Treatment of Pulmonary Hypertension in a Community Hospital Serena Von Ruden, PharmD, RN, BSN St. Francis Hospital Federal Way, WA Franciscan Health System HPI: 66 year old male with advanced oxygendependent COPD and known pulmonary hypertension (PH) admitted with abdominal ascites and peripheral edema Pulmonary hypertension diagnosed in 2008 Maintained on sildenafil 50 mg PO TID RHC in previous 12 months but results not available Labs: Hypoxia with compensated respiratory acidosis Mild lactic acidosis Mildly elevated BNP Adequate renal function Radiography & Ultrasound: CT angio demonstrated evidence of acute PE to RML and bilateral LL segmental arteries BLE doppler ultrasound (+) VTE 1
Echocardiography: Severe RA dilation Estimated PASP 57 mmhg Severely enlarged RV with significantly reduced systolic function Mildly dilated LA LV size WNL with low normal systolic function, EF 50% Clinical presentation: SpO 2 84-90% on 13 L oxy mask at rest Desat to 70% with activity SBP 80-90s Pulmonary Hypertension Disease of pulmonary vasculature Diagnosis requires RHC Mean PAP 25 mmhg at rest Vascular remodeling Pulmonary vasoconstriction RV failure Thrombosis in situ Ryerson CJ, et al. Resp Research. 2010;11:12.; Galie N, et al. Eur Respir J. 2009;34:1219.; Barst RJ, et al. J Am Coll Cardiol. 2009;54:S78.;Bishop BM, et al. Pharmacotherapy. 2012;32(9):838. Humbert M, et al. New Eng J Med. 2004;351:1425. 2
WHO Group Classification WHO Group Description 1 Pulmonary artery hypertension Primary Therapy None, consider advanced therapies 2 Left heart disease Treat underlying heart disease 3 Lung disease and/or hypoxia 4 Chronic thromboembolism 5 Unclear multifactorial mechanisms Treat underlying cause of hypoxia and/or correct with supplemental oxygen Anticoagulation or surgical clot removal Treat underlying cause Simmoneau G, et al. J Am Coll Cardiol. 2004;43:S5.; Galie N, et al. Eur J Heart. 2009;30:2493. Question Into which WHO group does our patient most likely fall? A. Group 2 B. Group 3 C. Group 4 D. Not enough information provided WHO Functional Class Class Description I No physical limitatons II Comfortable at rest but ordinary physical activity results in undue fatigue, dyspnea, CP, or syncope III Comfortable at rest but less than ordinary physical activity results in symptoms IV Symptoms with any degree of physical activity; may be present at rest Rubin LJ, et al. Chest. 2004;126:7S. 3
Cardiology and pulmonology consulted Furosemide started at 0.5 mg/kg/hr Dobutamine started at 2.5 mcg/kg/min Norepinephrine p started to maintain MAP > 65 Anticoagulation with heparin and warfarin per pharmacy Continue sildenafil and oxygen Consider transfer to UW (patient declined) Pharmacy consult for consideration of advanced therapy initiation Question Which of the following are drug targets for advanced PH therapy? A. camp B. cgmp C. Endothelin receptors D. All of the above Advanced Therapy Options Infused therapies Flolan (epoprostenol) Remodulin (treprostenil) Veletri (epoprostenol) Inhaled therapies Ventavis (iloprost) Tyvaso (treprostenil) Prostacyclin derivatives Oral therapies Adcirca (tadalafil) Letairis (ambrisentan) Revatio (sildenafil) Tracleer (bosentan) Phosphodiesterase type 5 inhibitors Endothelin receptor antagonists 4
What is the role for advanced therapy options? Directed at PH instead of underlying causes Group 1: most evidence for use Group 2: usually avoided Group 3: not recommended (may worsen V/Q mismatch and increase hypoxia) Group 4: may consider in functional class II, III, IV despite adequate primary therapy Group 5: currently being investigated Ryerson CJ, et al. Resp Research. 2010;11:12.; Galie N, et al. Eur Respir J. 2009;34:1219.; Barst RJ, et al. J Am Coll Cardiol. 2009;54:S78.;Bishop BM, et al. Pharmacotherapy. 2012;32(9):838. Advanced Therapy Options Infused therapies Flolan (epoprostenol) Remodulin (treprostenil) Veletri (epoprostenol) Inhaled therapies Ventavis (iloprost) Tyvaso (treprostenil) Oral therapies Adcirca (tadalafil) Letairis (ambrisentan) Revatio (sildenafil) Tracleer (bosentan) Prostacyclin Derivatives Pulmonary arterial vasodilation via smooth muscle relaxation via camp Inhibits smooth muscle cell growth Inhibits platelet aggregation Medication Route Annual Cost epoprostenol Flolan Continuous IV infusion $24,500 Veletri Continuous IV infusion $31,000 treprostenil Remodulin Continuous SQ infusion $31,000 Remodulin Continuous IV infusion $125,000 Tyvaso Inhalation QID while awake $180,000 iloprost Ventavis Inhalation 6-9 times daily while awake $54,000 Bishop BM, et al. Pharmacotherapy. 2012;32(9):838. 5
Advanced Oral Therapies Phosphodiesterase Type 5 Inhibitors Decrease metabolism of second messenger cgmp causing vascular smooth muscle dilation Endothelin-1 Receptor Antagonists Inhibits pulmonary arterial vasoconstriction and smooth muscle cell proliferation Available only through restricted distribution programs Medication Annual Cost sildenafil (Revatio ) $19,000 tadalafil (Adcirca ) $15,000 Medication Annual Cost bosentan (Tracleer ) $83,000 ambrisentan (Letairis ) $78,000 Bishop BM, et al. Pharmacotherapy. 2012;32(9):838. Neither Tyvaso or Ventavis were immediately available Possible to special order Ventavis but this would take several days Potential insurance issues for continuation post-discharge Flolan available onsite Used via continuous nebulization for ARDS Limited data on use of inhaled Flolan for PH MD hesitant to start continuous IV infusion Flolan as patient not candidate for outpatient therapy Buckley MS, Feldman JP. Pharmacotherapy. 2010;30(7):728. Decided to maximize dobutamine infusion, continue to diurese with furosemide, titrate O 2 to maintain SpO 2 88-92%, and wait for anticoagulation to decrease clot burden Repeat echocardiography: h Continued severe RA dilation with estimated PASP 50 mmhg Evidence of new LV systolic dysfunction with EF 40-45% and global hypokinesis 6
Conclusion Limited options for advanced PH therapy initiation in community setting due to high cost and restricted distribution of these agents Important to diurese, optimize inotropy, maintain adequate oxygenation, and provide anticoagulation Generally patients should be referred to specialty tertiary centers for further workup and management Questions? 7