 1.93,
  2.54, plt0.001).
• 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 753
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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 pred) 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 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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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
• ??????????? ???????, ?????????, ??????
  ???????????????????
• Confidence interval
• ????? (RR) ??????, ????95???????????95????????
  ??? ?????????????? (precision)
  ???????????????????????

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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)

• ??????????????????(number needed to treat,
  NNT)???????????????.
• NNT ????????????(absolute risk reduction,
  ARR)????, ?? NNT 1/ARR.
• ?NNT??,??????????

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??????????,???????????????
?? COPD No exacerbation ???? Mucolytic? P?
?? COPD No exacerbation 42 ?? 60?? lt 0.05
?? COPD No exacerbation 58 ??? 40 ???

• RRR(relative risk reduction) (58-40)/58 31
• ARR(absolutre risk reduction) 58-4018
• NNT(number needed to treat to prevent one
  failure) 1/ (ARR) 5.5..
• ????????RRR?????,??????????NNT????????100?COPD????
  ?mucolytic??,???58?????,??100??????mucolytic??,???
  40?????,??mucolytic??,???100?COPD???????18?????,??
  ?,???5.5????????,???NNT????

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COPD mucolytics reduce exacerbations and days of
disability
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• ?????????????????
• ???????

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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

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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 23 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.

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Wake up
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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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??????!
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Step 3---??????(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?

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2. Are the valid results of this randomized
trial important ?CER Control Event Rate ,
???(???)????????ERRExperimental Event Rate ,
???????????ARR Absolute Risk ReductionCER-EER
ARI Absolute Risk Increase CER-EER
NNT Number needed to be treat1/ARR
????????????????????
NNH Number needed to be harmed1/ARI
?????????????????????
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See Table III , ??cough????
13.8 cs/h x100h 2x1000

• CER 69
  0.69
• EER 55.5
  0.555
• ARRCER-EER0.135
• NNT1/ARR7.48
• ???stable COPD??,?100?????1000??????,?placebo???8
  ?cough????1?cough???

baseline
11.1 cs/h x 100h
2x1000
placebo
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Again see Table III
13.8 cs/h x 100h

• CER
  69 0.69
• EER
  53.5 0.535
• ARRCER-EER0.155
• NNT1/ARR6.457
• ???stable COPD??,?100?????1000??????,?
  codeine???7?cough????1?cough???

2 x 1000
baseline
10.7 cs/h x 100h
2 x 1000
codeine
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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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