Pulmonary Arterial Hypertension Handout 2024 PDF

Pulmonary Arterial Hypertension Alfred Custer, Pharm.D., MBA, BCPS Pharmacotherapy II, October 22, 2024 Learning Objectives Recall information about initial presentation of pulmonary arterial hypertension (PAH). – Define PAH and summarize symptoms/risk factors associated with...

Pulmonary Arterial Hypertension Alfred Custer, Pharm.D., MBA, BCPS Pharmacotherapy II, October 22, 2024 Learning Objectives Recall information about initial presentation of pulmonary arterial hypertension (PAH). – Define PAH and summarize symptoms/risk factors associated with this condition. – Discuss the significance of vasoreactivity testing and its impact on selection of pharmacologic therapy. – Recall conventional therapy agents and the rationale for their use. Select a first-line or second-line pharmacologic agent (CHEST 2019) for the treatment of PAH. Identify characteristics of pharmacologic therapy options for PAH including route of administration, adverse effects, and efficacy. Anatomy and Physiology Multiple causes, similar effects: – Arterial vasoconstriction – Proliferation of endothelial cells – Thrombosis – Inflammation Progressive in nature http://jama.jamanetwork.com/article.aspx?articleid=184661  Diagnosis Pulmonary arterial pressure – Pressure in the pulmonary arteries Affected by pressure from the heart as well as inherent pressure from the vessels Pulmonary capillary wedge pressure – Measure of the heart’s contribution to pulmonary arterial pressure Indirect measure of pressure in left atrium https://upload.wikimedia.org/wikipedia/commons/e/ea/Pulmonary_artery_catheter_english.JPG Definition Pulmonary hypertension (PH) ≠ PAH – PAH criteria: mPAP ≥ 20mm Hg and PCWP ≤ 15 mm Hg WHO Classification of PH – Group 1- PAH – Group 2- PH Due to Left Heart Disease – Group 3- PH Due to Lung Disease and/or Hypoxemia – Group 4- Chronic Thromboembolic PH – Group 5- PH with Unclear Multifactorial Mechanisms Pathophysiology Genetics – BMPR2 mutation- inhibits smooth muscle cell apoptosis, leads to proliferation – ALK-1 mutation- small vascular malformation, immune response mediation Other risk factors – HIV infection – Portal hypertension – Schistosomiasis- one of the most common causes worldwide – Congenital heart disease – Persistent pulmonary HTN of the newborn- circulation disorder at birth – Connective tissue disease (e.g. lupus, systemic sclerosis, rheumatoid arthritis) Idiopathic (IPAH) Drug-induced- appetite suppressants, amphetamines, cocaine, chemotherapy agents Pathophysiology Mediators of PAH – Prostacyclin (PGI2)- antiproliferation, vasodilator Levels typically lower in PAH – Endothelin-1 (ET-1)- causes cell replication, vasoconstrictor Production increased, clearance reduced in PAH – Nitric oxide (NO)- vasodilator Reduced synthesis in PAH – Serotonin (5-HT)- vasoconstriction via 5-HT1B receptor Levels may be increased in PAH – Cytokines, coagulation mediators Classification WHO Functional Classification of PAH – Class I- No limitation of activity; physical activity does not cause increase in symptoms – Class II- Mild limitation of physical activity; no discomfort at rest, symptoms with normal activity – Class III- Less-than-normal activity causes limiting symptoms – Class IV- Symptoms at rest; unable to perform physical activities Symptoms Classic symptoms: – Dyspnea (increased on exertion) – Pre-syncope/ syncope – Chest pain – Fatigue – Weakness Symptoms of progressing/advanced disease – Lower extremity edema – Hypotension – Cyanosis – Wheezing – Use of accessory muscles during breathing – Heart murmur due to valve regurgitation Symptoms https://phassociation.org/pulmonary-hypertension-ph/symptoms-of-ph-2/ Pharmacotherapy Goals Reduction of symptoms – “Step down” or maintain functional class status – Mitigate progressive nature of disease – Decrease number of hospitalizations Improvement in physical ability – Six-minute walk distance (6MWD) Cardiopulmonary hemodynamics – Right heart catheterization – Echocardiography Vasoreactivity Assessment Test performed during right heart catheterization to determine if the patient will respond to vasodilator therapy – Agents: inhaled NO, IV epoprostenol (synthetic PGI2) or adenosine – Positive response: reduction of mPAP by ≥10mm Hg to ≤40mm Hg Vasoreactivity Assessment Calcium channel blockers should be used in patients with a positive vasodilator response – Diltiazem, nifedipine, or amlodipine – Risks associated with use in non-responders: e.g. reflex tachycardia, sympathetic stimulation – Limited duration of efficacy CHEST 2019 50% do not respond after 1 year Guidelines Conventional Therapy ESC/ERS 2022 Guidelines Oral anticoagulation (e.g. warfarin, INR goal of 1.5-2.5) Consider for IPAH, hereditable PAH, or drug-induced PAH based on limited data Loop diuretics – Furosemide dosed to maintain euvolemic state Recommended for patients with right ventricle dysfunction based on expert opinion Oxygen therapy – Goal O2 saturation ≥92% Recommendation based on evidence in COPD Digoxin – Target concentration of 0.5-0.8 ng/mL for symptomatic benefit No longer included as a recommendation, may be used to address arrhythmia PAH-Specific Pharmacotherapy Endothelin receptor antagonists (ETRA) – Prevents vasoconstriction, cell proliferation caused by increased ET-1 levels – Bosentan (Tracleer)- 62.5mg daily for 4 weeks, increased to 125mg twice daily PO – Ambrisentan (Letairis)- 5-10mg daily PO – Macitentan (Opsumit)- 10mg daily PO PAH-Specific Pharmacotherapy Phosphodiesterase (PDE5) inhibitors – Increases intracellular cGMP, reduces vasoconstriction/proliferation of vascular smooth muscle cells – Sildenafil (Revatio)- 20mg three times daily PO Higher doses often used (unapproved) – Tadalafil (Adcirca)- 40mg once daily PO PAH-Specific Pharmacotherapy Prostacyclin and its analogs (prostanoids) – Increases levels of PGI2 for vasodilatory and antiproliferative effects – Epoprostenol (Flolan)- 2-4 ng/kg/min IV titrated up to 20-40 ng/kg/min – Treprostinil (Remodulin)- 1.25 ng/kg/min IV or SC, titrated up or down based on response PAH-Specific Pharmacotherapy Prostacyclin and its analogs (prostanoids) cont. – Treprostinil (Tyvaso)- 3 breaths (18mcg) inhaled orally 4 times daily, titrated according to response Goal maintenance dose of 9 breaths 4 times daily – Treprostinil (Orenitram)- 0.125mg PO 3 times daily or 0.25mg PO twice daily titrated up according to response – Iloprost (Ventavis)- 2.5 mcg inhaled 6-9 times daily, titrated to dose of 5mcg inhaled up to 9 times daily PAH-Specific Pharmacotherapy NEW prostanoid (12/2015): – Selexipag (Uptravi): selective prostacyclin receptor agonist – Dose: 200mcg PO twice daily initial dose, increased weekly by 200mcg twice daily to highest tolerated dose Max. 1600mcg twice daily PAH-Specific Pharmacotherapy Guanylate cyclase stimulator – Causes increase in production of cGMP, reduces vasoconstriction/proliferation of vascular smooth muscle cells – Riociguat (Adempas)- 1mg three times daily PO titrated as tolerated, max dose of 2.5mg TID PAH-Specific Pharmacotherapy NEW drug (3/2024): – Sotatercept (Winrevair): recombinant fusion protein that balances pro-proliferative and anti-proliferative signaling to modulate vascular proliferation – Dose: 0.3 mg/kg subcutaneous once every 3 weeks; increase to target dose 0.7 mg/kg once every 3 weeks once Hb and platelet counts are verified to be within an acceptable range. PAH-Specific Pharmacotherapy CHEST 2019 CCB therapy if indicated Guidelines Class I – Monitoring + conventional therapy as appropriate – Treatment of underlying disease states, contributing causes – Birth control, immunizations (recommended for all patients) Class II – 1st-line: ambrisentan (ETRA) + tadalafil (PDE5 inhibitor) – 2nd-line: ambrisentan, sildenafil, bosentan, macitentan, tadalafil, riociguat Prostacyclin analogs should not be used PAH-Specific Pharmacotherapy CHEST 2019 Class III Guidelines – 1st-line: ambrisentan + tadalafil – 2nd-line: ambrisentan, sildenafil, bosentan, macitentan, tadalafil, or riociguat IV epoprostenol, IV/SC treprostinil suggested as initial therapy in patients with evidence of rapid progression/ poor prognosis – May add inhaled or oral prostanoid PAH-Specific Pharmacotherapy Class IV – 1st line: IV epoprostenol or IV/SC treprostinil – 2nd line: Inhaled prostanoid in combination with an oral PDE-5 inhibitor and an oral ETRA PAH-Specific Pharmacotherapy Keep It Simple, Students! Class II & III: – 1st-line agents: Ambrisentan + tadalafil – 2nd-line agents: Monotherapy with ETRA, PDE-5 inhibitor, or riociguat (best evidence with ambrisentan and sildenafil) Class III with rapid progression: – Treat like Class IV Class IV: – 1st-line agents: Parenteral prostanoids – 2nd-line therapy: Combination of inhaled prostanoid, oral PDE-5 inhibitor, and oral ETRA Adverse Effects PGI2 and analogs: – Systemic administration: hypotension, tachycardia, thrombocytopenia, CNS effects (HA, dizziness), flu-like syndrome, jaw pain, flushing – Inhaled products: flushing, cough, jaw spasms, HA, insomnia, hypotension, flu-like syndrome Lower risk of AEs overall than IV/SC products PDE5 inhibitors – HA, hypotension, myalgias, cardiovascular events reported (typically during or after sexual activity) Adverse Effects ETRA – Hepatotoxicity (bosentan), anemia, edema, HA, sinus congestion – High risk of teratogenicity if taken during pregnancy (boxed warning, REMS program) Riociguat – HA, N/V/D, dizziness, hypotension, anemia, GERD, palpitations – High risk of teratogenicity if taken during pregnancy (boxed warning, REMS program) Adverse Effects Sotatercept – Bleeding (epistaxis risk >20%), erythrocytosis (hemoglobin levels above upper limit of normal), thrombocytopenia – Rash, telangiectasia – Avoid use in pregnancy Summary PAH refers to a group of progressive conditions that increase the pulmonary artery pressure apart from the influence of intracardiac pressures Multiple pathways are associated with development of PAH, but overall themes include vasoconstriction, smooth muscle cell proliferation, and inflammation. While conventional therapies are used for complication prophylaxis or symptom management, 4 classes of medications have been found to treat PAH. Although supporting studies are limited, therapy options are selected based on patient classification. References Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2022; 43: 3618–3731. 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; 155(3): 565-586.