Title: Real World Effects of Medications for Chronic Obstructive Pulmonary Disease
Funder: Department of Health and Social Care

Abstract: Chronic obstructive pulmonary disease (COPD) affects 3 million UK citizens. It is a progressive disease characterised by airflow obstruction, with acute exacerbations requiring urgent treatment, and often hospitalisation. Smoking cessation is the most effective intervention, but long term pharmacological treatment is also generally required. Evidence for treatment guidelines is based on randomised trial results, but there are important evidence gaps due to differences between trial patients and the intended target population; all UK patients with COPD. Evidence of medication effects in routine clinical care is needed to understand the balance of treatment risks and benefits. Randomised trials are vital to establish treatment efficacy and safety before licensing, but treatment effects are not always the same when used in the general population and national drug licensing authorities are increasingly seeking real world evidence on which to make decisions. Additionally, large quantities of electronic health records are becoming progressively more available to researchers. The combination of demands for evidence and increased data availability means we now need rigorous methods and established best practice to translate complex data into evidence of medication effects. This project brings together a multidisciplinary team of epidemiologists, medical statisticians, primary and secondary care physicians from international centres of excellence. We will use data from the UK Clinical Practice Research Datalink (CPRD) linked with hospital episode statistics (HES) to identify a representative sample of UK patients with COPD. This world-renowned database has comprehensive medical records for a nationally representative sample of ~8% of the UK population. The main challenge for this project is to make unbiased comparisons between treatments allowing inference about treatment effects, for which we will use advanced propensity score techniques. Research objectives developed with input from people with COPD are: 1. Optimise the use of CPRD data for estimating COPD treatment effects by replicating findings of the landmark COPD trial TORCH. Using individual patient data from TORCH, we will assemble a cohort in the CPRD with similar characteristics to TORCH participants and test whether observational data can generate comparable results to trials, using cohort methodology. 2. Determine risks and benefits of COPD treatments in people excluded from TORCH. Outcomes are pneumonia, COPD exacerbation, mortality and time to treatment change. Groups to be studied include the elderly (>80 years), people with substantial comorbidity and people with and without underlying cardiovascular disease. 3. Determine the risks and benefits of currently available pharmacological COPD management in mild COPD to determine the best strategies for people in whom evidence is lacking. Feasibility work suggests the CPRD has sufficient power to demonstrate a change in annual exacerbation rate from 0.5 to 0.4 per patient, for all study questions. By answering these questions, we will obtain important evidence about the effects of drugs for COPD, using highly efficient methods with in-built robust validation against the results of a randomised trial. This validation step will determine whether or not the observational data from the CPRD are appropriate to answer these kinds of questions. The methodological framework we will develop will also be applicable for future questions about the effectiveness of drugs as used in the NHS.

Lay abstract: Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease, common in people who smoke. People with COPD have occasional disease flare ups requiring urgent treatment, and in some cases hospitalisation. Stopping smoking is known to be the most effective way to manage COPD, but long term treatment with medication is also generally needed. Medications used to treat people with COPD have been tested in randomised trials, and the evidence obtained from these trials has been used to create treatment guidelines for people with COPD. Unfortunately, randomised trials have strict inclusion and exclusion rules that mean many groups of people with COPD in the general community are not eligible and have not been studied. For instance, people aged over 80 years, people with lots of other illnesses as well as COPD and those with mild COPD disease. This means treatment decisions for these unstudied groups of patients are based on the assumption that information obtained in randomised trials applies to very different types of patients. We don’t know whether this assumption is at all reasonable as the effects of medications often vary in different sorts of people. This project will measure important effects of COPD treatments directly in patient groups not included in trials, so we can make better decisions about their treatments in future. Design and Methods The Clinical Practice Research Datalink (CPRD) contains high quality anonymised electronic patient health records which have been collected when a patient sees their GP. These records are maintained by GPs and, linked to hospital records, are an extremely valuable resource for research. With CPRD data, we will be able to compare outcomes between different treatments used in routine clinical care. We will compare between different treatment choices in COPD and measure how they impact on pneumonia, COPD flare ups, the need to change COPD treatment, and death. Treatments to be compared are long-acting beta-agonists, long acting muscarinic antagonists, inhaled corticosteroids, and combinations of these drugs. First we will see how well COPD treatments work in people who are similar to those included in a large COPD randomised trial called TORCH. Following this, we will see how well the treatments work in people not included in this trial; specifically people aged over 80 years, people with multiple other illnesses, and people with mild COPD. The project will be overseen by an independently chaired advisory group including COPD patient representatives. Dissemination The evidence we obtain will be shared with stakeholder groups e.g. The British Lung Foundation, presented at scientific conferences and published in peer-reviewed journals. We will also work closely with policy makers such as the Medicines and Healthcare products Regulatory Agency and the National Institute for Health and Care Excellence, to ensure the findings are able to input to treatment guidelines.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY