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Selecting the Right Patient for the Right Treatment
Current treatment guidance suggests which drug option to consider first when managing COPD. In the UK NICE guidelines, drugs suitable for patients who are not controlled on the initial therapy have been suggested, but more extended treatment algorithms have yet to be developed. One of the axioms of asthma care is that treatment can be stepped down when the patient is stable, but this approach has not been applied to COPD until recently. The WISDOM study that was designed to identify subgroups of patients who exacerbated when ICS are withdrawn. Previous studies noted an increase in exacerbations when steroids were stopped abruptly and there was symptomatic deterioration after this was done, even in patients receiving long-acting bronchodilators. WISDOM recruited 2,488 patients with moderate to severe COPD, gave everyone LABA/ICS and a LAMA for 6 weeks, then randomized patients to a regimen of gradually reducing ICS over 6 months or maintenance of the previous treatment. To the surprise of this author, there was no significant difference in exacerbation rates in patients who received dual bronchodilator treatment without ICS (Fig. 4), although the difference in severe events crossed the noninferiority margin; that is, we could not exclude the benefit of ICS, and lung function and health status showed smaller but statistically significant differences 9 months after ICS treatment had been totally stopped. We should be cautious in interpreting these data. We do not know whether the same results would have been true had we stopped one of the bronchodilator components rather than the ICS and whether differences would have emerged over a longer follow-up period. However, it is reasonable to suppose that graduated changes in treatment after a period of stabilization with aggressive treatment is possible and suggests that we may be able to maintain these patients on less treatment than we have currently used.
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Figure 4.
Differences in the likelihood of experiencing an exacerbation between patients continuing with ICS–LABA and LAMA and those receiving LAMA alone in whom ICS were stopped. There was no differences in the exacerbation risk overall between treatments. The confidence intervals for the risk of severe events crossed the noninferiority margin and so the possibility of some effect in this subgroup cannot be excluded. Reproduced with permission from Magnussen et al.
There is considerable theoretical attraction in identifying patients who respond to a greater or lesser degree depending on the presence of specific genetic mutations that influence the efficacy of drug treatment. While this has been explored in small numbers of people receiving β-agonists, predominantly in asthma, one large trial has looked at the relative benefits of LABA and ICS by including genetic profiling as part of its study plan. Differences with a specific genotype in the effectiveness of LAMA compared with LABA could reflect true differences in the potency of the latter group, as has been postulated previously. Prospective studies stratifying patients according to their genotype would be of interest, but, as yet, are unlikely to translate into something that influences drug selection in the clinic.
The WISDOM data imply that not all patients benefit from long-term inhaled steroid treatment. Studies from Leicester and Oxford in the United Kingdom have led to the concept of a more "eosinophilic" COPD where the benefit of anti-inflammatory treatment is greatest as compared with a "pauci-inflammatory" patient who needs only regular bronchodilator drugs. There are data from the acute response to corticosteroid treatment in exacerbation that support this idea. This may even be true with other anti-inflammatory agents such as benralizumab as has been suggested in one post hoc analysis. This topic will undoubtedly receive more attention as data from old clinical trials are interrogated to see if an effect can be detected. The eosinophil count appears to be a more reliable marker than other predicted "asthmatic features" such as the bronchodilator response, which varies with time and does not predict the response to therapy.
A related clinical concept has recently emerged from a large Canadian database study of elderly (older than 65 years) COPD patients given LABA-ICS as their first-line treatment and compared with those who received LABA alone. In general, there was a reduced hospitalization/mortality in the group who received LABA-ICS with particular benefit in those patients who had had some form of prior asthma history or, if this was absent, in patients who had received only LABA without LAMA treatment. This emphasizes the need to identify the earlier history of our COPD patients and to remember this when making treatment decisions.
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