intravenous epoprostenol adult inpatient clinical practice
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Intravenous Epoprostenol – Adult – Inpatient Clinical Practice Guideline
Table of Contents
EXECUTIVE SUMMARY ........................................................................................................... 2
DEFINITIONS ............................................................................................................................ 2
SCOPE ...................................................................................................................................... 4
METHODOLOGY ...................................................................................................................... 4
INTRODUCTION ....................................................................................................................... 5
RECOMMENDATIONS .............................................................................................................. 6
UW HEALTH IMPLEMENTATION ............................................................................................. 8
REFERENCES .......................................................................................................................... 9
CPG Contact for Changes: CPG Contact for Content: Name: Philip Trapskin, PharmD, BCPS Name: Cindy Gaston, PharmD, BCPS Phone Number: 608-263-1328 Phone Number: 608-265-8161 Email Address:[email protected] Email Address: [email protected]
Guideline Author: Matt Willenborg, PharmD, BCPS
Coordinating Team Members: C. Gaston, PharmD, BCPS
Review Individuals/Bodies: J. Runo, MD; D. Dalsing, MSN, RN; Anna Krupp, MSN, RN, CCRN; M. Pietruszka, PharmD,BCPS, AAHIVP, CNSC
Committee Approvals/Dates: Original approval date: October 2006 Pharmacy & Therapeutics Committee: September 2015
Release Date: September 2015
Next Review Date: September 2018
Note: Active Table of Contents -- Click to follow link
Copyright © 2015 University of Wisconsin Hospitals and Clinics AuthorityContact: Lee Vermeulen, [email protected] Last Revised: 09/[email protected]
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Executive SummaryGuideline Overview Intravenous (IV) epoprostenol is a high risk medication administered by continuous infusion for the treatment of idiopathic or heritable pulmonary arterial hypertension and pulmonary arterial hypertension associated with scleroderma spectrum of diseases. The purpose of this guideline is to provide recommendations for the proper utilization and monitoring of intravenous epoprostenol. This document provides guidance for drug-specific procedures related to inpatient handling and administration of intravenous epoprostenol and provides considerations related to admission and discharge procedures for patients receiving intravenous epoprostenol.
Definitions 1. Pulmonary arterial hypertension (PAH) is defined by a mean pulmonary artery pressure
>25 mm Hg; pulmonary capillary wedge pressure, left atrial pressure, or left ventricularend-diastolic pressure ≤ 15 mm Hg; and pulmonary vascular resistance > 3 Woodunits.1,2
2. Six minute walk distance (6MWD) is a quantitative value of the total distance a patient isable to walk in a six minute period. This test is used to evaluate changes in exercisecapacity.
3. World Health Organization Functional Class (WHO FC) is a means of classifying diseaseseverity in PAH developed by the World Health Organization and modified after the NewYork Heart Association functional classification according to level of function andassociated symptoms. Increasing WHO FC reflects more severe symptoms and greaterrestriction in activity.
Key Practice Recommendations 1. For treatment naive PAH patients with WHO FC III symptoms who have evidence of
rapid progression of their disease, or other markers of a poor clinical prognosis, considerinitial treatment with a parenteral prostanoid. More specifically in these patients: wesuggest continuous IV epoprostenol to improve functional class, improve 6MWD, andimprove cardiopulmonary hemodynamics. (Class I Level C)
2. For PAH patients in WHO FC III who have evidence of progression of their disease,and/or markers of poor clinical prognosis despite treatment with one or two classes oforal agents, consider the addition of a parenteral or inhaled prostanoid. Morespecifically in these patients: we suggest IV epoprostenol to improve WHO FC, improve6MWD, and improve cardiopulmonary hemodynamics. (Class I Level C)
3. For treatment naive PAH patients in WHO FC IV, consider initiation of monotherapy witha parenteral prostanoid agent. More specifically in these patients: we suggestcontinuous IV epoprostenol to improve WHO FC improve 6MWD, and improvecardiopulmonary hemodynamics. (Class I, Level C)
4. In PAH patients initiating therapy with IV epoprostenol, we recommend against theroutine simultaneous initiation of bosentan. (Class III, Level C)
5. In patients with congestive heart failure due to severe left ventricular systolic dysfunction(NHYA Class III/IV) the use of IV epoprostenol is not recommended due to lack ofbenefit. (Class III, Level C)
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Companion Documents 1. Inhaled Epoprostenol in Adult and Pediatric Patients Clinical Practice Guideline2. Intravenous Administration of Formulary Medications – Adult Clinical Practice Guideline
Pertinent UW Health Policies & Procedures 1. Nursing Policy 10.21 IV Epoprostenol Administration (Adult and Pediatric)2. Epoprostenol Pharmacy Operating Procedure3. Administrative Policy 8.17 Administration of Medications
Patient Resources 1. Health Facts for You - Pulmonary Hypertension Medications – prostacyclin analogs2. Health Facts for You – Pulmonary Hypertension
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Scope Intravenous epoprostenol dosing and management for patients with WHO FC III-IV pulmonary arterial hypertension newly initiated on intravenous epoprostenol during hospitalization and patients whose existing intravenous epoprostenol therapy is being continued during their hospital stay.
Intended Users: This document is intended to be used by physicians, advanced practice providers, registered nurses, and pharmacists involved with the care of patients receiving intravenous epoprostenol therapy.
Target Population: Patients with WHO FC III-IV pulmonary arterial hypertension who are being newly initiated on intravenous epoprostenol during hospitalization and patients whose existing epoprostenol therapy is being continued during their hospital stay.
Interventions and Practices Considered: This document focuses on the proper initiation and titration of intravenous epoprostenol in the hospital based on goal therapeutic parameters and titration-limiting side effects. This guideline also contains information related to transitioning a patient from their outpatient intravenous epoprostenol supply to inpatient epoprostenol.
Major Outcomes Considered: Patients receiving IV epoprostenol therapy should experience significant improvement in clinical symptoms of pulmonary arterial hypertension measured by improvement in WHO FC, improvement in exercise capacity measured with a 6MWD, and improvement of cardiopulmonary hemodynamics. Specific hemodynamic effects include increased cardiac index and stroke volume; and decreased pulmonary vascular resistance, total pulmonary resistance, mean systemic arterial pressure, and pulmonary artery pressure.3
Methodology A modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) developed by the American Heart Association and American College of Cardiology (Figure 1) has been used to assess the Quality and Strength of the Evidence in this Clinical Practice Guideline.4
A literature search was performed using the PUBMED database with search terms “epoprostenol”, “intravenous epoprostenol”, “pulmonary arterial hypertension”. Articles were included if they provided information on initiation of epoprostenol therapy, epoprostenol dosing,
administration and monitoring, and discharge considerations.
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Figure 1: Quality of Evidence and Strength of Recommendation Grading Matrix
Introduction Pulmonary arterial hypertension (PAH) is a progressive syndrome in which fibrotic and proliferative changes in pulmonary arteries lead to increased pulmonary vascular resistance, right heart failure, and eventual death.5-7 The incidence of PAH is 5-52 cases per million people.8 Patients left untreated have an estimated mean survival of 2.8 years from diagnosis. With treatment, current survival for patients with PAH is 85%, 68%, 57%, and 49% at 1, 3, 5, and 7 years from diagnosis, respectively.9,10
Epoprostenol, a potent vasodilator and platelet inhibitor, is used to treat symptoms, improve hemodynamics, and improve exercise capacity in patients with WHO FC III-IV PAH.11,12 Epoprostenol has also been shown to improve survival in patients with severe idiopathic PAH.12-
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The in-vivo half-life of IV epoprostenol is estimated to be 3-5 minutes. Epoprostenol should be administered intravenously via a continuous infusion through a dedicated central venous catheter.7 Any interruption of the infusion can lead to life-threatening hemodynamic compromise from rebound pulmonary arterial hypertension. To prevent interruptions, epoprostenol is administered via computerized ambulatory drug delivery (CADD) pumps on an outpatient basis which allow drug to be run for twenty-four hours without refilling the drug reservoir.15 Inpatient use of epoprostenol at the University of Wisconsin Hospital involves the use of standard hospital infusion pumps. Most complications with intravenous epoprostenol administration result from delivery system malfunctions.
These recommendations aim to assist in converting patients from their home infusion pumps to hospital supplies without interruption of the infusion. The guidelines also serve to aid in initiating and maintaining therapy in epoprostenol naive patients.
Recommendations 1. Qualifying for initiation of intravenous epoprostenol
1.1. For treatment naive PAH patients with WHO FC III symptoms who have evidence ofrapid progression of their disease, or other markers of a poor clinical prognosis, consider initial treatment with epoprostenol. 3,15 (Class I, Level B)
1.2. For PAH patients in WHO FC III who have evidence of progression of their disease, and/or markers of poor clinical prognosis despite treatment with one or two classes of oral agents, consider the addition of IV epoprostenol. 3,15 (Class I, Level B) For treatment naive PAH patients in WHO FC IV, consider initiation of monotherapy with a parenteral prostanoid agent. More specifically in these patients: we suggest continuous IV epoprostenol to improve WHO FC improve 6MWD, and improve cardiopulmonary hemodynamics. 3,15 (Class I, Level B)
1.2.1. A referral form for Veletri® is available at http://www.accredo.com/sitecore/media/Accredo/Referral%20Form%20PDFs/Veletri.pdf
1.2.2. The Advanced Pulmonary attending physician is responsible for submitting the referral prior to initiation of therapy. (Class I, Level C)
1.2.3. Complete insurance screening prior to admission to the hospital for initiation of therapy. (Class I, Level C)
1.2.4. Intravenous epoprostenol should not be used in the case of denial by Accredo Therapeutics after receiving the completed Pulmonary Arterial Hypertension Referral form for home epoprostenol therapy. (Class III, Level C)
2. In PAH patients initiating therapy with IV epoprostenol, routine simultaneous initiation ofbosentan is not recommended.3 (Class III, Level C)
3. In patients with congestive heart failure due to severe left ventricular systolic dysfunction(NHYA Class III/IV) the use of IV epoprostenol is not recommended due to lack of benefit.16
(Class III, Level C)
4. Continuation of outpatient IV epoprostenol therapy4.1. Patients admitted to UW Hospital on chronic epoprostenol IV therapy should continue
treatment with epoprostenol upon arrival to the inpatient care unit without interruption of the medication. (Class 1, Level C)
4.1.1. Due to the short half-life of IV epoprostenol (3-5 minutes), any interruption of continuous epoprostenol therapy can result in rapid onset of PAH symptoms causing dyspnea, decreased exercise tolerance, and right heart failure.
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4.1.2. Patients should be transitioned from the patient’s outpatient IV epoprostenol (Flolan® or Veletri®) via outpatient infusion pumps to UWHC epoprostenol (Veletri®) and infused using Alaris pumps. (Class I, Level C)
4.2. Hemodynamically stable patients may be treated outside of an intensive care in a patient care area with staff trained to manage IV epoprostenol (e.g., D6/5 IMC). This includes both stable dose and titration of dose (both increase and decrease) on D65 IMC. (Class IIb, Level C)
4.3. Patients receiving IV epoprostenol should be followed by the Advanced Pulmonary Service while hospitalized. The admitting service is responsible for notifying the Advanced Pulmonary Service of the patient’s admission and inpatient location. (Class I, Level C)
5. Dosing and titration of IV epoprostenol5.1. A reasonable starting dose for patients newly initiated on IV epoprostenol is 1-2
ng/kg/min.17-22 (Class I, Level B) 5.2. Titrate the dose as ordered by the Advanced Pulmonary Service prescriber until a
therapeutic dose is reached or until dose-limiting side effects occur (Table 2). (Class I, Level C)
5.2.1. If side effects occur, the Advanced Pulmonary Service prescribing clinician should be contacted. (Class I, Level C)
5.2.2. Increase the IV epoprostenol dose if PAH symptoms persist. Increase the infusion by 1-2 ng/kg/min at intervals sufficient to allow assessment of clinical response; these intervals should be no shorter than 15 minutes.17-19 (Class I, Level B)
Table 2: Common side effects of epoprostenol initiation and dose escalation17 (without regard to concomitant therapies)
Side Effect Patients (%)
Flushing 58
Headache 49
Nausea/vomiting 32
Hypotension 16
Anxiety, nervousness, agitation 11
Chest pain 11
Dizziness 8
Bradycardia 5
Abdominal pain 5
Musculoskeletal pain 3
Dyspnea, back pain 2
Sweating, dyspepsia, hypesthesia/paresthesia, tachycardia 1
5.3. When continuing home epoprostenol therapy as an inpatient, the patient’s epoprostenol specific dosing weight should be used for dosing IV epoprostenol regardless of actual body weight. All titration must be dosed based on epoprostenol specific dose weight. (Class I, Level C)
6. Patients on IV epoprostenol should be closely monitored6.1. Continuous evaluation of pulmonary function, including oxygen saturation and
increased dyspnea. (Class I, Level C)
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6.2. All patients on epoprostenol should have blood pressure, heart rate, and oxygen saturation recorded at least every 4 hours. (Class I, Level C)
6.3. Additional hemodynamic monitoring may be required for unstable patients and patients that are actively being titrated on epoprostenol (e.g., cardiac index, peripheral vascular resistance, total pulmonary resistance, mean pulmonary arterial pressure and stroke volume). (Class I, Level C) 6.3.1. Continuous monitoring for changes in non-respiratory PAH symptoms including
chest pain, fatigue, syncope and peripheral edema. (Class I, Level C) 6.3.2. Continuous monitoring for dose-limiting side effects including hypotension,
flushing, headache, nausea/vomiting and diarrhea. (Class I, Level C) 6.3.3. Systemic inflammatory response monitoring for catheter related infection.
6.4. Patients on IV epoprostenol therapy should be closely monitored for side effects. Patients most frequently experience side effects with initiation and escalation of epoprostenol dose. The most frequent side effects in this case are flushing, headache, nausea/vomiting and hypotension (Table 2). The most frequent side effects for patients on chronic therapy include jaw pain, flushing, headache, myalgias and diarrhea. Both IV epoprostenol preparations (Veletri® and Flolan®) have similar adverse effect profiles.23,24 (Class I, Level C)
UW Health Implementation
Potential Benefits/harms: - Adoption of a standardized guideline for intravenous epoprostenol infusion optimizes
patient safety and transitions of care.- Intravenous epoprostenol therapy provides improved patient survival, diminishes
symptoms of pulmonary arterial hypertension and improves patient quality of life forpatients with WHO Class III-IV pulmonary arterial hypertension.
- Abrupt discontinuation of epoprostenol therapy may result in worsening of pulmonaryarterial hypertension symptoms and could lead to significant hemodynamic compromiseand death.
- Intravenous line or catheter infections are possible with intravenous epoprostenolinfusion. Sepsis was reported at a rate of 0.3 infections per patient per year in patientsreceiving intravenous epoprostenol.16
- Improper transitions from a patient's home infusion pump to inpatient infusion pumpsmay lead to bolus administration of epoprostenol.
- Transitioning from outpatient epoprostenol therapy to inpatient epoprostenol therapymay require a change of epoprostenol concentration. Improper conversion could lead tooverdosage or underdosage.
Qualifying Statements The recommendations for selecting patients to be started on intravenous epoprostenol in the document represent current guideline recommendations. This guideline should be used in conjunction with the Epoprostenol Pharmacy Operating Procedure and Nursing Policy 10.21 IV Epoprostenol Administration (Adult and Pediatric). When evidence is absent or insufficient to provide evidence-based guideline recommendation statements, the best expert consensus statements were included.
Implementation Plan/Tools 1. Guideline will be housed on U-Connect in a dedicated folder for CPGs.
Copyright © 2015 University of Wisconsin Hospitals and Clinics AuthorityContact: Lee Vermeulen, [email protected] Last Revised: 09/[email protected]
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2. Links to this guideline will be updated and/or added in appropriate Health Link or equivalenttools, including:
3. Ordering IV epoprostenol in Health Link3.1. Enter order for IV epoprostenol 500 mcg/100 mL for epoprostenol naïve patients and
patients on chronic therapy with a low infusion rate. 3.2. A higher concentration 1500 mcg/100 mL can be considered for patients receiving
chronic outpatient therapy at a high infusion rate. 3.3. The dose of IV epoprostenol must be ordered in ng/kg/min. 3.4. Dosing of IV epoprostenol is based on the patient’s drug-specific weight and must be
documented in the administration instruction order. 3.5. The pharmacist will initially order two bags of IV epoprostenol. One for administration
and a back-up bag to be kept in the refrigerator. 3.5.1. An additional bag of IV epoprostenol will be maintained in the refrigerator on
the patient care area at all times. Refrigerated bags of epoprostenol (Veletri®) can be stored for up to 7 days and administered over 24 to 48 hours depending on the epoprostenol concentration.
3.5.2. Nursing staff will order additional epoprostenol bags in Health Link. The nurses will order a bag to ensure the next scheduled bag is prepared and on the unit approximately two hours prior to the anticipated hang time.
Disclaimer CPGs are described to assist clinicians by providing a framework for the evaluation and treatment of patients. This Clinical Practice Guideline outlines the preferred approach for most patients. It is not intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely establish the only appropriate approach to a problem.
References 1. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension.
J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.2. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of
epoprostenol therapy. Circulation. 2002;106(12):1477-1482.3. Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial
hypertension in adults: CHEST guideline and expert panel report. Chest. 2014;146(2):449-475.4. Jacobs AK, Kushner FG, Ettinger SM, et al. ACCF/AHA clinical practice guideline methodology
summit report: a report of the American College of Cardiology Foundation/American HeartAssociation Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(2):213-265.
5. Chin KM, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51(16):1527-1538.6. McGoon MD, Kane GC. Pulmonary hypertension: diagnosis and management. Mayo Clin Proc.
2009;84(2):191-207.7. 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 Forceon Expert Consensus Documents and the American Heart Association developed in collaborationwith the American College of Chest Physicians; American Thoracic Society, Inc.; and thePulmonary Hypertension Association. J Am Coll Cardiol. 2009;53(17):1573-1619.
8. Farber HW, Miller DP, Meltzer LA, McGoon MD. Treatment of patients with pulmonary arterialhypertension at the time of death or deterioration to functional class IV: insights from the REVEALRegistry. J Heart Lung Transplant. 2013;32(11):1114-1122.
9. Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator inpatients newly diagnosed with pulmonary arterial hypertension. Chest. 2012;141(2):354-362.
Copyright © 2015 University of Wisconsin Hospitals and Clinics AuthorityContact: Lee Vermeulen, [email protected] Last Revised: 09/[email protected]
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10. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-termsurvival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry.Chest. 2012;142(2):448-456.
11. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonaryhypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. AnnIntern Med. 2000;132(6):425-434.
12. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol(prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med.1996;334(5):296-301.
13. Barst RJ, Rubin LJ, Long WA, et al. Primary pulmonary hypertension study group. A comparisonof intravenous epoprostenol with conventional therapy for primary pulmonary hypertension. ThePrimary pulmonary hypertension study group. N Engl J Med. 1996;334:296-301.
14. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primarypulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4):780-788.
15. Veletri [package insert]. San Francisco , CA: Actelion Pharmaceuticals US, Inc; 2012. .16. Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy
for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST).Am Heart J. 1997;134(1):44-54.
17. Flolan (intavenous epoprostenol) [Package Insert]. GSK. March 2011.18. Oudiz RJ, Farber HW. Dosing considerations in the use of intravenous prostanoids in pulmonary
arterial hypertension: an experience-based review. Am Heart J. 2009;157(4):625-635.19. Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary
arterial hypertension. Respir Med. 2010;104(1):9-21.20. Strange G, Fowler R, Jary C, Dalton B, Stewart S, Gabbay E. Integrated care and optimal
management of pulmonary arterial hypertension. J Multidiscip Healthc. 2009;2:67-78.21. Agarwal R, Gomberg-Maitland M. Current therapeutics and practical management strategies for
pulmonary arterial hypertension. Am Heart J. 2011;162(2):201-213.22. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial
hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60-72.23. Chin KM, Badesch DB, Robbins IM, et al. Two formulations of epoprostenol sodium in the
treatment of pulmonary arterial hypertension: EPITOME-1 (epoprostenol for injection inpulmonary arterial hypertension), a phase IV, open-label, randomized study. Am Heart J.2014;167(2):218-225 e211.
24. Sitbon O, Delcroix M, Bergot E, et al. EPITOME-2: An open-label study assessing the transitionto a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension.Am Heart J. 2014;167(2):210-217.
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