Inhaled corticosteroids and the increased risk of pneumonia: what’s new? A 2015 updated review

Proposed mechanism of action

Several mechanisms have been proposed by which ICS could increase the risk of pneumonia, which are mostly related to their immunosuppressive effects. To compare, inhaled FP in doses of 1000 μg daily raise serum cortisol levels in the same way as 10 mg daily of oral prednisone [Lipworth, 1999], a dose proven high enough to produce a two-fold increase in the risk of pneumonia in patients with rheumatoid arthritis [Wolfe et al. 2006].

Although it is generally accepted that ICS have a protective effect against the development of AECOPD, a secondary analysis of a large RCT has brought attention to the fact that a considerable amount of the pneumonia events associated with the use of FP were preceded by an unresolved AECOPD [Calverley et al. 2011]. The presence of chronic bacterial colonization of the airways has been implicated is the frequency and severity of AECOPD [Patel et al. 2002], particularly in patients with bronchiectasis [Patel et al. 2004]. However, even though ICS are known to increase bacterial load in stable COPD [Garcha et al. 2012], the role of changes in bacterial load as determinants of an AECOPD is not yet conclusive [Sethi et al. 2007]. Although traditionally it was believed that bacterial colonization in COPD developed in a previously sterile lung, advances in molecular microbiology have revealed the existence of a normal pulmonary microbiota, and that its displacement by other organisms may be detrimental to host health [Dickson et al. 2014]. COPD patients have alterations in their lung microbiome that may result in chronic infection with potentially pathogenic micro-organisms [Miravitlles and Anzueto, 2015]. Furthermore, the use of ICS may itself alter the lung microbiome [Pragman et al. 2012; Huang et al. 2014], but whether this has implications for the protection against AECOPD or for the development of pneumonia is as yet unknown.

The paradoxical double effect of ICS consisting of increased episodes of pneumonia despite their protective effect on exacerbations is another area of debate. Furthermore, ICS-induced pneumonia events have consistently shown unmodified or even lower mortality rates (see the ICS-induced pneumonia mortality section). A plausible explanation could be that, in the same way that ICS can favor the development of pneumonia, ICS could also have a beneficial counterbalancing modulating effect on the local anti-inflammatory response after the onset of pneumonia. The complexity of the interactions between these mechanisms precludes a definite explanation (Figure 1). It has been demonstrated that patients with COPD have a distinct inflammatory pattern in response to CAP compared with patients without COPD [Crisafulli et al. 2013]. Also, in those with COPD, both AECOPD and CAP display characteristic inflammatory profiles [Gutierrez et al. 2010; Huerta et al. 2013]. The potential immunomodulatory effect of ICS in COPD is supported to some extent by several studies. The inhibition of nuclear factor kappa B (NF-ƙB) by ICS in COPD, one of the proposed mechanisms for the therapeutic effect of ICS, could lead to the suppression of normal host responses to bacterial infection [Singanayagam et al. 2010]. A systematic review and meta-analysis showed that ICS therapy in stable COPD translated as lower CD4 and CD8 cell counts in bronchial biopsies and reduced neutrophil and lymphocyte counts in BAL [Jen et al. 2012]. Also, in a 2014 observational study, previous use of ICS in patients hospitalized for CAP was associated with a reduced systemic inflammatory response, as evidenced by lower interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels [Ferrer et al. 2014]. Reduction of the pro-inflammatory response in pneumonia could thus lead to less subsequent organ dysfunction and, therefore, better clinical outcomes [Martinez et al. 2011]. Against this hypothesis, however, a 2011 observational study on the impact of ICS on pneumonia outcomes in patients with COPD found no significant difference in the levels of markers of systemic inflammation such as C-reactive protein and white cell count [Singanayagam et al. 2011]. Similarly, another prospective observational study found that, although patients with COPD and CAP have higher levels of C-reactive protein, procalcitonin, TNF-α and IL-6 compared with those with AECOPD, prior administration of ICS had no modulating effect on these early inflammatory biomarkers [Huerta et al. 2013].

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Figure 1.

Complexity and heterogeneity of the inflammatory response in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and pneumonia and possible impact of inhaled corticosteroids (ICS).

In another observational study, previous use of ICS did not influence the inflammatory response, clinical presentation, severity, infectious etiology, hospital mortality, or readmission rates during an AECOPD [Crisafulli 2014].

Interestingly, clinical studies so far have failed to show a consistent benefit of systemic corticosteroid administration in CAP outcomes [Salluh et al. 2008; Nie et al. 2012], which also does not support the concept of a mitigating effect of ICS on local inflammatory response. Newer studies have recently reported that the use of systemic corticosteroids could be beneficial in severe CAP with a high inflammatory response [Torres et al. 2015], or with septic shock requiring vasopressors [Tagami et al. 2015]. Moreover, the Swedish multicenter STEP study showed that a 7-day treatment with prednisone in patients with CAP led to a reduction in time to clinical stability, to an overall reduction of length of hospital stay, and to a reduction in duration of intravenous antibiotic treatment, independent of severity [Blum, 2015]. Finally, a meta-analysis that included 13 RCTs and 2005 patients reported a reduction of 3% in mortality, 5% in the need for mechanical ventilation, and 1 day in the duration of hospitalization for patients with CAP treated with systemic corticosteroids. Despite these recent findings, it still remains a controversial subject that will need further clarification in future trials.

Finally, targeted inhibition of other anti-inflammatory pathways to prevent AECOPD, the mechanism of action of the oral PDE-4 inhibitor roflumilast, has not been associated with increased pneumonia rates in clinical trials to date [Chong et al. 2013; Yan et al. 2014]. Also, in the large REACT trial, in which roflumilast was administered to patients with severe COPD already under treatment with LABA/ICS combination, there were no differences in the rate of pneumonia between the LABA/ICS + roflumilast group versus the LABA/ICS-only group [Martinez et al. 2015].

All of the above findings reinforce the concept that, given the heterogeneity in the inflammatory response in CAP and AECOPD, the immunomodulatory effects that ICS have on the airways’ innate and adaptive defense mechanisms can lead to different patterns of cytokine activation, which can in turn impact differently on the occurrence of AECOPD and pneumonia. These mechanisms are quite complex and yet not fully elucidated.

ICS intra-class differences

Previous BUD RCTs and meta-analyses consistently failed to show an increase in pneumonia events [Tashkin et al. 2008; Rennard et al. 2009; Sin et al. 2009]. Surprisingly, newer studies were not entirely able to rule out BUD as responsible for increased pneumonia rates. The Canadian case–control study by Suissa and colleagues (see Observational studies section, above) found a moderate 17% increase in the rate of serious pneumonia, which did not increase with the dose of BUD [Suissa et al. 2013]. The trial with BUD/FOR pMDI by Sharafkhaneh and colleagues (see the Randomized controlled trials section) reported a 6.4% incidence of nonfatal pneumonia with the 320/9 µg formulation, compared with a 4.7% and 2.7% incidence with the 160/9 µg formulation and placebo, respectively [Sharafkhaneh et al. 2011]. In the Cochrane meta-analysis by Kew and Seniukovich (see Meta-analyses section), BUD also increased nonfatal serious adverse pneumonia events compared with placebo by 62%, with the largest effect also observed with the 640 µg dose [Kew and Seniukovich, 2014].

The absence of adequately powered, long-term, head-to-head trials precludes any definitive conclusions on intra-class differences in risk. Two previously mentioned meta-analyses (see the Meta-analyses section) compared BUD and FP against each other by means of an adjusted indirect comparison, using placebo as a common comparator [Halpin et al. 2011; Kew and Seniukovich, 2014]. Halpin and colleagues reported a 41% lower incidence of pneumonia-related serious adverse events with BUD/FOR compared with FP/SAL, but with not enough events to conclusively report on pneumonia-related mortality [Halpin et al. 2011]. Using the same statistical method, Kew and colleagues conducted an indirect comparison of BUD versus FP monotherapy against placebo. The only significant difference reported was a higher risk of nonserious (community-managed) pneumonia events with FP than with BUD [OR 1.86; 95% CI 1.04–3.34], with no significant differences with respect to serious pneumonia events or mortality [Kew and Seniukovich, 2014]. In the Swedish case–control study PATHOS, BUD was associated with a 73% fewer pneumonia events than with FP [Janson et al. 2013].

Differences in the molecular structures of ICS formulations are known to alter their relative potency ratios and duration of action. For this reason, intra-class differences between BUD and FP might be the result of BUD’s inferior bio-availability, duration of action and potency [Johnson, 1998]. However, evidence from the BUD studies has been invariably more inconsistent, as well as being derived from studies of shorter duration. Furthermore, FP has a much more widespread use in moderate-to-severe COPD than BUD, since only the former is commercially available in devices containing the high doses that are usually prescribed for those patients. Therefore, patients prescribed BUD might be those with less severe COPD, or asthma instead of COPD and, consequently, be at lower risk for pneumonia compared with subjects receiving FP. All of these factors make it difficult to draw conclusions on possible intra-class differences in the risk of causing pneumonia between FP and BUD. Only RCTs comparing both compounds head-to-head will be able to clarify this issue.

A pooled analysis of two large RCTs of identical design (total n = 2251) that compared the mometasone furoate/formoterol (MF/FOR) combination against each component alone and placebo reported that pneumonia was infrequent (<2%) across all treatment groups during the safety extension period [Tashkin et al. 2012].

The recently introduced long-acting FF, with structural similarities to FP and an allegedly superior pharmacological profile [Rossios et al. 2011], has also been shown to increase pneumonia rates in patients with COPD in a proportion similar to that reported for FP [Crim, 2015]. According to the manufacturer’s label information, 100 µg FF daily is approximately equivalent to twice daily 250 µg FP, and 200 µg FF daily is equivalent to twice daily 500 µg FP [Electronic Medicines Compendium (eMC), 2015a].

Dose–effect relationship

In many of the trials discussed so far, the unadjusted higher risk of pneumonia was associated with longer duration of use, more potent ICS formulations, and higher doses. This became especially clear in a large database study which showed that individuals receiving high daily doses of ICS (equivalent to >1000 µg of FP) had a 70% greater risk of pneumonia hospitalization [Ernst et al. 2007]. However, this dose–effect relationship could not be verified in subsequent observational studies [Joo et al. 2010; Janson et al. 2013] (see the Observational Studies section). Similarly, RCTs that used half that FP dose (500 µg daily) also showed an almost two-fold increase in the risk of pneumonia [Ferguson et al. 2008; Anzueto et al. 2009]. Many RCTs have also reported on this dose–effect relationship (Table 1). However, the FF/VIL combination trial on exacerbations assessed three different doses of that formulation (50, 100 and 200 µg FF) and showed no reduced pneumonia risk with the lower doses [Dransfield et al. 2013] (see the Randomized controlled trials section). A recent Cochrane meta-analysis of both BUD and FP found no dose-related effect for FP, but pneumonia rates appeared to be higher with the highest doses of BUD [Kew and Seniukovich, 2014] (see the Meta-analyses section).

Residual effect

Previously, based on the findings of two large retrospective studies [Ernst et al. 2007; Joo et al. 2010], we described the presence of a persistently increased risk of pneumonia even after 12 months of drug discontinuation [Marzoratti et al. 2013]. This residual effect was much shorter in a more recent observational study, which reported a 69% increase in the rate of pneumonia with a gradual decrease in risk after discontinuation, until it was no longer evident after six months [Suissa et al. 2013]. At the time of writing this review, the same group of investigators published online the results of a large case–control study, in which a 37% decrease in the rate of serious pneumonia was noted after ICS discontinuation. It took four months after ICS withdrawal for the risk of pneumonia to drop to 50%, after which it remained stable for the rest of the follow-up period [Suissa et al. 2015].

ICS-induced pneumonia mortality

As mentioned above, a remarkable finding in previous RCTs and meta-analyses was that, although there was a considerable amount of evidence in favor of ICS being responsible for an increased incidence of pneumonia, no parallel increase in mortality could be demonstrated [Drummond et al. 2008; Singh and Loke, 2010]. In the more recent FF/VIL study, concern was raised with regard to an excess of pneumonia-related mortality was reported. In fact, seven out of the eight deaths in the study were registered in the 200 µg arm [Dransfield et al. 2013]. The increased number of pneumonia-related deaths in the highest dose arm is statistically significant (not reported in the study paper). According to the full study report of the sponsoring pharmaceutical company, these seven deaths were reported in only one of the replicate studies (Study 1) and, even more importantly, four of them were recorded in the same center in the Philippines.

Two prospective observational studies that assessed the prevalence of ICS use and outcomes in patients hospitalized for pneumonia reported no significant increase in mortality after 6 and 12 months of ICS use, respectively [Singanayagam et al. 2011; Ferrer et al. 2014]. Some studies even found a decreased risk of short-term mortality. Two case–control studies assessed the impact of prior outpatient use of ICS on 30- and 90-day mortality in a cohort of hospitalized COPD patients with pneumonia, extracted from the database of the Department of Veterans Affairs [Malo de Molina et al. 2010 Chen et al. 2011]. Both studies reported a reduced 30- and 90-day mortality rate in the ICS users group. One of the studies also reported that there was less need for mechanical ventilation in the ICS group [Chen et al. 2011]. Less incidence of pulmonary complications, such as pleural effusion in current ICS users hospitalized for pneumonia, have also been reported [Sellares et al. 2013]. On the other hand, in a pooled analysis of observational data, Loke and colleagues concluded that prior ICS use was not consistently associated with lower mortality from CAP in COPD patients [Loke et al. 2013]. The authors emphasize the fact that reports of reduced mortality in current ICS users at the time of hospitalization came from three studies that enrolled patients from the same Veterans Affairs database [Joo et al. 2010; Malo de Molina et al. 2010; Chen et al. 2011], thus perhaps limiting the applicability of their findings to that particular population.

ICS and pneumonia in asthma

Given that ICS are the most effective treatment in asthma, findings from COPD trials of pneumonia as a consequence of ICS use implies that asthmatic patients treated with these drugs could also be at risk. Because patients with asthma do not generally have as many major confounding risk factors for developing pneumonia (i.e. advanced age and comorbid diseases) and the clinical manifestations of the disease do not overlap as much with the adverse effects of the medication used to treat it, patients with asthma may represent a more useful population in which to investigate the risk of pneumonia as a consequence of ICS use. On the other hand, for the reasons mentioned before, the number of pneumonia events in asthma studies is expected to be very low, so any adverse impact of ICS would be hard to measure.

O’Byrne and colleagues published the results of a retrospective, industry-sponsored analysis of a dataset of asthma patients who had been included in double-blind randomized trials of at least 3 months’ duration [O’Byrne et al. 2011]. With 86 trials included, and over 50,000 patients, they compared the effects of BUD versus controls and BUD versus FP. In their analysis, the authors found no differences in the risk of pneumonia, the dose - response relationship for the development of pneumonia with BUD, or any intra-class difference between BUD and FP. However, in another more recent case - control study of a UK primary care database, the authors reported a two-fold increase in the risk of pneumonia or lower respiratory tract infection with the highest dose of ICS, after adjusting for confounders [McKeever et al. 2013]. Lastly, another case-control cohort study in a Japanese population suggested that the risk of nontuberculous mycobacteriosis may be greater in asthmatic patients treated with ICS, with older individuals, who have more severe airflow limitation and receive higher doses of ICS therapy, being at greater risk [Hojo et al. 2012].

Despite these findings, the inflammatory profiles of asthma and COPD are quite different [Fabbri et al. 2003], so extrapolations between these two conditions regarding susceptibility to ICS-induced pneumonia are unlikely to be valid. COPD and asthma patients are almost invariably excluded from therapeutic clinical trials of the other condition, but the fact that clinical characteristics of both COPD and asthma can coexist in the same patient may have important therapeutic implications. Sputum eosinophilia has been demonstrated as predicting clinical response to systemic glucocorticoids [Bafadhel et al. 2012] and to ICS [Brightling et al. 2005; Kitaguchi et al. 2012]. The benefits of ICS treatment in the recently well-characterized asthma–COPD overlap syndrome (ACOS) is discussed later (see the Risk/benefit ratio and indications section).

Other ICS-related infections

The proposed immunosuppressive mechanism responsible an increase in bacterial pneumonia cases among long-term users of ICS suggests that the risk of infection by other micro-organisms could also be increased. In fact, several studies have raised safety concerns about the risk of tuberculosis (TB) and other pulmonary infections.

In a 2014 Japanese meta-analysis of RCTs of ICS therapy for COPD lasting at least six months, ICS treatment was associated with a significantly higher risk of TB (OR 2.29; 95% CI 1.04–5.03) but not influenza. The risk of TB was even higher for patients living in endemic areas [Dong et al. 2014]. Another 2014 meta-analysis reported that ICS use increases the risk of TB among patients with COPD and patients with history of past pulmonary TB [Songshi et al. 2014]. Two case–control studies also suggest that ICS may be a risk factor non-TB mycobacterial (NTM) pulmonary disease [Hojo et al. 2012; Andréjak et al. 2013].

Risk/benefit ratio and indications

While ICS have become a key element in the treatment of asthma, their role in patients with stable COPD remains unclear, and may be beneficial only for a specific subset of ICS responders, but not for everyone [Alcázar Navarrete et al. 2015]. Taking into consideration that an elevated risk of pneumonia with ICS use has been repeatedly found in studies of various designs, this safety concern should be balanced with the available evidence on efficacy, with particular emphasis on reduction of exacerbations and survival.

Trying to apply personalized medicine principles to such a complex and heterogeneous disease as COPD represents a real challenge. In order to achieve this goal, attempts are being made to identify clinical phenotypes with clear therapeutic implications, in order to optimize the pharmacological treatment of COPD [Han et al. 2010]. One of the best characterized phenotypes to date is the exacerbation-susceptibility phenotype which was defined in the ECLIPSE study [Hurst et al. 2010] as the presence of two or more AECOPD episodes in a year. This trait has been proven to be independent of disease severity, and stable over time and was found to be present in up to one third of COPD patients [Hurst et al. 2010]. Other clinically relevant subgroups or phenotypes such as chronic bronchitis, eosinophilic COPD, and asthma–COPD overlap syndrome (ACOS) have been described. Their definition and potential implications for targeted therapeutic strategies have been reviewed elsewhere [Miravitlles et al. 2013; Turner et al. 2015]. An elevated blood eosinophil count has been demonstrated to be a frequent trait in patients with COPD, with a prevalence of 37% in the ECLIPSE cohort [Singh et al. 2014], and peripheral blood eosinophilia could represent a potential biomarker of response to ICS in patients with COPD. In fact, in a post hoc analysis of data from the 1-year FF/VIL exacerbation study, the reduction in AECOPD across all doses of FF compared with VIL alone in patients with eosinophil is above the 2% cut-off point (29% versus 10%), progressively increased up to 42% for those with eosinophil counts ⩾6%. Patients treated with VIL alone, on the other hand, had higher exacerbation rates with increasing eosinophil count. However, there was no association observed between the blood eosinophil count and the risk of pneumonia [Pascoe et al. 2015].

In a recent consensus document from Spain, formal indications for ICS have been limited to the frequent exacerbator and the mixed asthma–COPD phenotypes. The participants also agreed on the feasibility of discontinuation of ICS outside these indications [Alcázar Navarrete et al. 2015]. It has already been demonstrated that in patients with COPD, at low risk for exacerbations, treatment with ICS can be withdrawn without serious detrimental effects on patients’ outcomes. In the INSTEAD trail, nonexacerbating patients with moderate COPD were successfully switched from FP/SAL to indacaterol (IND) with no impact on exacerbation rates over six months [Rossi et al. 2014b]. The OPTIMO study involving patients with FEV1 greater than 50% and less than two exacerbations per year reported similar results [Rossi et al. 2014a]. Evidence suggests that ICS withdrawal could also be well tolerated in more severe patients at a higher risk of exacerbations. The most recent and largest RCT on ICS withdrawal is the WISDOM study, in which the risk of moderate-to-severe AECOPD did not increase in patients with severe COPD and a history of exacerbations who gradually discontinued ICS therapy over 3 months. However, contrary to what it would have been expected, there was only a nonsignificant 5% reduction in the risk of pneumonia after 12 months in the withdrawal arm [Magnussen et al. 2014]. Sudden, instead of gradual, withdrawal of ICS seems to be well tolerated for COPD patients at low risk of exacerbation [Rossi et al. 2014a], but not for those with more severe disease and frequent exacerbations [Wouters et al. 2005]. At the time of writing this review, Suissa and colleagues published online the results of a case–control study from a cohort of more than 100,000 ICS users during a follow-up period of 4.9 years. They reported a 37% decrease in the rate of serious pneumonia with ICS discontinuation. The rate of risk reduction ranged from 20% in the first month to 50% by the fourth month after discontinuation, and was more evident for FP than for BUD (RR 0.58 versus 0.87) [Suissa et al. 2015].

Conversely, the widespread prescription of the ICS-containing inhalers for COPD regardless of severity stage or clinical phenotype carries the potential risk of overtreatment, with the associated increase in costs, and in serious adverse effects such as pneumonia. In a study that analyzed data extracted from records of London general practices, the investigators reported a 25% incidence of overtreatment with ICS when compared with the 2011 revised GOLD guidelines’ recommendations [White et al. 2013]. According to another observational study from Italy, ICS were over-prescribed in up to 62% of the subjects [Corrado and Rossi, 2012]. A post hoc analysis of data for 5162 patients from the phase III TONADO studies, which used a tiotropium/olodaterol (TIO/OLO) combination, reported that nearly 40% of patients who were classified as having GOLD A or B disease were on ICS maintenance therapy at study entry [Watz et al. 2015]. This lack of adherence to current GOLD recommendations may be favored for many reasons: (1) the fact that ICS and LABAs are frequently only available in a single combined inhaler that usually contains high doses of the ICS component; (2) uncertainty in the diagnosis of asthma versus COPD, or the inability to rule out an overlap between the two conditions; and (3) the concern of triggering an exacerbation by withdrawing the ICS component in a patient who maintains persistent clinical stability while on ICS/LABA maintenance therapy.

While ICS alone are not recommended in stable COPD, the ICS/LABA combination is commonly prescribed for COPD patients with severe disease or frequent exacerbations (or both), according to most current COPD management guidelines, [GOLD, 2015; Criner et al. 2015]. However, the methodological accuracy of previous trials that reported lower rates of exacerbations and improved survival with the ICS/LABA combination compared with monotherapy with long-acting bronchodilators, has been questioned extensively. The lack of a true intention-to-treat analysis for the outcome of exacerbations in the TORCH study is an example [Ernst et al. 2015]. Also worth mentioning is the inappropriate calculation of the number needed to treat (NNT) in most COPD exacerbations trials, as reported by Suissa [Suissa, 2013]. According to the investigators, the event-based approach to NNT or number needed to harm (NNH) calculation is not valid when patients have uneven follow-up time periods (which is true in most trials) and when, instead of binary outcomes that only occur once in each patient during the study period, there is the possibility of recurring events in the same patient over time (as is the case with AECOPD). In fact, they found that after the correct calculation of the NNT, in FP studies longer than 1 year such as TORCH and INSPIRE, considerably fewer patients needed to be treated with ICS to induce a pneumonia, compared with the number of patients needed to be treated in order to prevent an AECOPD [Suissa, 2013]. This undoubtedly has a major impact in clinical decisions and in cost–benefit analyses. Applying the same correction for the results of the newer FF/VIL trial by Dransfield and colleagues, we found that, similar to what Susissa and colleagues reported for two 1-year studies, the NNT for the 100 μg dose to prevent an exacerbation is 10, and the NNH to cause a pneumonia with the same dose is 35 (see the Randomized controlled trials section).

One 2012 updated meta-analysis challenges the superiority of ICS/LABA combination over LABA monotherapy in preventing exacerbations, and concludes that both treatments have similar effects on mortality [Nannini et al. 2012]. Also, in one of the two replicate COPD exacerbation studies with the new FF/VIL combination, no significant difference in exacerbation rate was found between the 200/25 μg FF/VIL and the VIL monotherapy arms [Dransfield et al. 2013]. LAMA monotherapy has also been investigated extensively. In the INSPIRE study, TIO was not inferior to FP/SAL for the prevention of AECOPD [Wedzicha et al. 2008]. A subsequent Cochrane meta-analysis reported similar findings [Welsh et al. 2013]. The new LABA/LAMA combinations have also shown some promising results. In the phase III LANTERN study, the subgroup of patients with a history of moderate to severe exacerbations experienced a 40% reduction in the rate of AECOPD with indacaterol/glycopyrronium (IND/GLY) compared with FP/SAL (RR 0.60; 95% CI 0.33–1.08) over a 26-week period. Moreover, a significant three-fold lower incidence of pneumonia was reported in the IND/GLY arm (0.8% versus 2.7%). Although the difference in the exacerbation rates did not reach statistical significance, these findings suggest that there is a potential role for LABA/LAMA combinations as replacements for ICS in preventing AECOPD [Zhong et al. 2015]. In this respect, an ongoing study will assess the rate of AECOPD over 52 weeks of treatment with IND/GLY or FP/SAL in approximately 3000 patients with a history of moderate to severe exacerbations in the previous year. Results are expected in 2016 [ClinicalTrials.gov identifier: NCT01782326]. Another ongoing study, with an estimated enrollment of 10,000 patients, will compare the annual rate of AECOPD in patients receiving umeclinidium/vilanterol (UME/VIL) against those receiving FF/VIL or the triple combination FF/UME/VIL. Results are expected in 2017 [ClinicalTrials.gov identifier: NCT02164513]. There is also an ongoing trial that will evaluate annual exacerbation rates with the TIO/OLO combination compared with TIO monotherapy, both delivered through the Respimat^® (GlaxoSmithKline, UK) inhaler [ClinicalTrials.gov identifier: NCT02296138], but no studies comparing this novel LABA/LAMA combination against ICS in terms of exacerbations have been reported to date.

When exacerbations are not controlled with the usual doses of the ICS/LABA combination, increasing the dose of these drugs is not advisable because of the flat dose–response curve and the potentially harmful side effects. This was evidenced by the lack of additional benefit in terms of exacerbations, and the excess deaths from pneumonia, with the highest dose of FF/VIL in the trial by Dransfield and colleagues [Dransfield et al. 2013]. Alternatives to this approach include the use of roflumilast, mucolytics and macrolides in carefully selected patients who are more likely to benefit from these therapies [GOLD, 2015; Criner et al. 2015] (Figure 1).