Editorial
Clinical Research in Pulmonary Hypertension Comes of Age
La investigación clínica en hipertensión pulmonar ha alcanzado la mayoría de edad
Joan Albert Barberà
Servicio de Neumología, Hospital Clínic de Barcelona, Centro de Investigación en Red de Enfermedades Respiratorias, Barcelona, Spain
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"afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Neumología, Hospital Clínic de Barcelona, Centro de Investigación en Red de Enfermedades Respiratorias, Barcelona, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La investigación clínica en hipertensión pulmonar ha alcanzado la mayoría de edad" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The first randomized clinical trial with epoprostenol in patients with pulmonary arterial hypertension (PAH) was published 18 years ago.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> This trial was the first in a series of controlled clinical trials which subsequently defined the current therapeutic approach to this devastating disease.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> That these outstanding advances could be achieved in such a short period of time is the result of basic researchers and clinicians, pharmaceutical companies and regulatory agencies joining forces in the rapid “translation” of laboratory concepts into clinical practice.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Data are now available from over 30 controlled clinical trials and several meta-analyses, from which evidence-based therapeutic algorithms in PAH have been developed.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In most of these trials, the change in distance covered in the 6-minute walking test (6MWT) was used as the primary endpoint. This variable provides information on the patient's symptoms and ability to perform daily activities, and is a predictor of mortality.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The 6MWT is a simple, low-cost, reproducible test that is widely available.</p><p id="par0015" class="elsevierStylePara elsevierViewall">However, 6MWT also has its limitations. Firstly, the change in distance walked is influenced by the baseline value and presence of comorbidities, and a “ceiling” effect has been observed,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> that is to say, the distance achieved in the initial months does not increase even if treatment is continued. Secondly, the test is not particularly sensitive to the effect of starting a new drug in patients already under treatment. Thirdly and more importantly, there is no correlation between changes in the 6MWT seen in the early months and long-term mortality.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">This critical analysis of the 6MWT as a primary endpoint in PAH clinical trials led to the proposal raised in the Fourth World Symposium on Pulmonary Hypertension (Dana-Point, 2008) of using composite endpoints associated with long-term morbidity and mortality in clinical trials.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Specifically, the use of time to clinical worsening was suggested as a primary endpoint. This is a composite endpoint that includes all-cause mortality, unscheduled hospitalization due to PAH, and clinical progression.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The Dana-Point proposal has been taken up in the designing of several clinical trials, the first of which was the recently published <span class="elsevierStyleItalic">Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcomes</span> (SERAPHIN).<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The aim of this study was to investigate whether long-term treatment with macitentan, a new dual endothelin receptor antagonist, reduced morbidity and mortality in PAH patients. A total of 742 patients were included in the study, which evaluated 2 doses of macitentan <span class="elsevierStyleItalic">versus</span> placebo. The primary endpoint was time from start of treatment to the first PAH-related clinical event or all-cause mortality. PAH-related events were transplantation, atrial septostomy, initiation of intravenous prostanoids or clinical worsening–worsening of 6MWT or symptoms or need for a new treatment. Mean study duration was 85–104 weeks, depending on the groups. The study showed that, compared to placebo, macitentan reduced the risk of a PAH-related event.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In most cases the first event was worsening of PAH. In previously untreated patients, a significant treatment effect was observed with the 2 study doses, while in patients who were already receiving treatment the effect was only significant for the higher dose. The effect of macitentan on death or PAH-related hospitalization was also analyzed as a secondary endpoint. The risk diminished significantly with both dose levels. However, the main component of this endpoint was PAH-related hospitalization, while the effect on death as a first event was not significant.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> This finding stems from the fact that death is not usually the first event to occur; it is more common that hospitalization due to clinical worsening precedes death.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The SERAPHIN trial is the first of a new generation of PAH trials featuring a more robust design and endpoints of clinical interest. Other trials studying morbidity and mortality as primary endpoints are currently underway. Of particular importance is the <span class="elsevierStyleItalic">Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension</span> (AMBITION), evaluating the strategy of initiating treatment with a combination of 2 drugs compared to conventional monotherapy.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The results of clinical trials with new drugs have recently been published. Hoeper et al.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> were the first to evaluate the effect of imatinib, an antiproliferative tyrosine kinase inhibitor, in PAH. This agent has previously been used in the treatment of chronic myeloid leukemia. The findings show that while imatinib improved exercise capacity and pulmonary hemodynamics in patients with advanced PAH already receiving combined treatment, the active treatment group developed significant adverse events, primarily subdural hematoma. For this reason, application for approval of imatinib in PAH has been withdrawn. Ghofrani et al.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> evaluated the effect of the soluble guanylate cyclase stimulator (sGC) riociguat on the distance walked in the 6MWT in patients with PAH<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and chronic thromboembolic pulmonary hypertension (CTEPH).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> SGCs are a new generation of compounds that act on the nitric oxide signaling pathway, increasing intracellular levels of cyclic guanosine monophosphate, producing a vasodilatory effect. Riociguat increased exercise capacity in both HAP and CTEPH patients. For this reason, riociguat was the first drug to receive approval in Europe for the indication of inoperable CTEPH or persistent CTEPH after pulmonary endarterectomy. Time to clinical worsening was also evaluated in these studies, but as a secondary endpoint, riociguat was shown to be beneficial in PAH patients.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Clinical research in pulmonary hypertension has made good progress, and 18 years after the publication of the first controlled clinical trial it is safe to say that it has finally come of age. Modern clinical trial designs are clearly oriented toward evaluating morbidity and mortality in a large patient population, follow-up periods are extensive, and new therapeutic routes, indications and treatment strategies are under investigation. This new generation of trials is providing data of great clinical importance, and there is little doubt that they will influence our approach to this disease in the near future.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Barberà JA. La investigación clínica en hipertensión pulmonar ha alcanzado la mayoría de edad. Arch Bronconeumol. 2014;50:463–464.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.J. Barst" 1 => "L.J. Rubin" 2 => "W.A. Long" 3 => "M.D. McGoon" 4 => "S. Rich" 5 => "D.B. Badesch" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199602013340504" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1996" "volumen" => "334" "paginaInicial" => "296" "paginaFinal" => "302" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8532025" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Updated treatment algorithm of pulmonary arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N. Galiè" 1 => "P.A. Corris" 2 => "A. Frost" 3 => "R.E. Girgis" 4 => "J. Granton" 5 => "Z.C. Jing" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2013.10.031" "Revista" => array:7 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2013" "volumen" => "62" "numero" => "25 Suppl." "paginaInicial" => "D60" "paginaFinal" => "D72" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24355643" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Miyamoto" 1 => "N. Nagaya" 2 => "T. Satoh" 3 => "S. Kyotani" 4 => "F. Sakamaki" 5 => "M. Fujita" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/ajrccm.161.2.9906015" "Revista" => array:7 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2000" "volumen" => "161" "numero" => "2 Pt 1" "paginaInicial" => "487" "paginaFinal" => "492" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10673190" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Provencher" 1 => "O. Sitbon" 2 => "M. Humbert" 3 => "S. Cabrol" 4 => "X. Jais" 5 => "G. Simonneau" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehi728" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J" "fecha" => "2006" "volumen" => "27" "paginaInicial" => "589" "paginaFinal" => "595" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16431875" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Savarese" 1 => "S. Paolillo" 2 => "P. Costanzo" 3 => "C. d’Amore" 4 => "M. Cecere" 5 => "T. Losco" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2012.01.083" "Revista" => array:7 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2012" "volumen" => "60" "paginaInicial" => "1192" "paginaFinal" => "1201" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22995024" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0213485311001629" "estado" => "S300" "issn" => "02134853" ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "End points and clinical trial design in pulmonary arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V.V. McLaughlin" 1 => "D.B. Badesch" 2 => "M. Delcroix" 3 => "T.R. Fleming" 4 => "S.P. Gaine" 5 => "N. Galiè" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2009.04.007" "Revista" => array:7 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2009" "volumen" => "54" "numero" => "1 Suppl." "paginaInicial" => "S97" "paginaFinal" => "S107" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19555863" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Macitentan and morbidity and mortality in pulmonary arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Pulido" 1 => "I. Adzerikho" 2 => "R.N. Channick" 3 => "M. Delcroix" 4 => "N. Galiè" 5 => "H.A. Ghofrani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1213917" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2013" "volumen" => "369" "paginaInicial" => "809" "paginaFinal" => "818" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23984728" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.M. Hoeper" 1 => "R.J. Barst" 2 => "R.C. Bourge" 3 => "J. Feldman" 4 => "A.E. Frost" 5 => "N. Galiè" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCULATIONAHA.112.000765" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "2013" "volumen" => "127" "paginaInicial" => "1128" "paginaFinal" => "1138" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23403476" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Riociguat for the treatment of pulmonary arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.A. Ghofrani" 1 => "N. Galiè" 2 => "F. Grimminger" 3 => "E. Grunig" 4 => "M. Humbert" 5 => "Z.C. Jing" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1209655" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2013" "volumen" => "369" "paginaInicial" => "330" "paginaFinal" => "340" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23883378" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Riociguat for the treatment of chronic thromboembolic pulmonary hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.A. Ghofrani" 1 => "A.M. d’Armini" 2 => "F. Grimminger" 3 => "M.M. Hoeper" 4 => "P. Jansa" 5 => "N.H. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 5 | 3 | 8 |
| 2024 October | 49 | 22 | 71 |
| 2024 September | 45 | 14 | 59 |
| 2024 August | 81 | 40 | 121 |
| 2024 July | 50 | 25 | 75 |
| 2024 June | 71 | 22 | 93 |
| 2024 May | 53 | 25 | 78 |
| 2024 April | 42 | 28 | 70 |
| 2024 March | 46 | 14 | 60 |
| 2024 February | 29 | 21 | 50 |
| 2023 March | 7 | 6 | 13 |
| 2023 February | 36 | 20 | 56 |
| 2023 January | 27 | 28 | 55 |
| 2022 December | 48 | 38 | 86 |
| 2022 November | 41 | 22 | 63 |
| 2022 October | 47 | 36 | 83 |
| 2022 September | 31 | 31 | 62 |
| 2022 August | 34 | 35 | 69 |
| 2022 July | 25 | 45 | 70 |
| 2022 June | 35 | 43 | 78 |
| 2022 May | 33 | 37 | 70 |
| 2022 April | 38 | 21 | 59 |
| 2022 March | 36 | 36 | 72 |
| 2022 February | 25 | 32 | 57 |
| 2022 January | 27 | 44 | 71 |
| 2021 December | 31 | 48 | 79 |
| 2021 November | 35 | 34 | 69 |
| 2021 October | 41 | 48 | 89 |
| 2021 September | 30 | 39 | 69 |
| 2021 August | 27 | 38 | 65 |
| 2021 July | 30 | 33 | 63 |
| 2021 June | 34 | 42 | 76 |
| 2021 May | 38 | 34 | 72 |
| 2021 April | 71 | 81 | 152 |
| 2021 March | 79 | 29 | 108 |
| 2021 February | 47 | 19 | 66 |
| 2021 January | 34 | 10 | 44 |
| 2020 December | 45 | 23 | 68 |
| 2020 November | 36 | 12 | 48 |
| 2020 October | 23 | 17 | 40 |
| 2020 September | 20 | 10 | 30 |
| 2020 August | 33 | 22 | 55 |
| 2020 July | 44 | 20 | 64 |
| 2020 June | 36 | 8 | 44 |
| 2020 May | 33 | 12 | 45 |
| 2020 April | 39 | 22 | 61 |
| 2020 March | 45 | 20 | 65 |
| 2020 February | 25 | 18 | 43 |
| 2020 January | 37 | 16 | 53 |
| 2019 December | 34 | 16 | 50 |
| 2019 November | 35 | 15 | 50 |
| 2019 October | 17 | 9 | 26 |
| 2019 September | 21 | 10 | 31 |
| 2019 August | 27 | 13 | 40 |
| 2019 July | 23 | 15 | 38 |
| 2019 June | 14 | 11 | 25 |
| 2019 May | 18 | 12 | 30 |
| 2019 April | 18 | 19 | 37 |
| 2019 March | 46 | 20 | 66 |
| 2019 February | 33 | 15 | 48 |
| 2019 January | 28 | 11 | 39 |
| 2018 December | 41 | 17 | 58 |
| 2018 November | 61 | 22 | 83 |
| 2018 October | 113 | 27 | 140 |
| 2018 September | 24 | 8 | 32 |
| 2018 May | 22 | 1 | 23 |
| 2018 April | 51 | 4 | 55 |
| 2018 March | 71 | 3 | 74 |
| 2018 February | 48 | 8 | 56 |
| 2018 January | 157 | 5 | 162 |
| 2017 December | 82 | 2 | 84 |
| 2017 November | 24 | 7 | 31 |
| 2017 October | 22 | 5 | 27 |
| 2017 September | 29 | 8 | 37 |
| 2017 August | 45 | 6 | 51 |
| 2017 July | 27 | 3 | 30 |
| 2017 June | 44 | 10 | 54 |
| 2017 May | 41 | 6 | 47 |
| 2017 April | 29 | 3 | 32 |
| 2017 March | 27 | 6 | 33 |
| 2017 February | 29 | 3 | 32 |
| 2017 January | 20 | 2 | 22 |
| 2016 December | 27 | 4 | 31 |
| 2016 November | 37 | 11 | 48 |
| 2016 October | 31 | 11 | 42 |
| 2016 September | 39 | 14 | 53 |
| 2016 August | 37 | 10 | 47 |
| 2016 July | 25 | 7 | 32 |
| 2016 March | 2 | 0 | 2 |
| 2016 February | 2 | 0 | 2 |
| 2015 December | 2 | 0 | 2 |
| 2015 October | 31 | 3 | 34 |
| 2015 September | 22 | 7 | 29 |
| 2015 August | 39 | 21 | 60 |
| 2015 July | 28 | 6 | 34 |
| 2015 June | 29 | 3 | 32 |
| 2015 May | 35 | 11 | 46 |
| 2015 April | 15 | 8 | 23 |
| 2015 March | 43 | 8 | 51 |
| 2015 February | 29 | 12 | 41 |
| 2015 January | 2 | 1 | 3 |
| 2014 December | 1 | 0 | 1 |
| 2014 November | 1 | 4 | 5 |
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