Inhaled steroids in COPD: Reasons for a debate
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Cattaruzza" "autores" => array:1 [ 0 => array:2 [ "Iniciales" => "M.S." "apellidos" => "Cattaruzza" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0873215915339436?idApp=UINPBA00004E" "url" => "/08732159/0000002100000004/v0_201604141144/X0873215915339436/v0_201604141144/en/main.assets" ] "en" => array:9 [ "idiomaDefecto" => true "titulo" => "Inhaled steroids in COPD: Reasons for a debate" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "175" "paginaFinal" => "177" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Alvar Agustí" "autores" => array:1 [ 0 => array:4 [ "nombre" => "Alvar" "apellidos" => "Agustí" "email" => array:1 [ 0 => "alvar.agusti@clinic.ub.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Pulmonary Service, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "textoCompleto" => "<p class="elsevierStylePara">The indications (and contraindications) of treatment with inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) are well established in the latest iteration of the Global Strategy for the Diagnosis, Management and Prevention of COPD (GOLD) document.<a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> According to this document, ICS are <span class="elsevierStyleItalic">indicated</span> in COPD patients with severe or very severe airflow limitation (FEV1 < 50% of predicted) and/or frequent exacerbations (ECOPD) that are not adequately controlled by long-acting bronchodilators (Evidence A) because they reduce the risk of future episodes of ECOPD.<a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> More recently, ICS have also been recommended for the treatment of the so-called Asthma-COPD overlap syndrome (ACOS).<a href="#bib23" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> On the contrary, ICS <span class="elsevierStyleItalic">should never be used</span> in mono-therapy (i.e., alone) in COPD patients<a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> (an important difference vs. asthma<a href="#bib24" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a>). Despite this, apparently straightforward situation, there is a lively debate on where ICS should be positioned in the treatment of COPD.<a href="#bib25" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> This Editorial briefly discusses what, in my opinion, are some of the main arguments that fuel this debate.</p><p class="elsevierStylePara">First, drug therapy in COPD was actually “inherited” from asthma and basically consisted in the use of long-acting β2 agonists (LABA) and ICS.<a href="#bib26" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a> It is only recently that new long-acting bronchodilators have been developed specifically for the treatment of COPD (not asthma), as best exemplified by tiotropium (a long acting anti-muscarininc agent; LAMA).<a href="#bib27" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">6</span></a> Even more recently, new fixed combination of LABA-LAMA's have been also developed for COPD and can now be prescribed in many markets.<a href="#bib28" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">, </span><a href="#bib29" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">8</span></a> To my mind, the availability of these new therapeutic alternatives will inevitably force the academic community to carefully re-consider the position ICS within the therapeutic armamentarium of COPD.<a href="#bib25" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> For instance, the recent ILLUMINATE study<a href="#bib28" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a> showed, not surprisingly, that lung function improvement was significantly better in patients who received a fixed combination of indacaterol (LABA) and glycopirronium (LAMA) than in those who received a fixed combination of salmeterol (LABA) and fluticasone propionate (ICS): two bronchodilators bronchodilate more than one!. Interestingly, authors did not find significant differences in the incidence of “adverse events” (including ECOPD).<a href="#bib28" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a> This observation may indicate that a LABA-LAMA combination has a similar effect on ECOPD than a LABA-ICS combination and, remember, according to GOLD, ICS are indicated in COPD to reduce the risk of future exacerbations.<a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> Yet, as it is often the case, the devil is in the details since: (1) this study lasted for 26 weeks only, probably a period of time that is too short to assess with certainty the effect of any treatment on the incidence of ECOPD; (2) the study included patients <span class="elsevierStyleItalic">without</span> a history of previous ECOPD,<a href="#bib28" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a> when it is well established that the best predictor of future ECOPD is a previous history of ECOPD<a href="#bib30" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">9</span></a>; and, (3) patients who had a moderate-to-severe ECOPD were withdrawn from the study.<a href="#bib28" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a></p><p class="elsevierStylePara">Second, likely as a consequence of ICS being “inherited” from asthma, as discussed above, there is ICS over prescription in COPD,<a href="#bib25" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> particularly in patients classified in GOLD groups A or B, where ICS should not be theoretically prescribed.<a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> Not surprisingly, therefore, there has been interest in studying the effect of ICS withdrawal in COPD. In this context, the WISDOM study published recently<a href="#bib31" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a> concludes that in patients with severe COPD receiving tiotropium (LAMA) plus salmeterol (LABA) plus fluticasone propionate (ICS), the gradual discontinuation of the latter until complete suppression does not increase significantly the risk of moderate or severe ECOPD, albeit there was a significantly greater decline in lung function in those patients in whom ICS was withdrawn.<a href="#bib31" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a> However, the devil is in the details again since: (1) an inclusion criterion in the WISDOM study was that patients must have had one or more ECOPD in the preceding year.<a href="#bib31" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a> Given that 70% of the patients finally included in the study were already on ICS treatment during this period (plus LABA, LAMA or both),<a href="#bib31" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a> this criteria implies <span class="elsevierStyleItalic">de facto</span> that patients who, while on ICS, had not had previous ECOPD were <span class="elsevierStyleItalic">excluded</span> from the study. In other words, the study excluded those patients who, theoretically, could benefit most from ICS and included those who, apparently, were not well controlled while on ICS. There should be no surprise then that ICS discontinuation in the latter did not have any major effect; and, (2) as acknowledged by the authors, there was a significant difference (43 ml in 10 months, <span class="elsevierStyleItalic">p</span> < 0.001) in the rate of FEV1 decline in favor of those patients who continued on ICS. Authors considered that this difference was not clinically relevant.<a href="#bib31" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a> Personally I have to disagree with this interpretation, since the FEV1 of these patients at entry in the study was 900 ml only.<a href="#bib31" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a> On the contrary, I believe that this indeed indicates that ICS treatment can contribute to reducing the excessive decline of lung function in COPD, as suggested by some previous reports.<a href="#bib32" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">, </span><a href="#bib33" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a> In fact, other previous studies had also shown already that ICS withdrawal leads indeed to enhanced FEV1 decline.<a href="#bib34" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">, </span><a href="#bib35" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">, </span><a href="#bib43" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">22</span></a></p><p class="elsevierStylePara">Third, and finally, treatment with ICS has been linked to an increased risk of pneumonia in COPD.<a href="#bib36" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">15</span></a> This also questions the positioning of ICS in the treatment of COPD. However, these are peculiar “pneumonias”, since they do not increase the risk of mortality and, in some studies, they may even reduce it.<a href="#bib37" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">16</span></a> Further, a forgotten element in this debate is the optimal ICS dose to be used in COPD. Given that the dose-response curve of ICS is relatively flat (at least in terms of lung function changes),<a href="#bib38" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">17</span></a> it is possible that lower doses of ICS may have a more favorable efficacy/risk ratio in COPD.</p><p class="elsevierStylePara">In summary, despite the apparently straightforward recommendations of GOLD in relation to the positioning of ICS in the treatment of COPD discussed at the beginning of this Editorial,<a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> certainly there are reasons for the debate. It is only through rigorous research that we will be able to answer these questions and to select those COPD patients who may benefit most from the use of ICS.<a href="#bib25" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">, </span><a href="#bib39" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">18</span></a> Having said that, however, it is also important to note that the framework of this debate can change radically if future research shows that ICS may have effects that go beyond ECOPD and/or lung function decline, including the chemoprevention of lung cancer,<a href="#bib40" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">19</span></a> one of the most frequent causes of death in COPD,<a href="#bib41" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">20</span></a> and/or the reduction of cardiovascular risk,<a href="#bib42" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">21</span></a> another very common cause of morbidity and mortality in these patients.<a href="#bib41" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">20</span></a> Stay tuned: the debate continues!</p><a name="sec0005" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p class="elsevierStylePara">I have received grant support and/or fees for speaking at conferences and/or participating in advisory boards related to COPD management from Almirall, AstraZeneca, Boheringer-Ingelheim, Chiesi, GSK, Kyorin, Menarini, MSD, Novartis, Takeda and TEVA.</p>" "pdfFichero" => "320v21n04a90433944pdf001.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:22 [ 0 => array:3 [ "identificador" => "bib22" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, GOLD executive summary. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 17 | 6 | 23 |
| 2024 October | 88 | 30 | 118 |
| 2024 September | 81 | 41 | 122 |
| 2024 August | 100 | 45 | 145 |
| 2024 July | 121 | 41 | 162 |
| 2024 June | 119 | 63 | 182 |
| 2024 May | 129 | 52 | 181 |
| 2024 April | 111 | 31 | 142 |
| 2024 March | 122 | 31 | 153 |
| 2024 February | 98 | 22 | 120 |
| 2024 January | 109 | 28 | 137 |
| 2023 December | 72 | 31 | 103 |
| 2023 November | 89 | 28 | 117 |
| 2023 October | 101 | 42 | 143 |
| 2023 September | 89 | 35 | 124 |
| 2023 August | 111 | 25 | 136 |
| 2023 July | 120 | 27 | 147 |
| 2023 June | 102 | 26 | 128 |
| 2023 May | 127 | 29 | 156 |
| 2023 April | 123 | 28 | 151 |
| 2023 March | 129 | 31 | 160 |
| 2023 February | 105 | 23 | 128 |
| 2023 January | 105 | 21 | 126 |
| 2022 December | 113 | 45 | 158 |
| 2022 November | 170 | 62 | 232 |
| 2022 October | 121 | 48 | 169 |
| 2022 September | 123 | 31 | 154 |
| 2022 August | 125 | 44 | 169 |
| 2022 July | 82 | 49 | 131 |
| 2022 June | 103 | 46 | 149 |
| 2022 May | 91 | 43 | 134 |
| 2022 April | 120 | 56 | 176 |
| 2022 March | 108 | 52 | 160 |
| 2022 February | 76 | 45 | 121 |
| 2022 January | 62 | 47 | 109 |
| 2021 December | 47 | 46 | 93 |
| 2021 November | 66 | 30 | 96 |
| 2021 October | 73 | 41 | 114 |
| 2021 September | 67 | 37 | 104 |
| 2021 August | 65 | 33 | 98 |
| 2021 July | 61 | 24 | 85 |
| 2021 June | 97 | 38 | 135 |
| 2021 May | 151 | 52 | 203 |
| 2021 April | 314 | 139 | 453 |
| 2021 March | 224 | 47 | 271 |
| 2021 February | 167 | 46 | 213 |
| 2021 January | 154 | 29 | 183 |
| 2020 December | 155 | 25 | 180 |
| 2020 November | 162 | 41 | 203 |
| 2020 October | 136 | 32 | 168 |
| 2020 September | 129 | 27 | 156 |
| 2020 August | 161 | 38 | 199 |
| 2020 July | 163 | 35 | 198 |
| 2020 June | 146 | 47 | 193 |
| 2020 May | 146 | 50 | 196 |
| 2020 April | 157 | 30 | 187 |
| 2020 March | 147 | 37 | 184 |
| 2020 February | 177 | 37 | 214 |
| 2020 January | 180 | 25 | 205 |
| 2019 December | 166 | 38 | 204 |
| 2019 November | 143 | 32 | 175 |
| 2019 October | 157 | 31 | 188 |
| 2019 September | 207 | 63 | 270 |
| 2019 August | 338 | 23 | 361 |
| 2019 July | 327 | 40 | 367 |
| 2019 June | 327 | 49 | 376 |
| 2019 May | 302 | 29 | 331 |
| 2019 April | 318 | 43 | 361 |
| 2019 March | 340 | 18 | 358 |
| 2019 February | 318 | 17 | 335 |
| 2019 January | 255 | 20 | 275 |
| 2018 December | 140 | 7 | 147 |
| 2018 November | 43 | 1 | 44 |
| 2018 October | 64 | 14 | 78 |
| 2018 September | 27 | 5 | 32 |
| 2018 August | 28 | 20 | 48 |
| 2018 July | 58 | 16 | 74 |
| 2018 June | 64 | 12 | 76 |
| 2018 May | 126 | 13 | 139 |
| 2018 April | 90 | 24 | 114 |
| 2018 March | 75 | 18 | 93 |
| 2018 February | 79 | 18 | 97 |
| 2018 January | 39 | 12 | 51 |
| 2017 December | 73 | 16 | 89 |
| 2017 November | 32 | 13 | 45 |
| 2017 October | 26 | 11 | 37 |
| 2017 September | 16 | 19 | 35 |
| 2017 August | 29 | 14 | 43 |
| 2017 July | 23 | 17 | 40 |
| 2017 June | 15 | 15 | 30 |
| 2017 May | 36 | 13 | 49 |
| 2017 April | 6 | 9 | 15 |
| 2017 March | 18 | 9 | 27 |
| 2017 February | 13 | 4 | 17 |
| 2017 January | 11 | 6 | 17 |
| 2016 December | 7 | 5 | 12 |
| 2016 November | 17 | 3 | 20 |
| 2016 October | 19 | 4 | 23 |
| 2016 September | 24 | 2 | 26 |
| 2016 August | 9 | 7 | 16 |
| 2016 July | 7 | 9 | 16 |
| 2016 June | 0 | 7 | 7 |
| 2016 May | 1 | 9 | 10 |
| 2016 April | 43 | 1 | 44 |
| 2016 March | 61 | 74 | 135 |
| 2016 February | 58 | 73 | 131 |
| 2016 January | 57 | 46 | 103 |
| 2015 December | 79 | 68 | 147 |
| 2015 November | 48 | 68 | 116 |
| 2015 October | 72 | 54 | 126 |
| 2015 September | 115 | 78 | 193 |
| 2015 August | 234 | 107 | 341 |
| 2015 July | 194 | 173 | 367 |
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