Chelsea Henderson, PharmD PGY-1 Pharmacy Practice Resident A hole-in-one: Mastering acute right-heart failure in patients with a patent foramen ovale (PFO) Chelsea Henderson, PharmD PGY-1 Pharmacy Practice Resident VA Boston Healthcare System

disclosures I have nothing to disclose

Objectives - Identify existing evidence for the off-label use of inhaled prostacyclin analogs and phosphodiesterase inhibitor therapy in patients with acute right-heart failure and a PFO - Describe appropriate treatment strategies to two real patient cases to manage acute-right heart failure due to a PFO and the associated complications

Patient case: “Mr. s” Patient case: “Mr. A” An 80 y/o male with a history of COPD with frequent exacerbations requiring prednisone and antibiotics and a significant cardiac history admitted due to hypoxia and increased dyspnea Patient appears fine by frequently desaturates without explanation 77 y/o male with shortness of breath and nausea, suspected to be a heart failure exacerbation (ejection fraction = 35%). Further workup shows evidence of RV strain, acute femoral deep vein thrombosis (DVT) and progressive and profound hypoxia.

Patient case: “Mr. s” Patient case: “Mr. A” 2015 right heart catheterization: hypertrophy and pulmonary hypertension, suspected to be Group III, possible regurgitation  Transthoracic echocardiogram (TTE) and agitated saline study (“Bubble study”) yields a diagnosis of PFO, shows right-to-left shunting of blood Patient goes into mixed cardiogenic-hypovolemic shock, bilateral pulmonary emboli discovered After shock is stabilized, TTE and agitated saline study (“Bubble study”) shows PFO

Patent Foramen Ovale (PFO) Congenital cardiac lesion found in up to 25% of the adult population undergoing a transthoracic echocardiogram Many patients remain asymptomatic PFO can cause shunting of the cardiac blood flow leading to hypoxemia, paradoxical emboli, and cryptogenic stroke Can be diagnosed with agitated saline contrast (“Bubble Study”) of the right heart Torbey E, Thompson PD. Patent foramen ovale: thromboembolic structure or incidental finding? Conn Med. 2011 Feb;75(2):97-105  Horton SC, Bunch TJ. Patent foramen ovale and stroke. Mayo Clin Proc. 2004 Jan;79(1):79-88 Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Crytogenic Stroke Study

Epoprostenol, Treprostinil and Iloprost Prostacyclin (PGI2) with strong vasodilatory effects throughout the vasculature, approved for pulmonary arterial hypertension(PAH) Group I De Wet CJ, Affleck DG, Jacobsohn E, Avidan MS, Tymkew H, Hill LL, Zanaboni PB, Moazami N, Smith JR. Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. J Thorac Cardiovasc Surg. 2004 Apr;127(4):1058-67. Mehmood M, Frank TA. Treatment of right heart failure: is there a solution to the problem? European Journal of Cardiology Practice. 14 (33) Dec 19 2016.

Epoprostenol, Treprostinil and Iloprost Off-label uses Acute vasodilator testing in patients with PAH Intraoperative pulmonary hypertension during cardiac surgery with cardiopulmonary bypass Acute respiratory distress syndrome (ARDS) Acute right-heart failure, refractory hypoxemia due to ventricular dysfunction De Wet CJ, Affleck DG, Jacobsohn E, Avidan MS, Tymkew H, Hill LL, Zanaboni PB, Moazami N, Smith JR. Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. J Thorac Cardiovasc Surg. 2004 Apr;127(4):1058-67. Mehmood M, Frank TA. Treatment of right heart failure: is there a solution to the problem? European Journal of Cardiology Practice. 14 (33) Dec 19 2016.

FDA-approved for PAH Group I for combination therapy sildenafil Phosphodiesterase (PDE5) inhibitor that prolong vasodilatory effects of nitric oxide, other vasodilatory agents FDA-approved for PAH Group I for combination therapy Added to epoprostenol to improve oxygenation, exercise capacity, delay clinical worsening Mehmood M, Frank TA. Treatment of right heart failure: is there a solution to the problem? European Journal of Cardiology Practice. 14 (33) Dec 19 2016. Product Information: REVATIO oral tablets, suspension, intravenous injection, sildenafil oral tablets, suspension, intravenous injection. Pfizer (per manufacturer), New York, NY, 2015.

Evidence for PGI2 and PDE5 use in right-heart failure with a PFO Pitsiou GG, Chavouzis N, Nakou C, et al 40 y/o woman with idiopathic pulmonary arterial hypertension (iPAH), severe dyspnea and hypoxia TTE: right ventricular hypertrophy with severe enlargement of the right ventricle, right atrium Agitated saline injections revealed severe right-to-left shunt through a PFO  Sildenafil 25 mg orally three times daily and inhaled iloprost 20 mcg aerolized six times daily initiated concomitantly  hemodynamic stability five days later Pitsiou GG, Chavouzis N, Nakou C, et al. Successful up-front combination therapy in a patient with idiopathic pulmonary hypertentions and patent foramen ovale: an alternative to epoprostenol therapy? J Heart Lung Transplant. 2009 Jun;28(6):651-3

Evidence for PGI2 and PDE5 use in right-heart failure with a PFO Elias S, Sviri S, Orenbush-Harroch E, et al. 67 y/o women with severe pulmonary hypertension, dependent on inhaled nitric oxide and mechanical ventilation (unable to wean) TEE: severe enlargement of the right ventricle with severe dysfunction, pulmonary hypertension, mitral regurgitation Agitated saline injections revealed severe right-to-left shunt due to a PFO Sildenafil 20 mg orally three times daily up to 60 mg three times daily x 5 days allowed full weaning after 25 days of mechanical ventilation and nitric oxide therapy Elias S, Sviri S, Orenbush-Harroch E, et al. Sildenafil to facilitate weaning from inhaled nitric oxide and mechanical ventilation in a patient with severe secondary pulmonary hypertension and a patent foramen ovale. Respir Care. 2011 Oct;56(10):1611-3

Patient case: “Mr. s” Patient case: “Mr. A” Inhaled epoprostenol started at 50 ng/kg/min (IBW) Weaned down from 50 ng/kg/min by increments of 10 ng/kg/min in intervals of 2 to 4 hours as tolerated Inhaled epoprostenol started at 50 ng/kg/min (IBW) Weaned down from 50 ng/kg/min by increments of 10 ng/kg/min in intervals of 2 to 4 hours as tolerated

Patient case: “Mr. s” Patient case: “Mr. A” Maintained on sildenafil 25 mg three times daily and epoprostenol for three days, then epoprostenol discontinued Despite his hemodynamic instability, bilateral PE and acute right-heart failure due to PFO, Mr. A fully recovered and is maintained on oral sildenafil 25mg three times daily Inhaled treprostinil started when epoprostenol dose weaned to 10 ng/kg/min x 2 doses of treprostinil, then epoprostenol discontinued Patient discharged to home and maintained outpatient on inhaled treprostinil four times daily and oral sildenafil 25 mg three times daily

summary Utilizing off-label inhaled prostacyclin and phosphodiesterase inhibitor therapy in patients with acute right-heart failure and a PFO may improve ventricular function and oxygenation

A hole-in-one: Mastering acute right-heart failure in patients with a patent foramen ovale (PFO) Questions? Chelsea Henderson, PharmD PGY-1 Pharmacy Practice Resident VA Boston Healthcare System chelsea.henderson@va.gov

Acknowledgements Lauren Finlay, PharmD Clinical Pharmacy Specialist, VABHS Bryan Wood, PharmD PGY-1 Residency Director

Assessment question #1 A patent foramen ovale (PFO) may result in which of the following… a. Acute left-heart failure b. Decreased systolic ejection fraction c. Cryptogenic stroke d. Prolonged PT/INR

Assessment question #1 A patent foramen ovale (PFO) may result in which of the following… a. Acute left-heart failure b. Decreased systolic ejection fraction c. Cryptogenic stroke d. Prolonged PT/INR

Assessment question #2 Which of the following medications has NOT been used for off-label treatment of acute right-heart failure? Furosemide Epoprostenol Sildenafil Iloprost

Assessment question #2 Which of the following medications has NOT been used for off-label treatment of acute right-heart failure? Furosemide Epoprostenol Sildenafil Iloprost

References Torbey E, Thompson PD. Patent foramen ovale: thromboembolic structure or incidental finding? Conn Med. 2011 Feb;75(2):97-105  Horton SC, Bunch TJ. Patent foramen ovale and stroke. Mayo Clin Proc. 2004 Jan;79(1):79-88 Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Crytogenic Stroke Study De Wet CJ, Affleck DG, Jacobsohn E, Avidan MS, Tymkew H, Hill LL, Zanaboni PB, Moazami N, Smith JR. Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. J Thorac Cardiovasc Surg. 2004 Apr;127(4):1058-67. Mehmood M, Frank TA. Treatment of right heart failure: is there a solution to the problem? European Journal of Cardiology Practice. 14 (33) Dec 19 2016. Product Information: REVATIO oral tablets, suspension, intravenous injection, sildenafil oral tablets, suspension, intravenous injection. Pfizer (per manufacturer), New York, NY, 2015. Pitsiou GG, Chavouzis N, Nakou C, et al. Successful up-front combination therapy in a patient with idiopathic pulmonary hypertentions and patent foramen ovale: an alternative to epoprostenol therapy? J Heart Lung Transplant. 2009 Jun;28(6):651-3 Elias S, Sviri S, Orenbush-Harroch E, et al. Sildenafil to facilitate weaning from inhaled nitric oxide and mechanical ventilation in a patient with severe secondary pulmonary hypertension and a patent foramen ovale. Respir Care. 2011 Oct;56(10):1611-3