Adult

Pulmonary Hypertension

Classification and Treatment Guidelines

Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37(1):67-119. This consensus document has the latest definition, classification, evaluation and management recommendations for patients with pulmonary hypertension.

PMID: 26320113

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McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009; 28:119:2250-94. This consensus statement is still referred to for the classification, evaluation, treatment, and monitoring of patients with pulmonary hypertension.

PMID: 19332472

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Diagnosis

Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003; 167:735-40. The cardiology literature indicates echocardiography-derived estimates of pulmonary artery pressures are accurate. This study found 52% of echo estimates were inaccurate (off by > 10 mmHg) in 166 lung transplant candidates and the difference was > 20 mmHg in 28%. In patients without hypertension, echo was more likely to overestimate pressures while in patients with pulmonary hypertension; it was as likely to over as underestimate. Accuracy and ability to obtain an estimate varied with the underlying disease.

PMID: 12480614

Fisher MR, Forfia PR, Chamera E, et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med 2009; 179:615-21. This prospective study of 65 patients undergoing right-heart catheterization for the diagnosis or management of pulmonary hypertension extends the findings of Arcasoy et al. above to patients without end-stage lung disease. Echo over or underestimated pulmonary artery pressure by > 10 mm Hg 52% of the time. The majority of patients had pulmonary arterial hypertension (WHO Group 1).

PMID: 19164700

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Treatment of pulmonary arterial hypertension

Calcium Channel Blockers

Rich S, Kaufman E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81. Study with suboptimal design but convincing hemodynamic data found improved survival and is the basis for use of CCBs in patients with a good response to vasodilators.

PMID: 1603139

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Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111:3105-3111. This retrospective analysis found that only 54% of the patients who had initial vasoreactivity and were placed on calcium channel blockers had a favorable long-term response. This finding prompted a revision in the consensus definition of a favorable response to acute vasodilator testing.

PMID: 15939821

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Prostacyclines

Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) and conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-301. RCT found the epoprostenol group had improved hemodynamics, quality of life, and survival.

PMID: 8532025

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Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 2015; 373:2522-2533. A randomized trial investigating the utility of selexipag, a novel oral prostacyclin-receptor agonist, in patients with Group I PAH. Patients could be treatment naive, or receiving stable doses of a PDE 5 inhibitor, an endothelin receptor antagonist, or both. 80% of participants were already on PAH therapy at the time of enrollment. They found significant improvement in their primary outcome, a composite of death from any cause or a complication related to PAH, but there was no mortality difference. Some concern regarding a dropout rate of 14% (vs 7% with placebo) in the treatment group.

PMID: 26699168

Endothelin Receptor Antagonists

Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369:809-18. This placebo-controlled RCT is noteworthy for use of a robust primary composite endpoint which included death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension.  The composite endpoint occurred in 46.4% of placebo group vs. 31.4% of the higher dose of macidentan. Macitentan carries lower risk of hepatotoxicity compared to besentan.

PMID: 23984728

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Type 5 Phosphodiesterase Inhibitors

Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148-57. Double-blind RCT comparing sildenafil (20, 40, or 80 mg po tid x 12 weeks) and placebo in 278 patients with symptomatic pulmonary arterial hypertension found sildenafil improved exercise capacity, WHO functional class, and hemodynamics.

PMID: 16291984

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Soluble Guanylate Cyclase Inhibitors

The following multi-centered double blind placebo controlled trials found a soluble guanylate cyclase inhibitor improved 6-minute walk distance in patients with PAH and chronic thromboembolic pulmonary hypertension (30 and 39 meters, respectively). Both trials found improvement in other functional and physiologic parameters.

Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-40.

PMID: 23883378

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Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319-29.

PMID: 23883377

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Combination Therapy

Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. New Engl J Med 2015: 373:834-844. This randomized trial is novel for focusing on the role of upfront combination therapy in symptomatic treatment-naive patients.  Patients received ambrisentan and tadalafil alone or in combination. The primary outcome (a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response) occurred in 18% of the combination group vs 31% in the pooled monotherapy group (hazard ratio 0.50, p < .001). This was driven by a decrease in hospitalization. There was no mortality difference or change in WHO functional class.

PMID: 26308684

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Last Reviewed: June 2019