Salmeterol/fluticasone combination instead of indacaterol or vice-versa?

Salmeterol/fluticasone combinationinstead of indacaterol or vice-versa? The Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasoneto Indacaterol (INSTEAD) study, published in the December edition of the European Respiratory Journal,concluded that that "patients with moderate COPD and no exacerbations in the previous year can beswitched from salmeterol/fluticasone (SFC) to indacaterol with no efficacy loss" We would like torespectfully challenge this conclusion (as suggested also by the acronym "INSTEAD") since, in ouropinion, the data presented do not support it. First, the study was designed and powered to address ashort-term (12 weeks), physiological question (the primary outcome was non-inferiority of lung functionchanges (through forced expiratory volume in 1 s (FEV1)). This study design does not allow any inferenceabout the relative clinical positioning of these two therapeutic alternatives at longer term (daily control orfuture risk, e.g. exacerbation, progression of disease, or mortality). Secondly, authors included in the study"patients receiving SFC 50/500 mg for ⩾3 months, with no chronic obstructive pulmonary disease (COPD)exacerbations for >1 year before the study ( patients for whom inhaled corticosteroid (ICS) is notrecommended)". In our opinion, their interpretation that ICS are not recommended in these patients isboth arguable and relevant. Arguable, because authors cannot disregard the possibility that patients didnot have exacerbations in the previous year precisely because they were treated with ICS. Relevant becauseif these patients did not really need ICS, then it should not surprise that ICS withdrawal was"non-inferior" to bronchodilator treatment. Finally, based on the INSTEAD results, the exact oppositeconclusions might be reached. This is, given that: 1) treatment with indacaterol is not inferior to treatmentwith SFC in terms of lung function ( primary outcome), and/or daily control (symptoms, quality of life);and, 2) there is no information on the long-term effects of indacaterol on the rate of exacerbations,whereas this is well established for the SFC combination in a properly designed and longer-term study the latter might be favoured over indacaterol. It goes without saying that both conclusions (this oneand that of the INSTEAD study) are speculative, and thus properly designed and powered studies arerequired before any evidence based recommendation on the use of ICS in COPD can be reliably made In any case, we congratulate the authors of the INSTEAD study for their interesting work thatcontribute to another piece of evidence on the debate of when to use ICS in COPD. However, we honestlybelieve that the clinical over-interpretation of their results may not be in the best interest of patients, sincethere is a group of patients with COPD who can clearly benefit from ICS in combination with long-actingbronchodilators, including those with repeated exacerbations (despite adequate bronchodilator treatment)and the asthma-COPD overlap syndrome @ERSpublicationsLung function and relevance on choice of indacaterol or salmeterol/fluticasone combination inmoderate COPD patients Leonardo M. Fabbri1 and Alvar Agusti2,3 1Respiratory Disease Unit, University of Modena and Reggio Emilia, Modena, Italy. 2Hospital Clinic de Barcelona,CIBER en Enfermedades Respiratorias (CIBERES), Barcelona, Spain. 3Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
Correspondence: Leonardo M. Fabbri, University of Modena and Reggio Emilia,Respiratory Disease Unit, Pozzo 71,Modena, Italy. Email: Received: Dec 10 2014 Accepted: Dec 11 2014 Conflict of interest: Disclosures can be found alongside the online version of this article at Rossi A, van der Molen T, Olmo RD, et al. INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD. Eur Respir J 2014; 44: 1548–1556.
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Eur Respir J 2015; 45: 1187–1188 DOI: 10.1183/09031936.00226314 Copyright ERS 2015 We read with interest the comments by L.M. Fabbri and A. Augusti on our article entitled "INSTEAD: arandomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD" . However, webelieve that those comments go well beyond the conclusion of the study, which is well supported by the data.
The Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasoneto Indacaterol (INSTEAD) trial examined a population of chronic obstructive pulmonary disease (COPD)patients with moderate airflow limitation without a history of exacerbations in the previous year, andon treatment with inhaled corticosteroids (ICS)/long-acting β-agonist (LABA) combination therapy for ⩾3months. After randomisation, 250 patients continued and completed 6-month treatments with salmeterol/fluticasone fixed-dose combination (SFC), while 246 patients completed 6-month treatments withindacaterol monotherapy, after switch from SFC without a washout period. The study data showed nodifference in lung function (forced expiratory volume in 1 s (FEV1) in the whole population andinspiratory capacity in a subgroup), symptoms, quality of life or exacerbations between the two arms andthe two therapy regimens. The conclusion of the study, which is difficult to challenge, was that thepopulation of COPD patients in the INSTEAD study does not need ICS, and that ICS can be safelywithdrawn, if that treatment was initiated. In fact, according to COPD management guidance, thesepatients should not receive ICS in addition to their maintenance treatment with long-actingbronchodilators The results of our study should be evaluated for the recruited population and not forpatients with either more severe COPD or frequent exacerbations, or both. It is important to emphasisethat INSTEAD excluded COPD patients with severe airflow limitation (FEV1 <50% predicted) and patientswith exacerbations in the previous year, i.e. grades III and IV Clearly, any history of either asthma orlike-asthma symptoms was in the exclusion criteria The INSTEAD randomised trial confirms theresults of a recent real-life study on >800 moderate COPD patients and supports the currentmanagement guidance on moderate COPD without history of exacerbations Were the patients inINSTEAD exacerbation-free in the previous year because they were treated with ICS? It seems veryunlikely, because they did not exacerbate when ICS was withdrawn. After careful reading we do not see anysignificant discrepancy between the conclusion of INSTEAD and the recommendation of a recent editorialClearly, the appropriate use of ICS in COPD is an important issue In fact, the possible benefit ofICS on airway inflammation and exacerbation rate was found to be associated with side-effects Any speculation on longer-term effects of indacaterol, and on the impact of ICS withdrawal in severeCOPD patients with history of exacerbations, goes well beyond the purpose, the design, and the data of theINSTEAD study, but is explored in other trials Likewise, we do not make any over interpretationeither of the potential benefits of ICS in severe "frequent exacerbators" COPD patients or on the useof the ICS/LABA combination in patients with the so called "asthma-COPD overlap syndrome" although it might be a very interesting debate We believe that INSTEAD data provides a significant contribution to the debate on the appropriate use ofICS in COPD patients

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