Management of pulmonary arterial hypertension (PAH) involves specific therapy, supportive therapy, and background therapy. PAH-specific therapy includes therapies that target the endothelin, prostacyclin, and nitric oxide (NO) pathways, and background therapy includes diuretics (for fluid overload), digoxin (for improved cardiac output), and warfarin (for thrombotic lesions).1,2
Calcium Channel Blockers
Calcium channel blockers (CCBs) are drugs that help decrease pulmonary blood pressure and significantly improve long-term survival in a subset of PAH patients (less than 10%) who responded favorably to acute vasodilator testing at the time of right heart catheterization (RHC). PAH patients who do not show a favorable response or are nonresponsive in the acute vasodilator testing should not be given CCB therapy due to potential side effects such as hypotension, syncope, and right heart failure. Vasoreactivity testing is recommended in patients with idiopathic PAH (IPAH), heritable PAH (HPAH), and PAH due to toxins/drugs.
Vasoactive patients should be treated with high doses of CCBs and monitored closely, with complete reassessment after 3-4 months. If adequate response is not observed, ie, improved hemodynamics and maintenance of WHO Functional Class (FC) I or II status, the patient should be considered nonvasoactive.
The CCBs commonly used for PAH include nifedipine, diltiazem, and amlodipine. The choice of CCB depends on the patients’ heart rate at baseline; nifedipine and amlodipine are used in patients with slower heart rate while diltiazem is used in patients with faster heart rate. Side effects of CCBs include systemic hypotension and lower limb peripheral edema.3
Vasodilators, particularly prostacyclin analogs and prostacyclin receptor (or IP receptor) agonists, are drugs that allow the blood vessels in the lungs to relax and are therefore used for the treatment of PAH. In patients with PAH, there is a reduction in the levels of prostacyclin, which is a potent vasodilator produced by endothelial cells. The lack of prostacyclin causes vasoconstriction and increased pulmonary blood pressure.
Thus, many drugs used to treat PAH target the prostacyclin pathway, such as synthetic analogs of prostacyclin and procyclin receptor agonists. Prostacyclin analogs include epoprostenol (intravenous), iloprost (intravenous, oral, or aerosol), and treprostinil (intravenous and subcutaneous).
Recently, the US Food and Drug Administration (FDA) granted priority review for the New Drug Application (NDA) for a powdered form of inhaled treprostinil (Tyvaso DPITM) for the treatment of PAH.4
An oral selective IP receptor agonist, selexipag, specifically binds to prostacyclin receptors and helps the pulmonary vessels to relax.1
Endothelin Receptor Antagonists
Endothelin receptor antagonists (ERAs) are drugs that promote vasodilation and help prevent constriction and narrowing of the pulmonary vasculature by blocking endothelin, a substance elevated in PAH that causes pulmonary vasoconstriction and muscle cell proliferation through its binding to endothelin receptors (A and B) on smooth muscle cells. Ambrisentan, bosentan, and macitentan are FDA-approved ERAs for the treatment of PAH.5
Phosphodiesterase-5 Enzyme Inhibitors
Phosphodiesterase type 5 enzyme inhibitors (PDE-5i) work by inhibiting the PDE-5 that catalyzes the degradation of cyclic guanosine monophosphate (cGMP), which is a substance that causes pulmonary vasodilation through the nitric oxide (NO)/cGMP pathway. The PDE-5i therapies approved for use in PAH patients include sildenafil and tadalafil and lead to significant pulmonary vasodilation, improve exercise tolerance ,and delay clinical worsening.6
Soluble Guanylate Cyclase Stimulators
Soluble guanylate cyclase (sGC) stimulators enhance cGMP production by stimulating the enzyme sGC directly (independent of nitric oxide), promoting pulmonary vasodilation. In addition, sGC stimulators increase the interaction of sGC with NO, stabilizing the sGC-NO complex that helps to relax the blood vessels in the lungs. Riociguat is an sGC stimulator approved for the management of chronic thromboembolic pulmonary hypertension (CTEPH) and PAH. Studies have shown that riociguat improves exercise capacity and WHO functional class and delays PAH worsening.6
Cardiac glycosides such as digoxin increase the heart’s contractile strength and thus assist the pumping of the heart. They work by blocking sodium-potassium ATPase transporters on the heart muscle cells, increasing intracellular calcium concentration and improving contraction. Although digoxin has been shown to improve right ventricular contractility and cardiac output in acute hemodynamic studies,7 there is a lack of data to support its long-term use in PAH. In a recent study of PAH patients with right ventricular failure (RVF), long-term use of digoxin did not show any benefit on patient survival.8
Diuretics are effective in reducing the fluid overload in PAH by eliminating excess fluid in the body. Due to increased pulmonary resistance in PAH, there is increased pressure and workload on the right ventricle that may lead to RVF. RVF is associated with increased total blood volume (fluid overload), which may lead to ascites, bowel congestion, and peripheral edema.
The most commonly used diuretics in PAH are loop diuretics, particularly furosemide, bumetanide, and torsemide. These act on the loop of Henle and effectively prevent reabsorption of sodium in the kidney, ridding excess fluid that puts pressure on the heart. Diuretic therapy in PAH requires close monitoring since diuretics may cause a decrease in electrolytes such as potassium.9
Other types of diuretics used in PAH include thiazide diuretics (eg, metolazone) that inhibit sodium reabsorption in the distal tubes in the kidney and aldosterone antagonists (eg, spironolactone) that work as a potassium-sparing diuretic by blocking aldosterone action on mineralocorticoid receptors.10
Anticoagulants are used for thinning blood and preventing blood clotting in PAH patients, who often have thrombotic pulmonary vascular lesions.
In patients with idiopathic PAH, heritable PAH, or anorexigen-associated PAH, long-term warfarin therapy is recommended, with an international normalized ratio goal of 1.5-2.5.3 A recent study found that anticoagulant therapy is effective in improving outcomes and quality of life in all PAH patients but those with connective tissue diseases.11
- Yaghi S, Novikov A, Trandafirescu T. Clinical update on pulmonary hypertension. J Investig Med. 2020;68(4):821-827. doi:10.1136/jim-2020-001291
- Mayeux JD, Pan IZ, Dechand J, et al. Management of pulmonary arterial hypertension. Curr Cardiovasc Risk Rep. 2021;15(1):2. doi:10.1007/s12170-020-00663-3
- Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492. doi:10.1136/bmj.j5492
- MannKind and United Therapeutics achieve a major milestone in the development of Tyvaso DPTM with new drug application acceptance from the FDA. News release. MannKind Corporation; June 16, 2021.
- Ishak Gabra NB, Mahmoud O, Ishikawa O, et al. Pulmonary arterial hypertension and therapeutic interventions. Int J Angiol. 2019;28(2):80-92. doi:10.1055/s-0039-1692452
- Parikh V, Bhardwaj A, Nair A. Pharmacotherapy for pulmonary arterial hypertension. J Thorac Dis. 2019;11(Suppl 14):S1767-S1781. doi:10.21037/jtd.2019.09.14
- 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(3):787-792. doi:10.1378/chest.114.3.787
- Saucedo H, Zayas-Hernandez NG, López-Flores JC, Pulido-Zamudio T. Digoxin effect in mortality associated to right ventricular dysfunction in patients with pulmonary hypertension. European Respiratory Journal. 2019;54:PA4751. doi:10.1183/13993003.congress-2019.pa4751
- Hansen L, Burks M, Kingman M, Stewart T. Volume management in pulmonary arterial hypertension patients: an expert pulmonary hypertension clinician perspective. Pulm Ther. 2018;4(1):13-27. doi:10.1007/s41030-018-0052-z
- Stickel S, Gin-Sing W, Wagenaar M, Gibbs JSR. The practical management of fluid retention in adults with right heart failure due to pulmonary arterial hypertension. Eur Heart J Suppl. 2019;21(Suppl K):K46-K53. doi:10.1093/eurheartj/suz207
- Jose A, Eckman MH, Elwing JM. Anticoagulation in pulmonary arterial hypertension: a decision analysis. Pulm Circ. 2019;9(4):2045894019895451. doi:10.1177/2045894019895451
Reviewed by Kyle Habet, MD, on 7/1/2021.