The pharmacoepidemiology of COPD: Recent advances and methodological discussion

Chronic obstructive pulmonary disease (COPD) threatens an emerging public health crisis. The two major drivers for this are the ageing of the world9s population and the impressive, if deplorable, success of the multinational tobacco companies at forcing open world markets. Although the World Health Organization estimates that COPD is the sixth most common cause of death worldwide and that by 2020 it will be the third most common, COPD is also an orphan condition that overwhelmingly affects the poor and has been broadly ignored by scientists and by governments. Although the cost-effectiveness of smoking cessation, pulmonary rehabilitation, and longterm oxygen therapy in the later stages of the disease are all high, there is little active treatment that can currently be offered. Recently, randomised controlled trials, specifically of inhaled corticosteroids (ICS) in patients with COPD have failed to show any modification of the decline in lung function associated with the disease. Analyses have, however, suggested that these drugs may reduce the number of exacerbations, which are related to quality of life. These findings remain controversial, since in some cases they are based on secondary analyses, have inevitably been carried out in selected populations, the results appear to be sensitive to the design of the trials and confidence intervals are often wide. More recently still, evidence has begun to emerge that the use of ICS and possibly long-acting b2-agonists may also reduce mortality as well as exacerbations in these patients. Exacerbations of COPD, particularly those leading to hospitalisation, are an important cost driver in the healthcare system and may account for three-quarters of the additional costs of a patient with COPD. With the lack of good alternative remedies, such an effect would clearly be important not only to patients but also to the health services. Much of the new evidence comes, however, not from experimental studies, but from observational studies based on a variety of administrative databases. Although these databases have had an important part in the development of information about drug effects since the 1960s, interpretation of the data contained in them is less straightforward. Most recently, S. Suissa proposed a particular problem with some of the estimates of the effects of ICS on COPD from these sources, the so-called problem of "immortal time". This bias arises when time is allocated to the control (or treatment) group as "incident-free" even though no incident could have occurred during the period because of the definitions used in the study. It was suggested that some of the reports that ICS are effective in reducing mortality in patients with COPD can be accounted for by this bias. Combined with the surprisingly large effects that have been estimated using these methods, this bias has cast doubt on the robustness of these reports9 findings. The issues raised are not only relevant to the current debate on the effectiveness of ICS in COPD but affect a wide range of common problems in health policy. Use of databases is important, not simply as a substitute for randomised clinical trials that would be too large or expensive to undertake. They are also important for a broader understanding of the effectiveness of drug treatments. Very often, trials that are undertaken raise unrealistic hopes for effectiveness in the broader population, either because they are carried out in a highly restricted patient group or because use of the medication in practice is restricted by availability or by patient compliance. These issues need to be explored and one method of doing this is through the use of administrative databases. Robust interpretation of these data is therefore key to adequate policy-making. The symposium reported here brought together a group of scientists who had experience in this field and many who had used different databases to explore the issue of the effectiveness of ICS and, in most instances, long-acting b2-agonists to improve the outcomes of patients with COPD. The result was not only an excellent review of what is known of the effectiveness of these drugs, but also an important review of the methods, problems, and potential pitfalls of the uses of administrative databases for pharmacoepidemiological research. The idea for the symposium arose from a discussion between S. Suissa of McGill University, Montreal, Canada, and J.B. Soriano of GlaxoSmithKline, Greenford, UK, and was financially supported by GlaxoSmithKline. The proceedings will be of interest to those interested in the treatment of COPD and also to any interested in the appropriate use of administrative databases in pharmacoepidemiology.