Is Distal Chronic Thromboembolic Pulmonary Hypertension Treatable with PAH Targeted Drugs?

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition that historically has a poor outcome with supportive medical treatment. Pulmonary endarterectomy (PEA) is the treatment of choice and offers the only chance of cure. A significant proportion of patients is either not suitable due to the distal distribution of the disease or has persistent pulmonary hypertension (PH) after PEA. Despite the lack of licensed therapies for CTEPH, the similarities in pathobiology of pulmonary arterial hypertension (PAH) and CTEPH has led to the compassionate use of PAH therapies in CTEPH patients. This article reviews the pathobiology of CTEPH and summaries the available evidence for the use of PAH-targeted drugs in CTEPH.

Keywords

chronic thromboembolic pulmonary hypertension - bosentan - prostanoids - riociguat and sildenafil

• References

• 1 Riedel M, Stanek V, Widimsky J, Prerovsky I. Long-term follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982; 81 (2) 151-158
• 2 Madani MM, Auger WR, Pretorius V , et al. Pulmonary endarterectomy: recent changes in a single institution's experience of more than 2,700 patients. Ann Thorac Surg 2012; 94 (1) 97-103 , discussion 103
• 3 Dartevelle P, Fadel E, Mussot S , et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004; 23 (4) 637-648
• 4 Becattini C, Agnelli G, Pesavento R , et al. Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism. Chest 2006; 130 (1) 172-175
• 5 Klok FA, van Kralingen KW, van Dijk APJ, Heyning FH, Vliegen HW, Huisman MV. Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. Haematologica 2010; 95 (6) 970-975
• 6 Martí D, Gómez V, Escobar C , et al. [Incidence of symptomatic and asymptomatic chronic thromboembolic pulmonary hypertension]. Arch Bronconeumol 2010; 46 (12) 628-633
• 7 Miniati M, Monti S, Bottai M , et al. Survival and restoration of pulmonary perfusion in a long-term follow-up of patients after acute pulmonary embolism. Medicine (Baltimore) 2006; 85 (5) 253-262
• 8 Pengo V, Lensing AWA, Prins MH , et al; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350 (22) 2257-2264
• 9 Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L. Pulmonary embolism: one-year follow-up with echocardiography doppler and five-year survival analysis. Circulation 1999; 99 (10) 1325-1330
• 10 Bonderman D, Jakowitsch J, Adlbrecht C , et al. Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension. Thromb Haemost 2005; 93 (3) 512-516
• 11 Bonderman D, Wilkens H, Wakounig S , et al. Risk factors for chronic thromboembolic pulmonary hypertension. Eur Respir J 2009; 33 (2) 325-331
• 12 Condliffe R, Kiely DG, Gibbs JSR , et al. Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension. Eur Respir J 2009; 33 (2) 332-338
• 13 Pepke-Zaba J, Delcroix M, Lang I , et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 2011; 124 (18) 1973-1981
• 14 Condliffe R, Kiely DG, Gibbs JSR , et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2008; 177 (10) 1122-1127
• 15 http://www.ic.nhs.uk/webfiles/Services/NCASP/audits%20and%20reports/NHS_IC_Pulmonary_Hypertension_Audit_V1.0.pdf
• 16 Galiè N, Kim NHS. Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 2006; 3 (7) 571-576
• 17 Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993; 103 (3) 685-692
• 18 Hassoun PM, Mouthon L, Barberà JA , et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009; 54 (1, Suppl): S10-S19
• 19 Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 2009; 104 (2) 236-244 , 28p, 244
• 20 Soon E, Holmes AM, Treacy CM , et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 2010; 122 (9) 920-927
• 21 Soon E, Holmes A, Treacy CM , et al. Inflammatory cytokines are elevated in patients with operable chronic thromboembolic pulmonary hypertension and predict outcome post-endarterectomy. Am J Respir Crit Care Med 2011; 183: A2287
• 22 Galié N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res 2004; 61 (2) 227-237
• 23 Kim H, Yung GL, Marsh JJ , et al. Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Eur Respir J 2000; 15 (4) 640-648
• 24 Kim H, Yung GL, Marsh JJ , et al. Pulmonary vascular remodeling distal to pulmonary artery ligation is accompanied by upregulation of endothelin receptors and nitric oxide synthase. Exp Lung Res 2000; 26 (4) 287-301
• 25 Bauer M, Wilkens H, Langer F, Schneider SO, Lausberg H, Schäfers H-J. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 2002; 105 (9) 1034-1036
• 26 Reesink HJ, Meijer RC, Lutter R , et al. Hemodynamic and clinical correlates of endothelin-1 in chronic thromboembolic pulmonary hypertension. Circ J 2006; 70 (8) 1058-1063
• 27 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351 (14) 1425-1436
• 28 Ulrich S, Fischler M, Speich R, Popov V, Maggiorini M. Chronic thromboembolic and pulmonary arterial hypertension share acute vasoreactivity properties. Chest 2006; 130 (3) 841-846
• 29 Suntharalingam J, Hughes RJ, Goldsmith K , et al. Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH). Vascul Pharmacol 2007; 46 (6) 449-455
• 30 Suntharalingam J, Treacy CM, Doughty NJ , et al. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest 2008; 134 (2) 229-236
• 31 Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998; 352 (9129) 719-725
• 32 Skoro-Sajer N, Hack N, Sadushi-Koliçi R , et al. Pulmonary vascular reactivity and prognosis in patients with chronic thromboembolic pulmonary hypertension: a pilot study. Circulation 2009; 119 (2) 298-305
• 33 Hoeper MM, Mayer E, Simonneau G, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Circulation 2006; 113 (16) 2011-2020
• 34 Bresser P, Pepke-Zaba J, Jaïs X, Humbert M, Hoeper MM. Medical therapies for chronic thromboembolic pulmonary hypertension: an evolving treatment paradigm. Proc Am Thorac Soc 2006; 3 (7) 594-600
• 35 Jenkins DP, Madani M, Mayer E , et al. Surgical treatment of . chronic thromboembolic pulmonary hypertension. Eur Respir J 2013; 41 (3) 735-742
• 36 Jamieson SW, Kapelanski DP, Sakakibara N , et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003; 76 (5) 1457-1462 , discussion 1462–1464
• 37 Jensen KW, Kerr KM, Fedullo PF , et al. Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy. Circulation 2009; 120 (13) 1248-1254
• 38 Auger WR, Kerr KM, Kim NHS, Ben-Yehuda O, Knowlton KU, Fedullo PF. Chronic thromboembolic pulmonary hypertension. Cardiol Clin 2004; 22 (3) 453-466 , vii
• 39 Freed DH, Thomson BM, Berman M , et al. Survival after pulmonary thromboendarterectomy: effect of residual pulmonary hypertension. J Thorac Cardiovasc Surg 2011; 141 (2) 383-387
• 40 Mayer E, Jenkins D, Lindner J , et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011; 141 (3) 702-710
• 41 Nagaya N, Sasaki N, Ando M , et al. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 2003; 123 (2) 338-343
• 42 Kerr KM, Rubin LJ. Epoprostenol therapy as a bridge to pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Chest 2003; 123 (2) 319-320
• 43 Bresser P, Fedullo PF, Auger WR , et al. Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension. Eur Respir J 2004; 23 (4) 595-600
• 44 Scelsi L, Ghio S, Campana C , et al. Epoprostenol in chronic thromboembolic pulmonary hypertension with distal lesions. Ital Heart J 2004; 5 (8) 618-623
• 45 Cabrol S, Souza R, Jais X , et al. Intravenous epoprostenol in inoperable chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant 2007; 26 (4) 357-362
• 46 Olschewski H, Simonneau G, Galiè N , et al; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347 (5) 322-329
• 47 Ono F, Nagaya N, Okumura H , et al. Effect of orally active prostacyclin analogue on survival in patients with chronic thromboembolic pulmonary hypertension without major vessel obstruction. Chest 2003; 123 (5) 1583-1588
• 48 Lang I, Gomez-Sanchez M, Kneussl M , et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest 2006; 129 (6) 1636-1643
• 49 Skoro-Sajer N, Bonderman D, Wiesbauer F , et al. Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension. J Thromb Haemost 2007; 5 (3) 483-489
• 50 Ghofrani HA, Schermuly RT, Rose F , et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2003; 167 (8) 1139-1141
• 51 Reichenberger F, Voswinckel R, Enke B , et al. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur Respir J 2007; 30 (5) 922-927
• 52 Hoeper MM, Kramm T, Wilkens H , et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005; 128 (4) 2363-2367
• 53 Bonderman D, Nowotny R, Skoro-Sajer N , et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005; 128 (4) 2599-2603
• 54 Hughes RJ, Jais X, Bonderman D , et al. The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study. Eur Respir J 2006; 28 (1) 138-143
• 55 Jaïs X, D'Armini AM, Jansa P , et al; Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension Study Group. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol 2008; 52 (25) 2127-2134
• 56 Reesink HJ, Surie S, Kloek JJ , et al. Bosentan as a bridge to pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg 2010; 139 (1) 85-91
• 57 Ghofrani HA, Hoeper MM, Halank M , et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010; 36 (4) 792-799
• 58 Ghofrani H, Grimminger F, Hoeper M , et al. Riociguat for the Treatment of Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Randomised, Double-Blind, Placebo-Controlled Study (CHEST-1). Chest 2012; 142 (4_Meeting Abstracts): 1023A-1023A
• 59 Lewczuk J, Piszko P, Jagas J , et al. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 2001; 119 (3) 818-823
• 60 Suntharalingam J, Machado RD, Sharples LD , et al. Demographic features, BMPR2 status and outcomes in distal chronic thromboembolic pulmonary hypertension. Thorax 2007; 62 (7) 617-622
• 61 www.cteph-association.org/registry