16 June 2011
An observational study has found that mortality was a relative 14% higher in adults (aged 66 years or more) who were initially prescribed tiotropium, compared with those initially prescribed a long-acting beta agonist (LABA). However, this appears to contrast with a finding from the POET-COPD randomised controlled trial, in which there was no significant difference in mortality between COPD patients randomised to tiotropium or salmeterol. Important limitations in both studies limit the conclusions which may be drawn from them.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
NICE guidance on COPD advises that people who experience exacerbations or persistent breathlessness despite use of a short-acting bronchodilator should be offered either a long-acting muscarinic antagonist (LAMA) or a LABA. The only LAMA currently licensed is tiotropium. If the option of a LABA is chosen in people with severe to very severe COPD (FEV1 <50% predicted) it should be offered in combination with an inhaled corticosteroid (ICS).
NICE does not give preference to either of these options. Given that a choice of treatment for an individual patient has to be made, health professionals and patients may wish to consider the outcomes of this study and the POET-COPD study, along with other factors such as the suitability to the individual of different inhaler devices, individual tolerability to treatment and, where relevant, possible adverse effects of inhaled corticosteroids.
What is the background to this?
The NICE guideline development group agreed that both classes of drug, LAMA and LABA, are clinically effective in COPD and there was no strong evidence (at the time the guidance was written) to favour one over the other. Using health administrative data from Ontario, Canada, this observational study compared survival in more than 46,000 patients with COPD (aged 66 years or older) who were newly prescribed either an inhaled LABA or tiotropium for a maximum of 5.5 years.
What does this study claim?
Overall, patients who were initially prescribed tiotropium had a modest but statistically significantly higher adjusted rate of death than those initially prescribed a LABA (39.9% vs. 36.5% respectively, adjusted hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.09 to 1.19; P<0.001). The authors state that at three years, the absolute risk increase with tiotropium was 6.3% (95%CI 5.4 to 7.2) but do not explain the method by which this was calculated. In addition, patients initially prescribed tiotropium were significantly more likely to suffer all secondary outcomes, which included composites of death and hospitalisations and emergency department visits for COPD and related respiratory diseases.
How does this relate to other studies?
The results of this study must be considered alongside the results of another recent study, the POET-COPD randomised controlled trial (RCT). This compared tiotropium with salmeterol (a LABA) over one year in people with moderate to very severe COPD (FEV1 70% predicted or less) who had had a moderate or severe exacerbation in the previous year. The study is discussed further in MeReC Rapid Review No. 3501.
The primary outcome of POET-COPD was the time to first moderate or severe exacerbation, which showed a statistically significant benefit from tiotropium. However, safety monitoring included all-cause mortality. There was an observed but not statistically significant reduction in the risk of death with tiotropium compared with salmeterol while on treatment and in the following 30 days (1.8% vs. 2.0%, respectively, HR 0.85, 95%CI 0.61 to 1.19, P=0.35); and in the risk of death over 360 days (including vital status collection of prematurely discontinued patients): 1.7% vs. 2.1%, respectively, HR 0.81 (95%CI 0.58 to 1.13), P=0.21. In addition, 30% of patients were using tiotropium at entry, and 52% were using LABAs at entry, thus the study may have selectively included patients who were tolerant of these drugs
In July 2009, the MHRA published the results of a comprehensive review of the use of LABAs, both as monotherapy and in combination with ICS, in COPD. The MHRA noted that although beta-2-agonists have the potential to cause cardiac side effects, no strong signal for an increased risk was identified in the review, even when LABAs were prescribed with a potassium-depleting diuretic. It concluded that “The overall balance of benefits and risks for LABAs in the treatment of COPD remains positive when used in line with current GOLD and NICE  guidelines”
Earlier data had suggested a possible increased risk of cardiovascular side effects with tiotropium. However, in 2010 the FDA reviewed data from UPLIFT, a four year RCT comparing tiotropium with placebo in COPD. The FDA concluded that “current data do not support the conclusion that there is an increased risk of stroke, heart attack, or death associated with tiotropium Handihaler.”
A single observational study, such as this one, can prove only association not causation and observational studies are prone to confounding. Unlike in the setting of an RCT, in ‘real life’, treatment plans are chosen, changed, or actively not chosen in the light of individual patients’ risk factors, preferences and tolerability or response to other drugs. Thus observed differences in outcomes may be due to differences among the patients, not only the different treatments. In this study, although considerable efforts were made to reduce confounding, and sensitivity analyses were undertaken, the data used did not include a precise measure of disease severity (e.g. lung function) or smoking status. In addition it is possible that some patients may have been misclassified as having COPD, rather than another respiratory disease (e.g. asthma). The authors of this study conclude that further research is needed to confirm their findings in RCTs and younger patients, and to examine the relative safety profiles of tiotropium and LABAs.
The results must also be considered in the light of the safety monitoring data in POET-COPD. In that study, which lasted only a year, there was an observed reduction in risk of death associated with tiotropium. However, this was not statistically significant (i.e. the possibility that there was no true difference in mortality risk between the two groups cannot be rejected ‘beyond reasonable doubt’). Moreover, the 95%CIs include the possibility of an increased risk of death in the tiotropium group similar to that seen in the Canadian observational study.,
RCTs generally provide a better level of evidence than observational studies because the randomisation inherent in their design considerably reduces the risk of confounding. The two treatment groups in POET-COPD were well matched in terms of factors such as age, smoking history, severity of COPD, and drug therapy at study entry (although no information is presented on the prevalence of pre-existing disease such as diabetes or other cardiovascular conditions). However, POET COPD was not set up to answer the same research question as the Canadian study and as noted above, many patients in it had been taking tiotropium and/or a LABA at entry. It therefore does not provide clearly better evidence on that question.
NICE guidance advises that people with COPD who experience exacerbations or persistent breathlessness despite use of a short-acting bronchodilator should either try a LAMA (currently tiotropium) or a LABA (or LABA plus ICS if their FEV1 is <50% predicted). In some cases, patients will have a clear preference based on factors such as their ability to use one type of inhaler device over another. The acquisition cost of tiotropium is currently greater than LABA alone but less than combination LABA+ICS. For some patients, consideration must also be given to the risks associated with inhaled corticosteroids, especially at the doses licensed in COPD, including diabetes, pneumonia, and psychological and behavioural effects, in addition to the more widely known systemic effects of ICS. This study and the POET-COPD RCT add to the information which professionals and patients will want to consider.
Gershon A, et al. Comparison of inhaled long-acting β-agonist and anticholinergic effectiveness in older patients with chronic obstructive pulmonary disease: a cohort study. Ann Intern Med 2011;154:583–92
Design: Population-based, retrospective cohort study.
Patients: 46,403 patients aged 66 years or more (mean age, 77 years; 49% women) who met a validated case definition of COPD on the basis of health administrative data from Ontario and were newly prescribed an inhaled LABA or tiotropium between 1st July 2003 and 31st March 2007.
Intervention and comparison: Patients initially taking tiotropium were matched 1:1 with those taking a LABA. Matching produced 15,532 matched pairs. Within the matched cohorts, median follow-up times for patients initially prescribed tiotropium and LABAs were 3.2 and 3.3 years, respectively (maximum 5.5 years).
Outcomes: The primary outcome was all-cause mortality. Secondary outcomes included composites of death, hospitalisations and emergency department visits for COPD, related respiratory diseases (influenza, acute bronchitis, or pneumonia), and cardiovascular disease (acute myocardial infarction, congestive heart failure, ischaemic heart disease, cardiac arrhythmias, or cerebrovascular disease).
Results: Overall mortality was 38.2%. Mortality was higher in patients initially prescribed tiotropium than in those initially prescribed a LABA (39.9% vs. 36.5%, respectively; adjusted HR 1.14, 95%CI 1.09 to 1.19, P<0.001). The authors state that at three years, the absolute risk increase with tiotropium was 6.3% (95%CI 5.4 to 7.2) but do not explain the method by which this was calculated. In addition, rates of all secondary outcomes were significantly higher in the tiotropium group, compared with the LABA group. For example, 61.0% of patients initially taking tiotropium suffered death, hospitalisation or an emergency department visit for COPD, compared with 56.4% in the LABA group (HR 1.11, 95%CI 1.07 to 1.16). Death or hospitalisation was 55.0% in the tiotropium group, compared with 50.5% in the LABA group (HR 1.11, 95%CI, 1.07 to 1.16).
Sponsorship: The study was funded by the Government of Ontario
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