Potential of Selexipag in Chronic Thromboembolic Pulmonary Hypertension Medical Therapy

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but potentially fatal disease. It is a progressive pulmonary vascular disorder characterized by luminal obliteration of the central and distal pulmonary arteries by organized thromboembolic material and fibrous stenosis.¹ CTEPH is classified as group 4 pulmonary hypertension (PH), and if left untreated, progresses to right heart failure and ultimately death.²

Article p 1866

Surgical pulmonary endarterectomy (PEA) to remove thromboembolic material is the treatment of choice for CTEPH.^3,4 However, around 40% of CTEPH cases are considered inoperable because of concerns such as inaccessible vascular obstruction or comorbidities.⁴ In addition to inoperable cases, there are patients who do not accept the risks associated with PEA. Moreover, there are also patients who experience persistent or recurrent CTEPH following PEA. For such inoperable, persistent or recurrent patients, the prescription of targeted drugs for pulmonary arterial hypertension (PAH) is typically considered. These PAH drugs target 3 pharmacologically accessible pathways: endothelin-1, nitric oxide (NO), and prostacyclin.^5,6 More recently, balloon pulmonary angioplasty (BPA) has become a treatment option for CTEPH in some specialist centers.^7,8

PAH and CTEPH have similar clinical presentations and histopathological vascular changes. For instance, in patients with CTEPH, distal small-vessel pulmonary vasculopathy or microvascular diseases (i.e., secondary small-vessel disease) develop similarly to PAH, including intimal thickening, intimal fibromuscular proliferation, and plexiform lesions.⁹ Secondary small-vessel disease is caused not only by mechanical obstruction with organized thrombus, but also by exposure to the high pressure by collateral blood supply from the bronchial and systemic arteries in obstructed territories (Figure). Therefore, rationale exists for the use of PAH-targeted drugs in CTEPH. Currently, only riociguat, which augments the NO pathway, is approved for inoperable CTEPH or persistent or recurrent CTEPH after PEA, based on the randomized controlled trials of the CHEST trials.¹⁰ However, other PAH-targeted drugs have often been used off-label for CTPEH based on several smaller studies,¹¹ and clinical experience. At present, macitentan, which targets the endothelin pathway, is another promising PAH-targeted drug for treatment of CTEPH.¹²

Figure.

In patients with chronic thromboembolic pulmonary hypertension (CTEPH), secondary small-vessel disease develops as a result of increased high shear stress caused by the occlusion of proximal pulmonary arteries by organized fibrotic clot. Secondary small-vessel disease can also occur by high pressure through anastomosis between the pulmonary arterial circulation and systemic circulation such as the bronchial arteries. Selexipag could work in CTEPH patients with secondary small-vessel disease.

Prostacyclin is a potent pulmonary vasodilator with antithrombotic and antiproliferative properties. Prostacyclin therapy was shown to be effective in treating patients with CTEPH in Japan.¹³ Selexipag is an available oral selective prostacyclin receptor agonist that is distinct from prostacyclin. In the GRIPHON trial that targeted patients with PAH, the risk of onset of morbidity/mortality events was lowered significantly by 40% with selexipag compared with placebo.¹⁴ Considering that CTEPH has secondary small-vessel disease, the efficacy of selexipag would be expected to be positive for inoperable cases.

In this issue of the Journal, the results of a double-blind, randomized, placebo-controlled, multicenter, phase 2 study of selexipag for Japanese patients with CTEPH by Tanabe and colleagues are published.¹⁵ Although patents treated with selexipag demonstrated a decrease in pulmonary vascular resistance (PVR), the effect did not reach statistical significance. However, in the group not concomitantly using other pulmonary vasodilators, PVR was significantly decreased compared with that in the placebo group. Safety-wise, selexipag was tolerated in Japanese patients with CTEPH. However, in this study, the sample size was not set for statistical power but instead set from a practical point of view that enrollment should be performed within the randomization period. Therefore, type II errors could not be avoided. In this sense, the study’s results are promising for future medical therapy for CTEPH and encourage us to conduct further clinical trials.

However, caution should be paid to interpreting the results of this study¹⁵ because of the rapidly changing landscape of CTEPH management. One limitation is that the study was conducted before riociguat was approved as a medical therapy for CTEPH patients. Therefore, it is unknown whether selexipag is effective for CTEPH patients with background riociguat therapy. Another limitation is that BPA is emerging as a safe and effective alternative for inoperable CTEPH patients or persistent or recurrent CTEPH following PEA.

There continues to be a group of patients with CTEPH who cannot undergo PEA or BPA, and riociguat alone cannot ameliorate their symptoms and hemodynamics. It is likely that the number of patients meeting these criteria will increase with age and occurrence of multiple morbidities Therefore, another medical therapy for CTEPH is required. The efficacy of selexipag in patients with CTEPH requires further study in future clinical trials.

Disclsoure

Both T. Kondo and Y. Nakano now belong to an endowed department of Actelion Pharmaceuticals Japan (now Janssen Pharmaceutical K.K.). S. Adachi belonged to endowed department of Actelion Pharmaceuticals Japan (now Janssen Pharmaceutical K.K.).

References

• 1.   Fukuda K, Date H, Doi S, Fukumoto Y, Fukushima N, Hatano M, et al; on behalf of the Japanese Circulation Society and the Japanese Pulmonary Circulation and Pulmonary Hypertension Society Joint Working Group. Guidelines for the treatment of pulmonary hypertension (JCS 2017/JPCPHS 2017). Circ J 2019; 83: 842–945.
• 2.   Kondo T, Okumura N, Adachi S, Murohara T. Editors’ Choice: Pulmonary hypertension Nagoya J Med Sci 2019; 81: 19–30.
• 3.   Ogino H, Ando M, Matsuda H, Minatoya K, Sasaki H, Nakanishi N, et al. Japanese single-center experience of surgery for chronic thromboembolic pulmonary hypertension. Ann Thorac Surg 2006; 82: 630–636.
• 4.   Kim NH, Delcroix M, Jais X, Madani MM, Matsubara H, Mayer E, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2019; 53: 1801915.
• 5.   Hirashiki A, Kondo T, Adachi S, Nakano Y, Kamimura Y, Shimokata S, et al. Goal-oriented sequential combination therapy evaluated using cardiopulmonary exercise parameters for the treatment of newly diagnosed pulmonary arterial hypertension: Goal-Oriented Therapy Evaluated by Cardiopulmonary Exercise Testing for Pulmonary Arterial Hypertension (GOOD EYE). Circ Rep 2019; 1: 303–311.
• 6.   Galie N, Channick RN, Frantz RP, Grunig E, Jing ZC, Moiseeva O, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2019; 53: 1801889.
• 7.   Madani M, Ogo T, Simonneau G. The changing landscape of chronic thromboembolic pulmonary hypertension management. Eur Respir Rev 2017; 26: 170105.
• 8.   Ogawa A, Matsubara H. After the dawn: Balloon pulmonary angioplasty for patients with chronic thromboembolic pulmonary hypertension. Circ J 2018; 82: 1222–1230.
• 9.   Simonneau G, Torbicki A, Dorfmuller P, Kim N. The pathophysiology of chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017; 26: 160112.
• 10.   Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013; 369: 319–329.
• 11.   Hoeper MM. Pharmacological therapy for patients with chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2015; 24: 272–282.
• 12.   Ghofrani HA, Simonneau G, D’Armini AM, Fedullo P, Howard LS, Jais X, et al. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): Results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respir Med 2017; 5: 785–794.
• 13.   Nagaya N, Sasaki N, Ando M, Ogino H, Sakamaki F, Kyotani S, et al. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 2003; 123: 338–343.
• 14.   Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 2015; 373: 2522–2533.
• 15.   Tanabe N, Fukuda K, Matsubara H, Nakanishi N, Tahara N, Ikeda S, et al. Selexipag for chrnoic thromboembollic pulmonary hypertension in Japanese patients: A double-blind, randomized, placebo-controlled, multicenter phase II study. Circ J 2020; 84: 1866–1874.