Medical Treatment of Pulmonary Arterial Hypertension

ABSTRACT

Pulmonary arterial hypertension (PAH) is a sinister condition that is often diagnosed late and is associated with a progressive clinical deterioration and premature death. However, over the past 10 years the field has seen a dramatic increase in the number of effective therapies underpinned by advances in our understanding of the pathobiology of this illness. Identification of dysfunctional signaling pathways in the pulmonary circulation provided novel therapeutic targets with the goal of reducing pulmonary vascular resistance and prevention of death from right ventricular failure. Treatment algorithms have now become more complex, with therapeutic options defined by pulmonary artery vasoreactivity, functional class, and response to treatment. Combination therapies are increasingly considered as clinical trials demonstrating the efficacy of this approach are emerging. Monitoring and measuring the response to treatment in clinical trials and clinical practice are evolving from the historical dependence on functional class and 6-minute walk test to include estimates of the delay in the time to clinical worsening and the response of emerging biomarkers.

KEYWORDS

Pulmonary arterial hypertension - medical treatment - combination therapy

REFERENCES

• 1 Badesch D B, Abman S H, Simonneau G, Rubin L J, McLaughlin V V. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines.  Chest. 2007;  131 1917-1928
• 2 Galiè N, Torbicki A, Barst R et al.. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology.  Eur Heart J. 2004;  25 2243-2278
• 3 Simonneau G, Galiè N, Rubin L J et al.. Clinical classification of pulmonary hypertension.  J Am Coll Cardiol. 2004;  43(12, Suppl S) 5S-12S
• 4 Mereles D, Ehlken N, Kreuscher S et al.. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.  Circulation. 2006;  114 1482-1489
• 5 Weiss B M, Zemp L, Seifert B, Hess O M. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996.  J Am Coll Cardiol. 1998;  31 1650-1657
• 6 Parambil J G, McGoon M D. Pregnancy and pulmonary hypertension. In: Oakley C, Warnes CA Heart Disease in Pregnancy. Malden, MA; Blackwell 2007: 59-78
• 7 Chan W S, Anand S, Ginsberg J S. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature.  Arch Intern Med. 2000;  160 191-196
• 8 Kenyon K W, Nappi J M. Bosentan for the treatment of pulmonary arterial hypertension.  Ann Pharmacother. 2003;  37 1055-1062
• 9 Warnes C A. Pregnancy and pulmonary hypertension.  Int J Cardiol. 2004;  97(Suppl 1) 11-13
• 10 Tarver J H, Rosas I, Diette G B et al.. Chronic ambulatory dopamine infusion therapy for refractory right heart failure due to pulmonary hypertension [abstract].  ARRCM. 2000;  161 A459
• 11 Fuster V, Steele P M, Edwards W D, Gersh B J, McGoon M D, Frye R L. Primary pulmonary hypertension: natural history and the importance of thrombosis.  Circulation. 1984;  70 580-587
• 12 Johnson S R, Granton J T, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension.  Chest. 2006;  130 545-552
• 13 Kawut S M, Horn E M, Berekashvili K K et al.. New predictors of outcome in idiopathic pulmonary arterial hypertension.  Am J Cardiol. 2005;  95 199-203
• 14 Rich S, Seidlitz M, Dodin E et al.. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension.  Chest. 1998;  114 787-792
• 15 Rich S, Brundage B H. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy.  Circulation. 1987;  76 135-141
• 16 Rubin L J, Badesch D B, Barst R J et al.. Bosentan therapy for pulmonary arterial hypertension.  N Engl J Med. 2002;  346 896-903
• 17 Sitbon O, Humbert M, Jaïs X et al.. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension.  Circulation. 2005;  111 3105-3111
• 18 Barst R J, Rubin L J, Long W A The Primary Pulmonary Hypertension Study Group et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.  N Engl J Med. 1996;  334 296-302
• 19 Badesch D B, Tapson V F, McGoon M D et al.. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial.  Ann Intern Med. 2000;  132 425-434
• 20 Jones D A, Benjamin C W, Linseman D A. Activation of thromboxane and prostacyclin receptors elicits opposing effects on vascular smooth muscle cell growth and mitogen-activated protein kinase signaling cascades.  Mol Pharmacol. 1995;  48 890-896
• 21 Rubin L J, Mendoza J, Hood M et al.. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial.  Ann Intern Med. 1990;  112 485-491
• 22 McLaughlin V V, Genthner D E, Panella M M, Hess D M, Rich S. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series.  Ann Intern Med. 1999;  130 740-743
• 23 Rosenzweig E B, Kerstein D, Barst R J. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects.  Circulation. 1999;  99 1858-1865
• 24 Krowka M J, Frantz R P, McGoon M D, Severson C, Plevak D J, Wiesner R H. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): a study of 15 patients with moderate to severe portopulmonary hypertension.  Hepatology. 1999;  30 641-648
• 25 Nunes H, Humbert M, Sitbon O et al.. Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2003;  15 1433-1439
• 26 Cabrol S, Souza R, Jais X et al.. Intravenous epoprostenol in inoperable chronic thromboembolic pulmonary hypertension.  J Heart Lung Transplant. 2007;  26 357-362
• 27 Rich S, McLaughlin V V. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension.  J Am Coll Cardiol. 1999;  34 1184-1187
• 28 McLaughlin V V, Gaine S P, Barst R J Treprostinil Study Group et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension.  J Cardiovasc Pharmacol. 2003;  41 293-299
• 29 Vachiéry J L, Hill N, Zwicke D, Barst R, Blackburn S, Naeije R. Transitioning from I.V. epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension.  Chest. 2002;  121 1561-1565
• 30 Tapson V F, McLaughlin V V, Gomberg-Maitland M et al.. Delivery of intravenous treprostinil at low infusion rates using a miniaturized infusion pump in patients with pulmonary arterial hypertension.  J Vasc Access. 2006;  7 112-117
• 31 Simonneau G, Barst R J, Galie N Treprostinil Study Group et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial.  Am J Respir Crit Care Med. 2002;  165 800-804
• 32 Barst R J, Galie N, Naeije R et al.. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil.  Eur Respir J. 2006;  28 1195-1203
• 33 Olschewski H, Simonneau G, Galiè N Aerosolized Iloprost Randomized Study Group et al. Inhaled iloprost for severe pulmonary hypertension.  N Engl J Med. 2002;  347 322-329
• 34 Opitz C F, Wensel R, Winkler J et al.. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension.  Eur Heart J. 2005;  26 1895-1902
• 35 Higenbottam T, Butt A Y, McMahon A, Westerbeck R, Sharples L. Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension.  Heart. 1998;  80 151-155
• 36 Galiè N, Humbert M, Vachiéry J L Arterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial.  J Am Coll Cardiol. 2002;  39 1496-1502
• 37 Barst R J, McGoon M, McLaughlin V Beraprost Study Group et al. Beraprost therapy for pulmonary arterial hypertension.  J Am Coll Cardiol. 2003;  41 2119-2125
• 38 Giaid A, Yanagisawa M, Langleben D et al.. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.  N Engl J Med. 1993;  328 1732-1739
• 39 Rubin L J, Badesch D B, Barst R J et al.. Bosentan therapy for pulmonary arterial hypertension.  N Engl J Med. 2002;  346 896-903
• 40 Dupuis J. Endothelin-receptor antagonists in pulmonary hypertension.  Lancet. 2001;  358 1113-1114
• 41 Dupuis J, Jasmin J F, Prié S, Cernacek P. Importance of local production of endothelin-1 and of the ET(B) receptor in the regulation of pulmonary vascular tone.  Pulm Pharmacol Ther. 2000;  13 135-140
• 42 Kirchengast M, Luz M. Endothelin receptor antagonists: clinical realities and future directions.  J Cardiovasc Pharmacol. 2005;  45 182-191
• 43 Channick R N, Simonneau G, Sitbon O et al.. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.  Lancet. 2001;  358 1119-1123
• 44 McLaughlin V V, Sitbon O, Badesch D B et al.. Survival with first-line bosentan in patients with primary pulmonary hypertension.  Eur Respir J. 2005;  25 244-249
• 45 Provencher S, Sitbon O, Humbert M, Cabrol S, Jaïs X, Simonneau G. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension.  Eur Heart J. 2006;  27 589-595
• 46 Galié N, Badesch D, Oudiz R et al.. Ambrisentan therapy for pulmonary arterial hypertension.  J Am Coll Cardiol. 2005;  46 529-535
• 47 Galiè N, Olschewski H, Oudiz R J Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2.  Circulation. 2008;  117 3010-3019
• 48 Oudiz R, Badesch D, Rubin L. ARIES-E: Long-term safety and efficacy of ambrisentan in pulmonary arterial hypertension [abstract].  Chest. 2007;  132 474a
• 49 Barst R J, Langleben D, Badesch D STRIDE-2 Study Group et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan.  J Am Coll Cardiol. 2006;  47 2049-2056
• 50 Barst R J. Sitaxsentan: a selective endothelin-A receptor antagonist, for the treatment of pulmonary arterial hypertension.  Expert Opin Pharmacother. 2007;  8 95-109
• 51 Barst R J, Langleben D, Frost A STRIDE-1 Study Group et al. Sitaxsentan therapy for pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2004;  169 441-447
• 52 Barst R J, Langleben D, Badesch D STRIDE-2 Study Group et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan.  J Am Coll Cardiol. 2006;  47 2049-2056
• 53 Benza R L, Mehta S, Keogh A, Lawrence E C, Oudiz R J, Barst R J. Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan.  J Heart Lung Transplant. 2007;  26 63-69
• 54 Langleben D, Hirsch A M, Shalit E, Lesenko L, Barst R J. Sustained symptomatic, functional, and hemodynamic benefit with the selective endothelin-A receptor antagonist, sitaxsentan, in patients with pulmonary arterial hypertension: a 1-year follow-up study.  Chest. 2004;  126 1377-1381
• 55 Galiè N, Ghofrani H A, Torbicki A Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group et al. Sildenafil citrate therapy for pulmonary arterial hypertension.  N Engl J Med. 2005;  353 2148-2157
• 56 Pepke-Zaba J, Gilbert C, Collings L, Brown M C. Sildenafil improves health-related quality of life in patients with pulmonary arterial hypertension.  Chest. 2008;  133 183-189
• 57 Galiè N et al.. Tadalafil therapy for pulmonary arterial hypertension.  Circulation. 2009;  119 2894-2903
• 58 Simonneau G, Rubin L J, Galiè N PACES Study Group et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial.  Ann Intern Med. 2008;  149 521-530
• 59 Wilkens H, Guth A, König J et al.. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension.  Circulation. 2001;  104 1218-1222
• 60 Ghofrani H A, Rose F, Schermuly R T et al.. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension.  J Am Coll Cardiol. 2003;  42 158-164
• 61 Ghofrani H A, Wiedemann R, Rose F et al.. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension.  Ann Intern Med. 2002;  136 515-522
• 62 United Therapeutics .TRIUMPH-1 trial of Viveta in pulmonary arterial hypertension meets primary endpoint. November 1, 2007. Available at: http://ir.unither.com/releasedetail.cfm?ReleaseID=272478
• 63 McLaughlin V V, Oudiz R J, Frost A et al.. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2006;  174 1257-1263
• 64 Hoeper M M, Leuchte H, Halank M et al.. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension.  Eur Respir J. 2006;  28 691-694
• 65 Humbert M, Barst R J, Robbins I M et al.. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2.  Eur Respir J. 2004;  24 353-359
• 66 Hoeper M M, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension.  Eur Respir J. 2004;  24 1007-1010
• 67 Mathai S C, Girgis R E, Fisher M R et al.. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension.  Eur Respir J. 2007;  29 469-475
• 68 Doyle R L, McCrory D, Channick R N, Simonneau G, Conte J. American College of Chest Physicians . Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.  Chest. 2004;  126(1, Suppl) 63S-71S
• 69 Orens J B, Estenne M, Arcasoy S et al.. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation.  J Heart Lung Transplant. 2006;  25 745-755
• 70 American Academy of Hospice and Palliative Medicine . National Consensus Project for Quality Palliative Care: Clinical Practice Guidelines for quality palliative care, executive summary.  J Palliat Med. 2004;  7 611-627
• 71 Hoeper M M, Galié N, Murali S et al.. Outcome after cardiopulmonary resuscitation in patients with pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2002;  165 341-344
• 72 McKenna S P, Doughty N, Meads D M, Doward L C, Pepke-Zaba J. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR): a measure of health-related quality of life and quality of life for patients with pulmonary hypertension.  Qual Life Res. 2006;  15 103-115
• 73 Nagaya N, Nishikimi T, Goto Y et al.. Plasma brain natriuretic peptide is a biochemical marker for the prediction of progressive ventricular remodeling after acute myocardial infarction.  Am Heart J. 1998;  135 21-28
• 74 Leuchte H H, Holzapfel M, Baumgartner R A et al.. Clinical significance of brain natriuretic peptide in primary pulmonary hypertension.  J Am Coll Cardiol. 2004;  43 764-770
• 75 Nagaya N, Nishikimi T, Uematsu M et al.. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension.  Circulation. 2000;  102 865-870
• 76 Fijalkowska A, Kurzyna M, Torbicki A et al.. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension.  Chest. 2006;  129 1313-1321
• 77 Raymond R J, Hinderliter A L, Willis P W et al.. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension.  J Am Coll Cardiol. 2002;  39 1214-1219
• 78 Yeo T C, Dujardin K S, Tei C, Mahoney D W, McGoon M D, Seward J B. Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension.  Am J Cardiol. 1998;  81 1157-1161
• 79 Forfia P R, Fisher M R, Mathai S C et al.. Tricuspid annular displacement predicts survival in pulmonary hypertension.  Am J Respir Crit Care Med. 2006;  174 1034-1041
• 80 Frantz R P, Benza R L, Kjellström B et al.. Continuous hemodynamic monitoring in patients with pulmonary arterial hypertension.  J Heart Lung Transplant. 2008;  27 780-788