Conditions

Treatment options for

Chronic Obstructive Pulmonary Disease

Treatment options:

Smoking cessation

For smokers with COPD, continued smoking reduces lung capacity (FEV1) by an average of 62ml per year1.

For those who manage to stop smoking, their lung capacity will immediately begin to stabilise.

  • Successful quitters’ lung capacity then just gradually reduces with age, at the same rate as lifelong non-smokers (32ml per year)1.

This graph shows changes in lung function over time in continuing smokers compared to quitters:

Reproduced with permission from BMJ Publishing (2).

note: ‘susceptible’ and ‘non-susceptible’ differentiate those smokers who will or will not develop pathological changes of COPD in response to smoking (i.e. some people get away with it).

When GPs told smokers their FEV1 results in terms of “lung age” (as opposed to litres), they were more likely to quit. Quit rates were 13.6% compared to 6.4% in a high-quality randomised study in UK general practice2.

Lung age calculators can be found online or can be estimated approximately using the graph above.

 

References

1)Lee P, Fry J. Systematic review of the evidence relating FEV1 decline to giving up smoking. BMC Med 2010; 8: 84

2)Parkes G, Greenhalgh T, Griffin M, Dent R. Effect on smoking quit rate of telling patients their lung age: the Step2quit randomised controlled trial.

Pulmonary rehabilitation

Pulmonary rehabilitation programmes improve exercise tolerance and quality of life (QoL) in people with COPD.

The effect is greater than that seen with inhaler therapies.

Improvement in CRQ QoL score +0.79 CRQ is a respiratory disease specific, validated, QoL score which measures from 0-7 across domains including dyspnoea, fatigue, emotional function and mastery (sense of control).

More than +0.5 is likely to be a noticeable improvement.

Improvement in 6-minute walking distance +44 metres This is under test conditions, walking on the flat at whatever speed is comfortable, and being allowed to stop as needed.

 

Assessing for asthmatic features or steroid responsiveness

A significant minority of patients with COPD will have pre-existing asthma, or have an element of steroid-responsiveness to their airway obstruction.

Those with asthmatic features, or features of steroid responsiveness, may benefit from a different approach to inhaler therapies (see the “Inhaled therapies” section below).

There are no clear distinctive features to define this group. NICE suggest the following as a guide:

Clinical features differentiating COPD and asthma

COPD Asthma
Smoker or ex-smoker Nearly all Possibly
Symptoms under age 35 Rare Often
Chronic productive cough Common Uncommon
Breathlessness Persistent and progressive Variable
Night time waking with breathlessness and/or wheeze Uncommon Common
Significant diurnal or day-to-day variability of symptoms Uncommon Common
  • Longitudinal observation of people (with spirometry, peak flow or symptoms) can help differentiate COPD from asthma.

Additional features which may help identify asthma or steroid responsiveness:

  • history of atopy
  • higher eosinophil count*
  • a large (over 400 ml) response to bronchodilators
  • a large (over 400 ml) response to 30mg oral prednisolone daily for 2 weeks
  • serial peak flow measurements showing 20% or greater diurnal or day-to-day variability.

*NICE does not suggest a threshold eosinophil count. GOLD guidelines suggest an eosinophil count of 0.1 x 109/L (<100 cells/uL) as a level below which patients are unlikely to benefit from inhaled corticosteroids2. A UK primary care study3 suggested a threshold of 0.15 x 109/L (150 cells/uL).

The NICE guideline contains more detail about diagnostic criteria and strategies for COPD.

 

References

1)National Institute for Health and Care Excellence. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. [London]: NICE; 2018. (NICE guideline [NG115])

2) GOLD report: 2022 update. Lancet Respir Med 2022 Feb; 10(2): e20

3)Ashdown H, Smith MMcFadden E et al. Blood eosinophils to guide inhaled maintenance therapy in a primary care COPD population. Jan;

Inhaled therapies

The place of different types of inhaled therapies in the treatment of COPD will vary from person to person, in terms of

  • whether they have features of asthma or steroid responsiveness,
  • their symptomatic response, and
  • what the goal of treatment is – to improve symptoms and/or prevent exacerbations?

This is complicated stuff, you may want to grab a cup of coffee 🙂 We’ve tried to make this as simple as possible, but it takes some digesting.

In the main graphics we show the average comparative benefits of these inhaled therapies in RCTs.

Regarding which inhaler and when, NICE suggests two strategies.

  • These are intended to be adjusted to an individual’s priorities and response to treatment.

First, think about which of these two categories your patient falls into:

Strategy for patients with no features suggesting asthma or steroid responsiveness

Strategy for patients with features suggesting asthma or steroid responsiveness

Control group
Treatment group
ARR -- Absolute Risk Reduction
NNT -- Number Needed to Treat
RRR -- Relative Risk Reduction
Control group
-
Treatment group
-
ARR - Absolute Risk Reduction
NNT - Number Needed to Treat
RRR - Relative Risk Reduction

Patients with COPD who took an inhaled LABA (salmeterol) had an increase in FEV1 of 51mls compared to those taking placebo inhaler

Control group
27.8 people have an exacerbation over 6 months
Treatment group
20.3 people have an exacerbation over 6 months
ARR 7.5% Absolute Risk Reduction
NNT 13 Number Needed to Treat
RRR 27% Relative Risk Reduction

If 100 people with COPD take a LABA (salmeterol), 7.5 fewer will have an exacerbation over 6 months compared to those who took a placebo inhaler

Control group
-
Treatment group
-
ARR - Absolute Risk Reduction
NNT - Number Needed to Treat
RRR - Relative Risk Reduction

No difference in quality of life measures or exercise tolerance were seen in these studies comparing LABA with placebo inhaler

Control group
-
Treatment group
-
ARR - Absolute Risk Reduction
NNT - Number Needed to Treat
RRR - Relative Risk Reduction

Patients with COPD who took an inhaled LAMA (tiotropium) had an increase in FEV1 of 30mls compared to those taking placebo inhaler

Control group
30.8 people will have an exacerbation of COPD over 6 months
Treatment group
23.2 people will have an exacerbation of COPD over 6 months
ARR 7.6% Absolute Risk Reduction
NNT 13 Number Needed to Treat
RRR 24.6% Relative Risk Reduction

If 100 people with COPD take a LAMA (tiotropium), 7.5 fewer will have an exacerbation over 6 months compared to those who took a placebo inhaler

Control group
8.4 people have a hospital admission for COPD over 6 months
Treatment group
5.6 people have a hospital admission for COPD over 6 months
ARR 2.7% Absolute Risk Reduction
NNT 36 Number Needed to Treat
RRR 32.6% Relative Risk Reduction

If 100 people with COPD take a LAMA (tiotropium), 7.5 fewer will have a hospitalisation for COPD over 6 months compared to those who took a placebo inhaler

Control group
-
Treatment group
-
ARR - Absolute Risk Reduction
NNT - Number Needed to Treat
RRR - Relative Risk Reduction

A small, statistically significant improvement in quality of life score was seen with tiotropium compared to placebo inhaler, but the size of the change was unlikely to represent a meaningful difference

Control group
-
Treatment group
-
ARR - Absolute Risk Reduction
NNT - Number Needed to Treat
RRR - Relative Risk Reduction

Changes in FEV1 were not reported in the studies comparing these treatments

Control group
16.6 people will have an exacerbation of COPD over 6 months
Treatment group
13.3 people will have an exacerbation of COPD over 6 months
ARR 3.3% Absolute Risk Reduction
NNT 30 Number Needed to Treat
RRR 19.9% Relative Risk Reduction

If 100 people with COPD take a LABA+LAMA combination, 3.3 fewer will have an exacerbation of COPD over 6 months compared to those who took a LABA alone

Control group
-
Treatment group
-
ARR - Absolute Risk Reduction
NNT - Number Needed to Treat
RRR - Relative Risk Reduction

A small, statistically significant improvement in quality of life score was seen with LABA+LAMA compared to LABA alone, but the size of the change was unlikely to represent a meaningful difference

Control group
-
Treatment group
-
ARR - Absolute Risk Reduction
NNT - Number Needed to Treat
RRR - Relative Risk Reduction

Patients with COPD who took a combined triple therapy inhaler (LABA+LAMA+ICS) had an increase in FEV1 of 54mls compared to those taking a combined double therapy inhaler (LABA+LAMA)

Control group
53 people will have an exacerbation of COPD over 1 year
Treatment group
50 people will have an exacerbation of COPD over 1 year
ARR 3% Absolute Risk Reduction
NNT 33 Number Needed to Treat
RRR 5.7% Relative Risk Reduction

If 100 patients with COPD take a combined triple therapy inhaler (LABA+LAMA+ICS), 3 fewer will have an exacerbation over 1 year compared to those who take a combined double therapy inhaler (LABA+LAMA)

Control group
-
Treatment group
-
ARR Absolute Risk Reduction
NNT Number Needed to Treat
RRR Relative Risk Reduction

Patients with COPD who took a combined triple therapy inhaler (LABA+LAMA+ICS) had an average of 0.91 exacerbations per year compared to an average of 1.21 exacerbations per year in those taking a combined double therapy inhaler (LABA+LAMA)

Control group
-
Treatment group
-
ARR - Absolute Risk Reduction
NNT - Number Needed to Treat
RRR - Relative Risk Reduction

A small, statistically significant improvement in quality of life score was seen with triple therapy compared to double therapy, but the size of the change was unlikely to represent a meaningful difference

Control group
4.6 people develop pneumonia over 1 year
Treatment group
7.6 people develop pneumonia over 1 year
ARR - Absolute Risk Reduction
NNT - Number Needed to Treat
RRR - Relative Risk Reduction

If 100 patients with COPD take a combined triple therapy inhaler (LABA+LAMA+ICS), 3 more will develop pneumonia over 1 year compared to those who take a combined double therapy inhaler (LABA+LAMA)

LABA inhalers

Headache, palpitations, tremor

1 in 10 – 100 people

Source: BNF

LAMA inhalers

Antimuscarinic side effects

1 in 10 – 100 people

  • e.g., constipation, cough, dizziness, dry mouth, headache, nausea

Source: BNF

Cardiovascular safety of tiotropium

Tiotropium via Respimat or HandiHaler device is now thought not to be associated with cardiovascular risk, though the MHRA suggests some caution in groups at very high cardiovascular risk.

more

In the 2000s, concern developed regarding excess cardiovascular death in patients using tiotropium Respimat devices seen in some analyses of clinical trials. This evidence was never conclusive, though a proposed mechanism was the rapid delivery of the drug causing an antimuscarinic effect on cardiac tissue.

A large trial published in 2015:

  • involved 17,135 patients over 2.3 years
  • compared tiotropium delivered by HandiHaler or Respimat devices
  • found no difference in cardiovascular or total mortality between the two1

The MHRA now suggests avoiding tiotropium only in particular groups (who were excluded from this last trial):

‘When using tiotropium delivered via Respimat or HandiHaler to treat chronic obstructive pulmonary disease (COPD):

  • take the risk of cardiovascular side effects into account for patients with conditions that may be affected by the anticholinergic action of tiotropium, including:
    • myocardial infarction in the last 6 months
    • unstable or life threatening cardiac arrhythmia
    • cardiac arrhythmia requiring intervention or a change in drug therapy in the past year
    • hospitalisation for heart failure (NYHA Class III or IV) within the past year
  • tell these patients to report any worsening of cardiac symptoms after starting tiotropium; patients with these conditions were excluded from clinical trials of tiotropium, including TIOSPIR
  • review the treatment of all patients already taking tiotropium as part of the comprehensive management plan to ensure that it remains appropriate for them; regularly review treatment of patients at high risk of cardiovascular events
  • remind patients not to exceed the recommended once daily dose
  • continue to report suspected side effects to tiotropium or any other medicine on a Yellow Card.’

Inhaled corticosteroids (ICS)

Oral candidiasis, taste altered, voice alteration

1 in 10 – 100 people

Source: BNF

Pneumonia

Up to 1 in 23 people with COPD develop pneumonia over 18 months as a result of ICS.

Rates are higher with fluticasone than budesonide, and vary according to baseline risk.

more

A 2014 Cochrane review3 found the following rates of pneumonia in RCTs:

Placebo group Inhaled Steroid Number Needed to Harm Relative Risk Increase
Fluticasone containing inhaler
All pneumonia 7.2% 11.6% 23 x 1.6
Pneumonia needing hospitalisation 2.5% 4.3% 56 x 1.7
Budesonide containing inhaler
All pneumonia 2.8% 3.1% 333 x 1.1
Pneumonia needing hospitalisation 0.9% 1.5% 167 x 1.7

No difference was seen in mortality due to pneumonia or all-cause mortality.

Note: the Number Needed to Harm is much higher in the budesonide trials. This is mainly due to a lower baseline risk of pneumonia in the budesonide study populations. The relative risks of budesonide and fluticasone are more closely matched.

MODERATE quality evidence

Fractures

1 in 333 people (approximately) with COPD sustain a fracture over 18 months as a result of ICS.

more

Systemic absorption of corticosteroids can reduce bone density.

A 2011 meta-analysis reviewed 16 RCTs involving 15,513 patients comparing ICS to placebo over an average of 18 months:

Placebo ICS Number Needed to Harm Relative Risk Increase
Any fracture 1.7% 2% 333 x 1.2

LOW quality evidence:

  • large RCTs, but main result only just statistically significant, and some uncertainty in reporting of results in some trials

Adrenal suppression

ICS have been shown to suppress adrenal function in physiological studies, though the absolute risk of acute adrenal crisis due to ICS is unknown and probably very low.

more

Physiological studies have shown suppression of adrenal function with increasing doses of ICS4. These form the basis of recommendations to provide patients with steroid emergency cards.

Dosage thresholds to provide steroid emergency cards are recommended in the BNF:

  • beclomethasone >1000mcg/day or equivalent
  • fluticasone >500mcg/day or equivalent

The BNF lists adrenal suppression as a “rare or very rare” side effect (1 in 1000 to <1 in 10,000)

 

References

1)Wise R, Anzuetto A, Cotton D et al. Tiotropium Respimat Inhaler and the Risk of Death in COPD. N Engl J Med 2013; 369: 1491-1501

2)MHRA. Tiotropium delivered via Respimat compared with Handihaler: no significant difference in mortality in TIOSPIR trial. 2015. Accessed online 4/1/23

3)Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD010115

4)Lipworth BJ. Systemic Adverse Effects of Inhaled Corticosteroid Therapy: A Systematic Review and Meta-analysis. Arch Intern Med 1999; 159(9): 941–955