Editorial
Novelties in the Treatment of Pulmonary Hypertension
Novedades en el tratamiento de la hipertensión pulmonar
a Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
b Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
c INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France
d Department of Medicine, Division of Respirology, University of Calgary, Calgary, Canada
e Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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Exciting recent advances have improved prognosis, however PAH and CTEPH remain disabling and life limiting conditions.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Currently approved medical therapies improve functional capacity, hemodynamics and delay clinical worsening by targeting the 3 main pathobiologic pathways: prostacyclin, endothelin, and nitric oxide. Recently, several new agents targeting the classic PAH pathways have been developed for the treatment of pulmonary hypertension. However, a targeted treatment that delays or reverses vascular remodeling remains elusive. Recent attempts to specifically inhibit or reverse vascular proliferation in PAH with imatinib, a tyrosine kinase inhibitor, were disappointing because of the high dropout rate due to adverse events (over 30%) and the high incidence of subdural hematoma.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Selexipag is a new oral selective PGI2 receptor agonist that targets the prostacyclin pathway. In the placebo-controlled GRIPHON study of 1156 patients with PAH, selexipag reduced the risk of death or PAH-related complications by 40%, an effect that was primarily driven by a reduction in disease progression and hospitalization for PAH; mortality was similar in both study groups.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Importantly though, the treatment effect was consistent across treatment naïve patients and those receiving background phosphodiesterase type 5 (PDE5) inhibitors and/or endothelin receptor antagonists. Unlike PDE5 inhibitors, riociguat acts by directly stimulating soluble guanylate cyclase, independent of nitric oxide availability. In recently published long-term extension studies of randomized controlled trials of PAH patients (PATENT-2)<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> and CTEPH patients (CHEST-2),<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> riociguat was well tolerated with sustained improvements in functional capacity and 6-minute walk distance in both patient populations. Riociguat is also the only targeted medication currently approved for treating CTEPH.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Combination therapy in PAH has gained momentum, however there remains some debate on the optimal strategy: upfront versus sequential addition of therapies. The COMPASS-2 study evaluated a strategy of sequentially adding bosentan to patients on background sildenafil for at least 12 weeks.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> This was a negative study with regards to the primary endpoint; however, a long recruitment period and high dropout rate resulted in the study being underpowered. In contrast, the AMBITION trial evaluated an upfront combination approach using ambrisentan and tadalafil versus monotherapy in treatment naïve patients.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> There was a 50% reduction in the primary endpoint with initial combination therapy, driven by a reduction in hospitalization for PAH. Based on the results of AMBITION, initial combination therapy with ambrisentan and tadalafil was given a class IB recommendation in the recent European guidelines.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> This recommendation is supported by a recent analysis from the French registry showing a 3-year survival of 84% in patients treated with initial dual oral combination therapy compared to an expected historical 3-year survival of 66%.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Although pulmonary endarterectomy remains the gold standard treatment for eligible CTEPH patients, many are not eligible for surgery due to inaccessible distal thromboembolic disease or comorbidities. Balloon pulmonary angioplasty (BPA), an endovascular procedure to widen narrowed or obstructed pulmonary arteries, has emerged as an exciting alternative treatment option for patients with non-operable CTEPH or patients with persistent pulmonary hypertension after endarterectomy. The first series published in 2001 demonstrated a reduction in mean pulmonary artery pressure (mPAP) of 9<span class="elsevierStyleHsp" style=""></span>mmHg, but reported a 5.6% rate of in-hospital death. Following refinements in the technique, several reports, mainly from Japan, now support the efficacy and safety of BPA. The hemodynamic benefits were summarized in a recent review article, which reported an overall reduction in mPAP of 12–21<span class="elsevierStyleHsp" style=""></span>mmHg from baseline, and a mortality rate of 0.0–3.4% after 2–5 angioplasty sessions.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> A recent Japanese study reported the results of 170 patients who underwent BPA over a 7 year period. They found sustained hemodynamic improvements, almost to within the normal range, in mPAP and pulmonary vascular resistance up to 3.5 years after BPA.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> In this series, the 1, 3, and 5-year survival rates were 98.7%, 98.0%, and 95.5%, however 1 death was attributed to multi-organ failure secondary to pulmonary artery injury, a known complication of BPA. Severe and fatal complications, including reperfusion edema or pulmonary artery perforation, may be minimized as the learning curve progresses. Although the indications and limitations have not been fully established, BPA has the potential to become a key treatment strategy for patients with non-operable CTEPH. An open-label, randomized controlled trial comparing BPA to riociguat in non-operable CTEPH patients is currently underway in France, with a primary endpoint of change in pulmonary vascular resistance at 26 weeks (RACE trial, <a href="ctgov:NCT02634203">NCT02634203</a>). This trial may help clarify the relative place of BPA and riociguat in a CTEPH treatment algorithm.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In conclusion, there have been important advances in the treatment of PAH and CTEPH over the past few years. However, PAH remains a progressive and fatal disease in most cases. Until the development of effective therapies that can slow or reverse vascular proliferation, inflammation and remodeling, parenteral prostanoids, combination therapy and lung transplantation are the only life-prolonging therapies. Patients with CTEPH now benefit from several therapeutic options including possible combinations of surgery, medical therapy and BPA. Riociguat and balloon pulmonary angioplasty are new effective options for CTEPH that result in significant clinical improvements for non-operable patients and those with persistent pulmonary hypertension after endarterectomy.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interests</span><p id="par0030" class="elsevierStylePara elsevierViewall">Dr. Humbert reports personal fees from Actelion Pharmaceuticals Ltd., grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Pfizer; and personal fees from Novartis, outside the submitted work. Dr. Weatherald has received grants from the European Respiratory Society and Canadian Thoracic Society; personal fees and non-financial support from Actelion and Bayer, outside the submitted work. Dr. Taniguchi has no conflict of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interests" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term safety and efficacy of imatinib in pulmonary arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.E. Frost" 1 => "R.J. Barst" 2 => "M.M. Hoeper" 3 => "H.-J. Chang" 4 => "R.P. Frantz" 5 => "Y. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 1 | 3 | 4 |
| 2024 October | 30 | 21 | 51 |
| 2024 September | 19 | 18 | 37 |
| 2024 August | 42 | 38 | 80 |
| 2024 July | 29 | 24 | 53 |
| 2024 June | 36 | 19 | 55 |
| 2024 May | 65 | 27 | 92 |
| 2024 April | 27 | 32 | 59 |
| 2024 March | 74 | 21 | 95 |
| 2024 February | 61 | 20 | 81 |
| 2023 March | 7 | 1 | 8 |
| 2023 February | 35 | 21 | 56 |
| 2023 January | 23 | 40 | 63 |
| 2022 December | 26 | 45 | 71 |
| 2022 November | 41 | 23 | 64 |
| 2022 October | 30 | 35 | 65 |
| 2022 September | 25 | 24 | 49 |
| 2022 August | 33 | 40 | 73 |
| 2022 July | 26 | 43 | 69 |
| 2022 June | 24 | 37 | 61 |
| 2022 May | 27 | 37 | 64 |
| 2022 April | 24 | 30 | 54 |
| 2022 March | 35 | 35 | 70 |
| 2022 February | 28 | 19 | 47 |
| 2022 January | 26 | 35 | 61 |
| 2021 December | 30 | 42 | 72 |
| 2021 November | 34 | 43 | 77 |
| 2021 October | 35 | 43 | 78 |
| 2021 September | 35 | 47 | 82 |
| 2021 August | 24 | 29 | 53 |
| 2021 July | 21 | 37 | 58 |
| 2021 June | 29 | 32 | 61 |
| 2021 May | 35 | 36 | 71 |
| 2021 April | 65 | 71 | 136 |
| 2021 March | 36 | 18 | 54 |
| 2021 February | 28 | 23 | 51 |
| 2021 January | 24 | 18 | 42 |
| 2020 December | 26 | 18 | 44 |
| 2020 November | 19 | 15 | 34 |
| 2020 October | 20 | 20 | 40 |
| 2020 September | 7 | 11 | 18 |
| 2020 August | 25 | 8 | 33 |
| 2020 July | 14 | 22 | 36 |
| 2020 June | 10 | 11 | 21 |
| 2020 May | 16 | 11 | 27 |
| 2020 April | 24 | 17 | 41 |
| 2020 March | 17 | 8 | 25 |
| 2020 February | 13 | 22 | 35 |
| 2020 January | 18 | 17 | 35 |
| 2019 December | 16 | 14 | 30 |
| 2019 November | 17 | 17 | 34 |
| 2019 October | 24 | 19 | 43 |
| 2019 September | 16 | 7 | 23 |
| 2019 August | 21 | 12 | 33 |
| 2019 July | 18 | 11 | 29 |
| 2019 June | 10 | 12 | 22 |
| 2019 May | 31 | 7 | 38 |
| 2019 April | 28 | 26 | 54 |
| 2019 March | 31 | 17 | 48 |
| 2019 February | 19 | 19 | 38 |
| 2019 January | 22 | 10 | 32 |
| 2018 December | 15 | 17 | 32 |
| 2018 November | 42 | 17 | 59 |
| 2018 October | 27 | 17 | 44 |
| 2018 September | 29 | 4 | 33 |
| 2018 May | 12 | 1 | 13 |
| 2018 April | 8 | 4 | 12 |
| 2018 March | 12 | 5 | 17 |
| 2018 February | 22 | 4 | 26 |
| 2018 January | 11 | 4 | 15 |
| 2017 December | 13 | 4 | 17 |
| 2017 November | 14 | 2 | 16 |
| 2017 October | 18 | 16 | 34 |
| 2017 September | 24 | 13 | 37 |
| 2017 August | 19 | 14 | 33 |
| 2017 July | 1 | 1 | 2 |
| 2017 May | 1 | 1 | 2 |
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