Pulmonary Arterial Hypertension (PAH)

Therapeutic strategies in pulmonary arterial hypertension (PAH) are aimed at reducing pulmonary vascular resistance (PVR) and remodeling due to excessive cell proliferation and reduced rates of apoptosis. In approximately 20% of patients, vasoconstriction plays a significant role in disease pathogenesis. Phosphodiesterase (PDE) inhibitors can help reduce PVR through their effects on nitric oxide (NO). NO is a vasodilator and inhibitor of vascular smooth muscle cell proliferation and platelet activation. Nitric oxide synthase (NOS) produces NO, and patients with PAH have decreased amounts of a specific isoform of this enzyme called endothelial NOS. The formation of NO leads to the activation of guanylate cyclase, which increases cyclic guanosine monophosphate (cGMP). PDE-5 is responsible for the degradation of cGMP, and inhibitors of PDE-5 have vasodilatory effects and possibly antiproliferative properties.¹  

Revatio (Sildenafil Citrate)

Revatio® contains the citrate salt of sildenafil and is an oral therapy for PAH. It is an inhibitor of cGMP-specific PDE-5 in smooth muscle cells of the pulmonary vasculature. This induces vasodilation of the pulmonary vasculature in PAH patients, with minimal effects on the peripheral vasculature.²

A randomized, double-blind, placebo-controlled study in 277 PAH patients, mostly with functional classes II and III, evaluated the safety and efficacy of Revatio over a 12-week period. All patients in the treatment arm experienced significant increases in mean 6-minute walk distance (6-MWD) of 45 to 50 meters compared to those given placebo. Additionally, all patients on Revatio achieved statistically significant reductions in mean pulmonary arterial pressure (mPAP) compared to those in the placebo group.²

The recommended dose of Revatio is 20 mg three times a day, taken every 4 to 6 hours with or without food. Adverse events (AEs) are fairly uncommon, and the discontinuation rate due to AEs is around 3%. Possible AEs include epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea exacerbation, rhinitis, diarrhea, myalgia, pyrexia, gastritis, sinusitis, and paresthesia. Serious AEs have been observed in male patients taking sildenafil citrate for erectile dysfunction, including serious cardiovascular, cerebrovascular, and vascular events such as myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages. Most, but not all, of these patients had pre-existing cardiovascular risk factors. This medication is contraindicated in patients who are using organic nitrates, regularly or intermittently, in any form.²

Get full prescribing information for Revatio at MPR

Adcirca (Tadalafil)

Adcirca™ (tadalafil) is a PDE-5 inhibitor indicated for the treatment of PAH in patients in the World Health Organization (WHO) group I category to improve exercise capability.³ 

A randomized, double-blind, placebo-controlled study was conducted in 405 patients with PAH (defined as mPAP ≥25 mmHg, pulmonary capillary wedge pressure ≤15 mmHg, and PVR ≥3 Wood units via right heart catheterization) over a period of 16 weeks. Participants were assigned to 1 of 5 groups in a 1:1 ratio to receive Adcirca (2.5, 10, 20, or 40 mg) or placebo. Patients taking 40 mg of Adcirca experienced a placebo-adjusted mean change in 6-MWD of 33 meters, which was apparent at week 8 and maintained through week 16 (95% CI, 15-50 m; P =.0004). Additionally, there was less clinical worsening in patients taking 40 mg of Adcirca than in those administered other doses or placebo. It is unclear whether this difference was statistically significant.³ 

The recommended dose of Adcirca is 40 mg once daily with or without food. It is not recommended to divide the dose over the course of the day (eg, 10 mg every 6 hours). The concomitant use of nitrates is a contraindication for Adcirca. The most common AE is headache. Adcirca should be used with caution in patients with cardiovascular disease, impaired autonomic control of blood pressure, or aortic stenosis. Patients should be advised to seek emergency treatment if they experience an erection lasting longer than 4 hours, sudden vision loss, or a sudden decrease in hearing. Adcirca should be avoided in patients taking potent CYP3A inducers (eg, rifampin).³ 

Get full prescribing information for Adcirca at MPR

Vardenafil

Vardenafil is sold under the trade names Levitra®, Staxyn®, and Vivanza®. These medications are only US Food and Drug Administration (FDA)-approved for the treatment of erectile dysfunction and may be used as off-label treatment in the management of PAH. Studies have demonstrated that vardenafil is effective and well tolerated in patients with PAH and that it improves 6-MWD.⁴ Long-term use of vardenafil is also associated with improvements in 6-MWD and may improve hemodynamic parameters.⁵  

References

1. 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;119(16):2250-2294. doi:10.1161/CIRCULATIONAHA.109.192230

2. Revatio. Prescribing information. Pfizer Inc; 2009. Accessed May 31, 2022.

3. Adcirca. Prescribing information. Eli Lilly and Company; 2009. Accessed May 31, 2022.

4. Jing ZC, Yu ZX, Shen JY, et al; Efficacy and Safety of Vardenafil in the Treatment of Pulmonary Arterial Hypertension (EVALUATION) Study Group. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011;183(12):1723-1729. doi:10.1164/rccm.201101-0093OC

5. Jing ZC, Jiang X, Wu BX, et al. Vardenafil treatment for patients with pulmonary arterial hypertension: a multicentre, open-label study. Heart. 2009;95(18):1531-1536. doi:10.1136/hrt.2009.169417

Reviewed by Hasan Avcu, MD, on 6/1/2022.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.