Drug treatments

Anticholinergics versus beta2 agonists (inhaled)

In this section:

Key points | Benefits and Harms | Comment

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Key points

  • For GRADE evaluation of interventions for COPD, see table.
  • It is unclear whether inhaled anticholinergics or inhaled beta2 agonists are the more consistently effective drug class in the treatment of COPD.
  • Short-acting anticholinergics seem to be associated with a small improvement in quality of life compared with beta2 agonists.
  • Long-acting inhaled anticholinergic drugs may improve lung function compared with long-acting beta2 agonists.
  • We found no clinically important results from RCTs comparing long-acting anticholinergics versus short-acting beta2 agonists in the treatment of people with COPD.
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Benefits and harms

Short-acting anticholinergic versus short-acting beta2 agonist:

We found 5 systematic reviews comparing anticholinergics versus beta2 agonists.[29][48][30][44][45] The reviews did not report data in terms of short- or long-term duration of treatment as defined in our Methods section, but by length of drug action. We report comparisons as reported in the reviews, and specify the duration of treatment where possible. One review compared anticholinergics as a class versus beta2 agonists as a class (see further information on studies for results).[30] One review (search date 2008, 11 RCTs, 3912 people) compared ipratropium versus short-acting beta2 agonists (metaproterenol, fenoterol, and salbutamol).[44]

Lung function and exercise capacity

Short-acting anticholinergic compared with short-acting beta2 agonist Ipratropium and short-acting beta2 agonists seem equally effective at 85 days at improving FEV1 (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Lung function

[44]

Systematic review

1917 people

6 RCTs in this analysis

Mean FEV1 peak response, 85 days of treatment

ipratropium

short-acting beta2 agonists

Absolute results not reported

WMD 0.00 L

95% CI –0.02 L to +0.01 L

P = 0.6

not-significant

not significant

COPD exacerbation and worsening of symptoms

Short-acting anticholinergic compared with short-acting beta2 agonist Ipratropium seems modestly more effective than a short-acting beta2 agonist at improving the dyspnoea component of the Chronic Respiratory Disease Questionnaire (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Symptom severity

[44]

Systematic review

1529 people

5 RCTs in this analysis

Improvement in the dyspnoea component of the Chronic Respiratory Disease Questionnaire, 85 days of treatment

ipratropium

short-acting beta2 agonists

Absolute results not reported

WMD 0.16

95% CI 0.09 to 0.23

P <0.001

not-calculated

ipratropium

Quality of life

Short-acting anticholinergic compared with short-acting beta2 agonist Ipratropium seems modestly more effective than a short-acting beta2 agonist at improving fatigue, emotion, and mastery components of the Chronic Respiratory Disease Questionnaire (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Quality of life

[44]

Systematic review

1529 people

5 RCTs in this analysis

Improvement in the fatigue component of the Chronic Respiratory Disease Questionnaire (CRQ), 85 days of treatment

ipratropium

short-acting beta2 agonists

Absolute results not reported

WMD 0.13

95% CI 0.02 to 0.23

P = 0.02

not-calculated

ipratropium

[44]

Systematic review

1529 people

5 RCTs in this analysis

Improvement in the emotion component of the CRQ, 85 days of treatment

ipratropium

short-acting beta2 agonists

Absolute results not reported

WMD 0.17

95% CI 0.05 to 0.29

P = 0.006

not-calculated

ipratropium

[44]

Systematic review

1529 people

5 RCTs in this analysis

Improvement in the mastery component of the CRQ, 85 days of treatment

ipratropium

short-acting beta2 agonists

Absolute results not reported

WMD 0.18

95% CI 0.06 to 0.30

P = 0.004

not-calculated

ipratropium

Mortality

No data from the following reference on this outcome.[44]

Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Adverse effects

[44]

Systematic review

1858 people

6 RCTs in this analysis

Proportion of people reporting an adverse effect

84/928 (9%) with ipratropium

111/930 (12%) with short-acting beta2 agonists

RR 0.75

95% CI 0.57 to 0.97

P = 0.03

There was significant heterogeneity (I2 = 60%) among studies in this analysis. The reason for the heterogeneity was not reported

small

ipratropium

Short-acting anticholinergic versus long-acting beta2 agonist:

We found 5 systematic reviews comparing anticholinergics versus beta2 agonists.[29][48][30][44][45] The reviews did not report data in terms of short- or long-term duration of treatment as defined in our Methods section, but by length of drug action. We report comparisons as reported in the reviews, and specify the duration of treatment where possible. One review compared anticholinergics as a class versus beta2 agonists as a class (see further information on studies for results).[30] Two systematic reviews (search date 2006, 8 RCTs, 3713 people,[30] and search date 2008, 6 RCTs, 2604 people[45]) compared short-acting anticholinergics versus long-acting beta2 agonists. Three RCTs were identified by both reviews. Both reviews included unpublished data obtained directly from drug companies. The reviews reported data on ipratropium versus salmeterol and ipratropium versus formoterol separately and reported on different outcomes.

Lung function and exercise capacity

Short-acting anticholinergic compared with long-acting beta2 agonist Ipratropium seems less effective than salmeterol at improving FEV1 at 12 weeks, but equally effective at improving the 6-minute walking distance test (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Lung function

[45]

Systematic review

458 people

2 RCTs in this analysis

Change in FEV1 from baseline, 12 weeks

ipratropium

salmeterol

Absolute results not reported

WMD –0.06 L

95% CI –0.11 L to 0 L

P = 0.05

Difference between groups was of borderline significance

not-calculated

salmeterol

Exercise capacity

[45]

Systematic review

471 people

2 RCTs in this analysis

Change in 6-minute walking distance, 12 weeks

ipratropium

salmeterol

Absolute results not reported

WMD +10.47 m

95% CI –1.24 m to +22.19 m

P = 0.08

not-significant

not significant

COPD exacerbation and worsening of symptoms

Short-acting anticholinergic compared with long-acting beta2 agonist Ipratropium and the long-acting beta2 agonists salmeterol and formoterol seem equally effective at improving COPD exacerbations (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
COPD exacerbations

[30]

Systematic review

538 people

2 RCTs in this analysis

Risk of COPD exacerbation

ipratropium

salmeterol

Absolute results not reported

OR (salmeterol v ipratropium) 0.81

95% CI 0.56 to 1.19

P = 0.29

not-significant

not significant

[30]

Systematic review

703 people

2 RCTs in this analysis

Other comment

The two RCTs were reported in three publications

Risk of COPD exacerbation

ipratropium

formoterol

Absolute results not reported

OR (formoterol v ipratropium) 0.78

95% CI 0.44 to 1.37

P = 0.39

not-significant

not significant

Quality of life

Short-acting anticholinergic compared with long-acting beta2 agonist Ipratropium and the long-acting beta2 agonists salmeterol and formoterol seem equally effective at 12 weeks at improving total score on the Chronic Respiratory Disease Questionnaire (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Quality of life

[45]

Systematic review

467 people

2 RCTs in this analysis

Total improvement in the Chronic Respiratory Disease Questionnaire (CRQ), 12 weeks

ipratropium

salmeterol

Absolute results not reported

WMD –0.58

95% CI –3.50 to +2.35

P = 0.7

not-significant

not significant

Mortality

No data from the following reference on this outcome.[30][45]

Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Adverse effects

[30]

Systematic review

538 people

2 RCTs in this analysis

Proportion of people withdrawing from a study because of adverse effects

ipratropium

salmeterol

Absolute results not reported

OR 0.45

95% CI 0.07 to 2.95

P = 0.40

not-significant

not significant

[30]

Systematic review

703 people

2 RCTs in this analysis

Proportion of people withdrawing from a study because of adverse effects

ipratropium

formoterol

Absolute results not reported

OR 1.84

95% CI 0.64 to 5.31

P = 0.26

not-significant

not significant

[45]

Systematic review

1365 people

4 RCTs in this analysis

Proportion of people withdrawing from a study because of adverse effects

30/682 (4%) with ipratropium

21/683 (3%) with salmeterol

RR 1.42

95% CI 0.82 to 2.45

P = 0.2

Further details on types of adverse effect associated with treatments not reported

not-significant

not significant

[45]

Systematic review

1365 people

4 RCTs in this analysis

Proportion of people reporting an adverse effect

365/682 (53.5%) with ipratropium

363/683 (53.1%) with salmeterol

RR 1.00

95% CI 0.91 to 1.10

P = 1

Further details on types of adverse effect associated with treatments not reported

not-significant

not significant

Long-acting anticholinergic versus short-acting beta2 agonist:

We found no systematic review or RCTs. One review compared anticholinergics as a class versus beta2 agonists as a class (see further information on studies for results).[30]

Long-acting anticholinergic versus long-acting beta2 agonist:

We found 5 systematic reviews comparing anticholinergics versus beta2 agonists.[29][48][30][44][45] The reviews did not report data in terms of short- or long-term duration of treatment as defined in our Methods section, but by length of drug action. We report comparisons as reported in the reviews, and specify the duration of treatment where possible. One review compared anticholinergics as a class versus beta2 agonists as a class (see further information on studies for results).[30] Three systematic reviews compared long-acting anticholinergic versus long-acting beta2 agonist.[29][48][30] There is some overlap in the RCTs identified by the reviews; however, no single RCT was identified by all three reviews. The reviews reported on different outcomes and different comparisons of long-acting anticholinergic versus long-acting beta2 agonist.

Mortality

Long-acting anticholinergic compared with long-acting beta2 agonist Tiotropium and salmeterol are equally effective at reducing all-cause mortality (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
All-cause mortality

[48]

Systematic review

1460 people

2 RCTs in this analysis

All-cause mortality

2/730 (0.2%) with tiotropium

6/730 (0.8%) with salmeterol

OR 0.38

95% CI 0.09 to 1.66

P = 0.20

not-significant

not significant

Lung function and exercise capacity

Long-acting anticholinergic compared with long-acting beta2 agonist Tiotropium seems more effective than salmeterol at improving FEV1 (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Lung function

[48]

Systematic review

1382 people

2 RCTs in this analysis

Improvement in FEV1

tiotropium

salmeterol

Absolute results not reported

WMD 28.97

95% CI 6.45 to 51.49

P = 0.01

not-calculated

tiotropium

COPD exacerbation and worsening of symptoms

Long-acting anticholinergic compared with long-acting beta2 agonist Tiotropium and salmeterol are equally effective at improving COPD exacerbations (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
COPD exacerbation

[48]

Systematic review

1460 people

2 RCTs in this analysis

Proportion of people with an exacerbation of COPD

159/730 (22%) with tiotropium

178/730 (24%) with salmeterol

Other comment

Two other reviews (search date 2002, 2 RCTs, 1830 people;[29] and search date 2006, 2 RCTs, 807 people[30]) found similar results for this comparison and outcome

OR 0.86

95% CI 0.67 to 1.11

P = 0.24

not-significant

not significant

Quality of life

Long-acting anticholinergic compared with long-acting beta2 agonist Tiotropium and salmeterol seem equally effective at improving St George's Respiratory Questionnaire scores (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Quality of life

[30]

Systematic review

807 people

2 RCTs in this analysis

Improvement in St George's Respiratory Questionnaire score

tiotropium

salmeterol

Absolute results not reported

OR (salmeterol v tiotropium) 0.79

95% CI 0.60 to 1.05

not-significant

not significant

Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect size (for ORs and RRs)Favours
Adverse effects

[30]

Systematic review

807 people

2 RCTs in this analysis

Proportion of people withdrawing from a study because of adverse effects

tiotropium

salmeterol

Absolute results not reported

OR (salmeterol v tiotropium) 2.16

95% CI 1.36 to 3.43

P = 0.001

No further information on adverse effects reported

moderate

tiotropium

No data from the following reference on this outcome.[29][48]

Further information on studies

[30]The review compared anticholinergics as a class versus beta2 agonists as a class. It found no significant difference between drug classes in mortality rate or risk of exacerbation of COPD (mortality [5 RCTs, 1925 people]: OR 4.36, 95% CI 0.73 to 25.93, P = 0.11; exacerbation of COPD [6 RCTs, 2048 people]: OR 0.94, 95% CI 0.76 to 1.17, P = 0.59; absolute numbers not reported). The review also found no significant difference between drug classes in proportion of people withdrawing from a trial because of adverse effects (OR 1.53, 95% CI 0.88 to 2.64; P = 0.13; absolute numbers not reported). The review also compared tiotropium versus formoterol (1 RCT, 74 people), but reported no data for this comparison.

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Comment

It has been suggested that older people have a greater bronchodilator response with anticholinergic drugs than with beta2 agonists, but we found no evidence for this.