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Semin Respir Crit Care Med 2013; 34(05): 620-626
DOI: 10.1055/s-0033-1355442
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

J. E. Cannon
1   Pulmonary Vascular Diseases Unit, Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
,
J. Pepke-Zaba
1   Pulmonary Vascular Diseases Unit, Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
› Author Affiliations
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Publication History

Publication Date:
13 September 2013 (online)

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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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 3 Dartevelle P, Fadel E, Mussot S , et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004; 23 (4) 637-648
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 11 Bonderman D, Wilkens H, Wakounig S , et al. Risk factors for chronic thromboembolic pulmonary hypertension. Eur Respir J 2009; 33 (2) 325-331
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 15 http://www.ic.nhs.uk/webfiles/Services/NCASP/audits%20and%20reports/NHS_IC_Pulmonary_Hypertension_Audit_V1.0.pdf
    PubMed
  • 16 Galiè N, Kim NHS. Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 2006; 3 (7) 571-576
    CrossrefPubMedGoogle Scholar
  • 17 Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993; 103 (3) 685-692
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 22 Galié N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res 2004; 61 (2) 227-237
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 27 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351 (14) 1425-1436
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 31 Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998; 352 (9129) 719-725
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 33 Hoeper MM, Mayer E, Simonneau G, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Circulation 2006; 113 (16) 2011-2020
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 35 Jenkins DP, Madani M, Mayer E , et al. Surgical treatment of . chronic thromboembolic pulmonary hypertension. Eur Respir J 2013; 41 (3) 735-742
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 42 Kerr KM, Rubin LJ. Epoprostenol therapy as a bridge to pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Chest 2003; 123 (2) 319-320
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 52 Hoeper MM, Kramm T, Wilkens H , et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005; 128 (4) 2363-2367
    CrossrefPubMedGoogle Scholar
  • 53 Bonderman D, Nowotny R, Skoro-Sajer N , et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005; 128 (4) 2599-2603
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 61 www.cteph-association.org/registry
    PubMed