Response to letter to the editor. Again on IMPACT: exacerbation after abrupt discontinuation of ICS and pneumonia in fluticasone furoate-containing FDCs

Dear Editors,

We read with interest the comments by Barnes et al. [1] on our expert review concerning the effect of triple inhaled corticosteroid (ICS)/long-acting β₂ adrenoceptor agonist (LABA)/long-acting muscarinic receptor antagonist (LAMA) therapy in chronic obstructive pulmonary disease (COPD) patients [2]. However, many of the outlined points have already been questioned in several other response letters and editorials, by proposing always the same comments [3–6] that were already fully addressed or discussed in just as many replies [7–9].

It is well known that the IMPACT (InforMing the PAthway of COPD Treatment) study was not designed as an ICS withdrawal trial. In any case, it is unquestionable that ~70% of patients randomized to the LABA/LAMA group were abruptly switched from an ICS-containing therapy, as reported in Table S4 of the Supplementary appendix of the primary publication [10]. The matter of the exacerbation rate with LABA/LAMA was further corroborated by the post-hoc analysis of the IMPACT study concerning the effect of ICS withdrawal and baseline inhaled treatment on exacerbations [11]. The forest plot reported in Figure 2 by Han et al. [11] clearly indicated that, among non-ICS users at screening, no difference was detected between triple therapy and dual bronchodilation with respect to the annual rate of moderate/severe exacerbations (rate ratio 0.88, 95%CI 0.76–1.03; p = 0.115) [11]. In contrast, COPD patients who were abruptly withdrawn from ICS therapy at randomization and assigned to the LABA/LAMA group experienced a higher frequency of moderate/severe exacerbations compared with triple therapy [11]. This evidence clearly indicates that abrupt ICS discontinuation may have deleterious effects on the risk of COPD exacerbations and that the beneficial action of triple therapy could have been overestimated [12,13].

We agree that not only the IMPACT and TRIBUTE (extrafine inhaled triple therapy vs dual bronchodilator therapy in COPD) studies included patients with a past diagnosis of asthma, but also the KRONOS (triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology vs dual therapies in chronic obstructive pulmonary disease) and ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) studies. However, it is important to highlight that, as we previously reported [14], up to 20% of COPD or asthmatic patients may display a mixed picture of overlapping clinical features of both COPD and asthma [15]. A large number of COPD patients enrolled in the IMPACT study presented physiological and/or biological characteristics of asthma at baseline (from 18% to 57%) [10] and even 20% of them presented a very high blood eosinophil level (≥310 cells·µL⁻¹) [16]. The inclusion of patients with an asthma-like profile may have potentially contributed to the higher exacerbation and mortality rates in the LABA/LAMA group [14,17,18], and this could also explain the discrepancy with the FLAME (Indacaterol–Glycopyrronium vs Salmeterol–Fluticasone for COPD) study [19], which excluded COPD patients with a history or features of asthma and showed superiority of LABA/LAMA over ICS/LABA for the prevention of COPD exacerbations.

With regard to the differential benefit/risk profile of triple therapies, in our expert review we have already reported the efficacy/safety ratio of triple fixed-dose combinations (FDCs) vs dual bronchodilator FDCs included in the ETHOS, KRONOS, IMPACT, and TRIBUTE studies [2]. Specific details are shown in Table 3 of our publication [2]. Interestingly, it resulted that triple combinations including budesonide (BUD) or beclomethasone dipropionate (BDP) were characterized by a superior efficacy/safety profile than those including fluticasone furoate (FF), as in the IMPACT study [2].

We disagree with the statement that ‘the benefit/risk ratio for all ICSs is very similar’ [1], instead there is the evidence of intra-class differences between ICS compounds, especially concerning the risk of pneumonia. The TRIBUTE and TRILOGY (single inhaler triple therapy vs ICS plus LABA therapy for COPD) studies demonstrated that BDP-containing therapies reduced the rate of moderate to severe exacerbations, by 15% and 23%, respectively, with no difference in the incidence of pneumonia compared with dual bronchodilation [20,21]. In contrast, the IMPACT study showed that FF administered in triple FDC was associated with a 53% greater risk of pneumonia compared with LABA/LAMA, with no difference between triple therapy and FF/vilanterol (hazard ratio 1.02, 95% CI 0.87–1.19; p = 0.85) [10]. Moreover, according to several recent meta-analyses, not only FF but also fluticasone propionate (FP) is associated with an elevated risk of pneumonia, compared with BUD [22,23]. All these findings could be explained in terms of inhaled pharmacokinetics of ICSs: FF is characterized by a greater lipophilicity than BUD and BDP, therefore prolonged lung retention and immunosuppression could have worsened airway susceptibility to infections and mucociliary clearance in COPD patients [24].

As correctly stated in the response letter [1] to our expert review, several phenotypical characteristics may potentially affect pneumonia risk such as age, sex, body mass index, airflow obstruction, as well as exacerbation and pneumonia history. Nevertheless, the IMPACT study [10] did not provide any subset analyses for these covariates; thus, it is impossible to define the risk of pneumonia within subgroups defined according to these risk factors. Certainly, providing such data in open access would allow independent research to thoroughly investigate the potential factors influencing the efficacy and safety profile of ICS/LABA/LAMA FDCs.

Concluding, it is a matter of fact that in the IMPACT study the abrupt discontinuation of ICS influenced the risk of exacerbation and FF-containing FDCs modulated the risk of pneumonia in COPD patients with an asthma-like profile.

Declaration of interest

P Rogliani has participated as a lecturer and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Mundipharma and Novartis. Her department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon. L Calzetta has participated as an advisor in scientific meetings under the sponsorship of Boehringer Ingelheim and Novartis, received non-financial support from AstraZeneca, a research grant partially funded by Chiesi Farmaceutici, Boehringer Ingelheim, Novartis and Almirall, and is or has been a consultant to ABC Farmaceutici, Recipharm, Zambon, Verona Pharma and Ockham Biotech. His department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis and Zambon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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