Pulmonary Arterial Hypertension

Background

• Pulmonary hypertension: continuous high blood pressure in the lungs

o Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg at rest
▪ Normal PAP: 8-20 mmHg

Classification

• The World Health Organization classifies PH into five groups

WHO Group Causes Treatment

(1) Pulmonary Arterial • Idiopathic • Targeted medications for
Hypertension (PAH) • Genetics PAH
• Medical conditions*
• Drugs**
(2) PH due to left heart disease • Congenital heart disease • Manage underlying heart
• Heart valve disease disease
• Left ventricular systolic or
diastolic dysfunction
(3) PH due to lung disease • COPD • Manage underlying lung
• Emphysema disease
(4) Chronic Thromboembolic PH • Blood clots in the lungs • Pulmonary
(CTEPH) thromboendarterectomy
• Medication therapy
(5) PH due to unknown causes • Sarcoidosis • Manage underlying
• Sickle cell anemia disease
• Hemolytic anemia
• Metabolic disorders
• Splenectomy
*connective tissue diseases (scleroderma, lupus), congenital heart disease, HIV, liver disease
**Anorexigens (aminorex, fenfluramine, benfluorex), dasatinib, methamphetamines, SSRIs, cocaine, etc.
Symptoms

• Fatigue, dyspnea, chest pain, syncope, edema, tachycardia

Diagnosis

• Echocardiogram – estimates PAP and PVR / RV function

• Blood work to test for underlying disease
• Exercise testing
• Right heart catheterization – estimates severity / assesses response to pulmonary vasodilators before initiating CCBs
WHO Functional Classes

Class 1 No limitation of physical activity. No symptoms of dyspnea with routine

exertion.
Class 2 Mild symptoms with exertion, including dyspnea and fatigue. No symptoms at
rest.
Class 3 Moderate dyspnea with routine activities and activities of daily living. No
symptoms at rest.
Class 4 Inability to perform minimal activities. Signs and symptoms of right heart
failure may be present. Dyspnea at rest.
Treatment guidelines:

Acute Vasoreactivity Test (AVT) – predicts response to calcium channel blockers

• Agents used: inhaled nitric oxide, IV epoprostenol, IV adenosine

• Positive → treat with oral CCB (long-acting nifedipine, long-acting diltiazem, amlodipine)

Treatment naïve PAH patients with WHO FC I

• Continued monitoring for disease progression → determine when to start therapy

Treatment naïve PAH patients with WHO FC II & Treatment naïve PAH patients with WHO FC III without evidence of rapid
disease progression or poor prognosis

• Patient able to tolerate combination therapy → combination therapy with ambrisentan and tadalafil
• Patient not able to tolerate combination therapy → monotherapy with either bosentan, macitentan, ambrisentan, riociguat, sildenafil,
tadalafil

PAH patients with WHO FC III with evidence of rapid disease progression or poor prognosis & PAH patients with WHO FC IV

• Patient able to manage parenteral prostanoids → continuous IV epoprostenol, IV treprostinil, or SC treprostinil

• Patient not able to manage parenteral prostanoids → consider addition of inhaled or oral prostanoid (FC III) / inhaled prostanoid in
combination with an oral PDE-5 inhibitor and an oral endothelin receptor antagonist

Patients with inadequate response to initial therapy

• Poor clinical status despite established PAH-specific monotherapy → add second class of PAH therapy
• Poor clinical status despite established PAH-specific dual therapy → add third class of PAH therapy

Phosphodiesterase-5 inhibitors
Sildenafil (oral, IV): 20 mg Q8H Tadalafil (oral): 40 mg QD
Clinical impact: improved 6MWD and functional capacity
CI: use with nitrates or riociguat
SEs/Warnings: headache, flushing, dyspepsia, hypotension, hearing loss, vision loss

Endothelin receptor antagonists

Bosentan (oral): 125 mg BID Ambrisentan (oral): 5 or 10 mg QD Macitentan (oral): 10 mg QD
Clinical impact: improved 6MWD, decreased hospitalization, delayed timed to clinical worsening
CI: Pregnancy
SEs/Warnings: hepatoxicity (bosentan), anemia, peripheral edema, headache, upper respiratory tract infection, hypotension

Prostacyclin derivatives & Prostacyclin receptor agonists

Epoprostenol (IV infusion): 2 ng/kg/min Iloprost (inhaled): Treprostinil (oral): 0.25 mg Selexipag (oral): 200 µg BID.
Increase as tolerated 2.5 or 5.0 µg 6-9 BID or 0.125 mg TID. Increase Increase as tolerated to maximum
inhalations/day 0.125 mg BID every 3-4d dose of 1600 µg BID
(inhaled): 18-54 µg (3-9
inhalations) QID
(SC or IV infusion): 1.25
ng/kg/min; increase 1.25
ng/kg/min per week based on
clinical response; after week 4
increase by 2.5 ng/kg/min per
week based on clinical response
Clinical impact: improved symptoms, 6MWD, and mortality
CI: HF (epoprostenol), severe hepatic impairment (oral treprostinil)
SEs/Warnings: hypotension, flushing, headache dizziness, rebound PH

Soluble cGMP stimulators

Riociguat (oral): 0.5-1 mg Q8H. Increase 0.5 mg every 2 weeks as tolerated to maximum dose of 2.5 mg
Clinical impact: Improved WHO FC and time to clinical worsening
CI: Pregnancy, use of PDE-5 inhibitors or nitrates
SEs/Warnings: headache, hypotension, dyspepsia, dizziness, N/V/D

References:

Klinger JR, Elliott CG, Levine DJ, et al. Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline and expert panel report. Chest. 2019. doi: 10.1016/j.chest.2018.11.030

2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension: Developed by the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the
European Respiratory Society (ERS). Eur Heart J. 2022

About Pulmonary Hypertension. Pulmonary Hypertension Association. Accessed April 10, 2023. https://phassociation.org/patients/aboutph/

Pulmonary Arterial Hypertension Symptoms and Diagnosis. American Lung Association. Updated January 10, 2023. Accessed April 10, 2023. https://www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-arterial-
hypertension/symptoms-diagnosis

McGee M, Whitehead N, Martin J, et al. Drug-associated pulmonary arterial hypertension. Clin Toxicol. 2018;56(9):801-809. doi: 10.1080/15563650.2018.1447119