Background: Chronic obstructive pulmonary disease treatment is informed by randomised controlled trial results, but it is unclear if these findings apply to people excluded from these trials. We used data from the TORCH (TOwards a Revolution in COPD Health) randomised controlled trial to validate non-interventional methods for assessing the clinical effectiveness of chronic obstructive pulmonary disease treatment in the UK Clinical Practice Research Datalink, before applying these methods to the analysis of people who would have been excluded from TORCH.
Objectives: To validate the use of non-interventional Clinical Practice Research Datalink data and methods for estimating chronic obstructive pulmonary disease treatment effects against trial results, and, using validated methods, to determine treatment effects in people who would have been excluded from the TORCH trial.
Design: A historical non-interventional cohort design, including validation against randomised controlled trial results.
Setting: The UK Clinical Practice Research Datalink.
Participants: People aged ≥ 18 years with chronic obstructive pulmonary disease registered in Clinical Practice Research Datalink GOLD between January 2000 and January 2017. For objective 1, we prepared a cohort that was analogous to the TORCH trial cohort by applying TORCH trial inclusion/exclusion criteria followed by individual matching to TORCH trial participants. For objectives 2 and 3, we prepared cohorts that were analogous to the TORCH trial that, nevertheless, would not have been eligible for the TORCH trial because of age, asthma, comorbidity or mild disease.
Interventions: The long-acting beta-2 agonist and inhaled corticosteroid combination product Seretide (GlaxoSmithKline plc) [i.e. fluticasone propionate plus salmeterol (FP-SAL)] compared with (1) no FP-SAL exposure or (2) exposure to salmeterol (i.e. the long-acting beta-2 agonist) only.
Main outcome measures: Exacerbations, mortality, pneumonia and time to treatment change.
Results: For objective 1, the exacerbation rate ratio was comparable to that in the TORCH trial for FP-SAL compared with salmeterol (0.85, 95% confidence interval 0.74 to 0.97, vs. TORCH trial 0.88, 95% confidence interval 0.81 to 0.95), but not for FP-SAL compared with no FP-SAL (1.30, 95% confidence interval 1.19 to 1.42, vs. TORCH trial 0.75, 95% confidence interval 0.69 to 0.81). Active comparator results were also consistent with the TORCH trial for mortality (hazard ratio 0.93, 95% confidence interval 0.65 to 1.32, vs. TORCH trial hazard ratio 0.93, 95% confidence interval 0.77 to 1.13) and pneumonia (risk ratio 1.39, 95% confidence interval 1.04 to 1.87, vs. TORCH trial risk ratio 1.47, 95% confidence interval 1.25 to 1.73). For objectives 2 and 3, active comparator results were consistent with the TORCH trial for exacerbations, with the exception of people with milder chronic obstructive pulmonary disease, in whom we observed a stronger protective association (risk ratio 0.56, 95% confidence interval 0.46 to 0.70, vs. TORCH trial risk ratio 0.85, 95% confidence interval 0.74 to 0.97). For the analysis of mortality, we saw a lack of association with being prescribed FP-SAL (vs. being prescribed salmeterol), with the exception of those with prior asthma, for whom we observed an increase in mortality (hazard ratio 1.49, 95% confidence interval 1.21 to 1.85, vs. TORCH trial-analogous HR 0.93, 95% confidence interval 0.64 to 1.32).
Conclusions: Routinely collected electronic health record data can be used to successfully measure chronic obstructive pulmonary disease treatment effects when comparing two treatments, but not for comparisons between active treatment and no treatment. Analyses involving patients who would have been excluded from trials mostly suggests that treatment effects for FP-SAL are similar to trial effects, although further work is needed to characterise a small increased risk of death in those with concomitant asthma.
Limitations: Some of our analyses had small numbers.
Future work: The differences in treatment effects that we found should be investigated further in other data sets. Currently recommended chronic obstructive pulmonary disease inhaled combination therapy (other than FP-SAL) should also be investigated using these methods.
Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 51. See the NIHR Journals Library website for further project information.
Keywords: CHRONIC OBSTRUCTIVE; ELECTRONIC HEALTH RECORDS; FLUTICASONE-SALMETEROL DRUG COMBINATION; PROPENSITY SCORE; PULMONARY DISEASE; SALMETEROL XINAFOATE; TREATMENT OUTCOME.
Chronic obstructive pulmonary disease affects 3 million people in the UK and is characterised by breathing difficulties that get worse over time, with sudden acute symptoms (exacerbations), possibly requiring hospitalisation. The evidence for use of medicines for treating chronic obstructive pulmonary disease comes from randomised controlled trial results. Randomised controlled trials generally include younger people with severe disease who do not have any other illnesses apart from chronic obstructive pulmonary disease, meaning that the effectiveness of these trials in all people with chronic obstructive pulmonary disease is unknown. Very large databases of anonymous electronic health records captured during NHS consultations can be used to study patients excluded from trials. However, confidence in results from studies using these data can be low because of fears of unaccounted bias, as patients are not randomised to treatment. In this project, we selected a group of patients from a very large electronic health record database called the Clinical Practice Research Datalink who were very similar to participants in a well-known large chronic obstructive pulmonary disease randomised controlled trial [the TORCH (TOwards a Revolution in COPD Health) trial]. When we analysed data from these patients, we found very similar results to the TORCH trial in relation to the reduction of exacerbations, development of pneumonia and time until death, when comparing one chronic obstructive pulmonary disease treatment with another. Having shown that our methods could be trusted to produce valid results when comparing one chronic obstructive pulmonary disease treatment with another, we then went on to analyse patients in the Clinical Practice Research Datalink who would have been excluded from the TORCH trial for the following reasons: aged > 80 years, having asthma as well as chronic obstructive pulmonary disease, or having only mild chronic obstructive pulmonary disease. For exacerbations, we found that, for people with milder chronic obstructive pulmonary disease, one of the treatments we studied seemed to work better than in the trial. For the analysis of mortality, we found that, for people with asthma as well as chronic obstructive pulmonary disease, one of the treatments seemed not to work so well, with more people dying. Future studies are needed in different populations (such as in a database from another country) to confirm these results.