Interprofessional Considerations in the Management of Pulmonary Arterial a Hypertension
Providing Continuing Education for Healthcare Professionals
Provided by ProCE, LLC and supported by an educational grant from Actelion Pharmaceuticals US, Inc., a Janssen Pharmaceutical Company of Johnson & Johnson. About the Faculty
James C. Coons, PharmD, FCCP, BCCP Dr. Jim Coons is an Associate Professor, Department of Pharmacy and Therapeutics, School of Pharmacy, at the University of Pittsburgh. He is also a clinical pharmacist specializing in cardiology at the University of Pittsburgh Medical Center (UPMC) Presbyterian Hospital. He maintains an active clinical practice in a cardiac intensive care unit as well as an advanced heart failure/pulmonary hypertension clinic. Dr. Coons has been active in the field of cardiovascular pharmacotherapy for 15 years. His clinical, research, and teaching activities focus on the management of patients with pulmonary hypertension, advanced heart failure, and acute coronary syndromes that undergo percutaneous coronary intervention. His research focuses on the clinical implementation of pharmacogenomics, comparative effectiveness and safety analyses, and the impact of novel technologies on student learning. In addition to his clinical and research responsibilities, Dr. Coons also serves as the program director for the PGY-2 cardiology pharmacy residency at UPMC. He also serves as an expert advisor and helps to lead cardiovascular medication initiatives and policies for UPMC, an integrated delivery network comprising 25 hospitals.
Martha Kingman, DNP, FNP-C Martha Kingman Liberty is a Family Nurse Practitioner in the pulmonary hypertension clinic at the University of Texas Southwestern Medical Center at Dallas. She is presently serving as sub-investigator in pulmonary hypertension clinical trials, and serves on several pulmonary hypertension advisory boards and steering committees. Martha is an active member of the PH Professional Network, currently Chair of the symposium planning committee and executive board member. She recently served on the Editorial Board of Advances in Pulmonary Hypertension. In 2000, she obtained her Master of Science in Nursing degree from Texas Woman’s University in Dallas. She accepted the job of nurse practitioner in the pulmonary hypertension program at UTSW Medical Center and remains in that role today. In May 2011 she obtained her Doctorate in Nursing Practice from Texas Christian University. The majority of her clinical work involves the follow-up outpatient care of a large group of pulmonary hypertension patients at UTSW Medical Center. Martha has 21 pulmonary hypertension publications and has spoken at local, national, and international conferences.
About the Faculty (continued)
Vallerie V. McLaughlin, MD, FACC, FAHA, FCCP Vallerie V. McLaughlin, MD, is the Kim A. Eagle, MD, Endowed Professor of Cardiovascular Medicine, Associate Chief Clinical Officer for Cardiovascular Services of the UMMG, Director of the Pulmonary Hypertension (PH) Program, and Associate Chief of Cardiovascular Medicine at the University of Michigan, Ann Arbor, Michigan. She is a Fellow of the American College of Cardiology, the American College of Chest Physicians and the American Heart Association, and is a member of the American Thoracic Society. She has served as Chair of the American Heart Association “Women in Cardiology” Committee, Chair of the American College of Cardiology/American Heart Association Clinical Expert Consensus Document on PH, member of the American College of Cardiology Scientific Sessions Program Committee, and member of the Scientific Committee for the World Symposium on Pulmonary Hypertension 2008, 2013, and 2018. Professor McLaughlin is a past Chair of the Scientific Leadership Council of the Pulmonary Hypertension Association, past Editor-in-Chief of Advances in Pulmonary Hypertension and past Chair of the Pulmonary Hypertension Association Board of Trustees. She was inaugurated as a charter member into the Clinical Excellence Society at the University of Michigan and is a founding member of the World Symposia on Pulmonary Hypertension Association. Her research interests focus on PH. Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
Interprofessional Considerations in the Management of Pulmonary Arterial a Hypertension
Providing Continuing Education for Healthcare Professionals
Provided by ProCE, LLC and supported by an educational grant from Actelion Pharmaceuticals US, Inc., a Janssen Pharmaceutical Company of Johnson & Johnson.
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Interprofessional Considerations in the Management of Pulmonary Arterial a Hypertension
Providing Continuing Education for Healthcare Professionals
Provided by ProCE, LLC and supported by an educational grant from Actelion Pharmaceuticals US, Inc., a Janssen Pharmaceutical Company of Johnson & Johnson.
ProCE, LLC www.ProCE.com 3 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
CME/CE Activity Information & Accreditation
ACPE Credit Designation (Pharmacist CE) ProCE, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE Universal Activity Number 0221-0000-21-017-L01-P has been assigned to this live knowledge-based activity (initial release date 3-4-21). This activity is approved for 1.25 contact hours (0.125 CEU) in states that recognize ACPE providers. The activity is provided at no cost to participants. Participants must complete the online post-test and activity evaluation within 30 days of the activity to receive pharmacy CE credit. No partial credit will be given. Statements of completion will be issued online at www.ProCE.com, and proof of completion will be posted in NABP CPE Monitor profiles. Joint Accreditation Statement In support of improving patient care, this activity has been planned and implemented by ProCE, LLC and Clinical Care Options, LLC (CCO). Clinical Care Options, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physician Continuing Medical Education CCO designates this live activity for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nursing Continuing Education The maximum number of hours awarded for this Continuing Nursing Education activity is 1.25 contact hours. AAPA Credit Designation Clinical Care Options, LLC has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.25 AAPA Category 1 CME credits. PAs should only claim credit commensurate with the extent of their participation.
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CME/CE Activity Information & Accreditation (continued) Target Audience: The target audience for this activity includes pharmacists, nurses, physicians and physician assistants.
Learning Objectives: At the conclusion of this activity, learners should be able to: • Examine the underlying pathogenic pathways, progression, and presentation of pulmonary arterial hypertension (PAH) • Compare and contrast current and emerging PAH treatments by mode of delivery, mechanism of action, adverse effects, and monitoring parameters • Discuss strategies to manage iatrogenic and progression-related scenarios to improve quality of life for PAH patients
Funding: This activity is supported by an educational grant from Actelion Pharmaceuticals US, Inc., a Janssen Pharmaceutical Company of Johnson & Johnson.
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Disclosures It is the policy of ProCE, LLC to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants any significant financial interest or affiliation with companies that manufacture or market products discussed during their presentation.
Clinical Care Options, LLC (CCO) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any relevant conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to CCO policy. CCO is committed to providing its learners with high-quality CME/CE activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.
The faculty and planners reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity:
‣ Dr. Coons has conducted contracted research for Pfizer and United Therapeutics; received consulting fees from Alnylam and Bristol Myers Squibb. ‣ Dr. Kingman has received consulting fees from Actelion/J&J, Bayer, and United Therapeutics. ‣ Dr. McLaughlin has conducted contracted research for and received consulting fees from Acceleron, Actelion, and United Therapeutics; received consulting fees from Altavant, Caremark, CiVi Biopharma, Gossamer Bio, and Liquidia ; conducted contracted research for Reata and Sonavie. ‣ Mr. Thibodeau does not have any relevant conflicts of interest to report. ‣ CCO and ProCE Staff have no relevant conflicts of interest to report.
9 Potential conflicts of interest were resolved with a peer review process provided by Daniel Thibodeau, MHP, PA-C, DFAAPA.
Disclosures (continued) Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
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ProCE, LLC www.ProCE.com 5 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
Faculty
James C. Coons, PharmD, FCCP, BCCP Martha Kingman, DNP, FNP-C Associate Professor Nurse Practitioner University of Pittsburgh School of Pharmacy Pulmonary Hypertension Program Clinical Pharmacist, Cardiology University of Texas Southwestern Medical Center at Dallas University of Pittsburgh Medical Center-Presbyterian Hospital Dallas, Texas PGY2 Cardiology Residency Program Director Pittsburgh, Pennsylvania
Vallerie V. McLaughlin, MD, FACC, FAHA, FCCP Kim A. Eagle, MD Endowed Professor of Cardiovascular Medicine Associate Chief Clinical Officer, Cardiovascular Services, UMMG Associate Chief, Cardiovascular Medicine Director, Pulmonary Hypertension Program University of Michigan Ann Arbor, Michigan
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Pulmonary Hypertension: Sorting out the Cause
Vallerie V. McLaughlin, MD, FACC, FAHA, FCCP
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ProCE, LLC www.ProCE.com 6 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
Audience What is the most common presenting Response symptom of pulmonary hypertension?
A. Syncope B. Chest Pain C. Dyspnea D.Lower extremity edema E. Cough
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Audience The diagnostic work up for PAH includes all Response of the following tests except:
A. Echocardiogram B. Ventilation Perfusion Scan C. Right Heart Catheterization D.Left Heart Catheterization E. PFT’s
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6th World Symposium on PH: Proposed Hemodynamic Definition of PH/PAH
Definitions Characteristics Clinical Groups mPAP >20 mmHg Pre-capillary PH PAWP ⩽15 mmHg 1, 3, 4, 5 PVR ⩾3WU mPAP >20 mmHg Isolated post- PAWP >15 mmHg 2, 5 capillary PH PVR <3 WU Combined pre- mPAP >20 mmHg and post-capillary PAWP >15 mmHg 2, 5 PH PVR ⩾3WU
15 Adapted from Simonneau G et al. Eur Resp J. 2019; 53: 1801913 [https://doi.org/10.1183/13993003.01913-2018.
Pulmonary arterial hypertension: a rare, but not an orphan, disease
. Rare: prevalence 15–50/million (incidence 6/million/year) . Pathophysiology: pulmonary artery endothelial cell dysfunction . Drugs: 14 agents approved in the last 25 years (orphan drug status) . Lung/heart–lung transplantation: if refractory to medical therapy
PGI2: -
NO: - ET-1: +
SMCs
Endothelial cell
16 Adapted from: Humbert M et al. Circulation 2014
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Mechanisms of Action of Approved Therapies for PAH Endothelin Prostacyclin Pathway Nitric Oxide Pathway Endothelial cells Pathway Endothelial cells Pre-proendothelin Proendothelin Arachidonic Prostaglandin I acid 2
L-arginine L-citrulline IP receptor agonists Prostacyclin Endothelin-1 Endothelin (prostaglandin I2) receptor A Endothelin receptor B Nitric Oxide Prostacyclin Exogenous cAMP derivatives nitric oxide Endothelin- Vasodilation cGMP and antiproliferation Vasoconstriction sGC stimulator receptor Phosphodiesterase and proliferation antagonists type 5 Vasodilation and antiproliferation Phosphodiesterase Smooth muscle cells type 5 inhibitor
Smooth muscle cells
17 Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.
Video #1
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ProCE, LLC www.ProCE.com 9 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
Common Symptoms of PAH
REVEAL = Registry to Evaluate Early And Long-term PAH disease management. US-based observational registry involving 54 academic and community-based treatment centers. 2967 patients enrolled between March 2006 and September 2007; 2525 patients met the hemodynamic Criterial for PAH. 32 of these patients were excluded from this analysis due to a missing date of PAH symptom onset, leaving final study population of this cohort analysis of 2493 patients
Adapted from Rich S et al. Ann Intern Med, 1987; 107:216-223. 19 Adapted fromBrown LM et al. Chest, 2011; 140:19-26.
ACCF/AHA Diagnostic Algorithm
20 Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
ProCE, LLC www.ProCE.com 10 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
History and Physical Exam Findings Are Insensitive Unless Advanced Disease/RV Failure Present History Exam (PH) Exam (RV Failure) • Dyspnea (86%) • Loud P2 • JVD; increased A • Fatigue (27%) • RV lift wave, V wave; hepatojugular reflex • Chest pain (22%) • Systolic murmur (TR; • RV S3, S4 • Edema (22%) inspiratory augmentation) • Pulsatile liver • Syncope (17%) • Early systolic click • Hepatomegaly • Dizziness (15%) • Midsystolic ejection murmur • Edema • Cough (14%) • Diastolic murmur (PR) • Ascites • Palpitations (13%) • Low BP, low PP, cool extremities
REVEAL. Brown LM et al. Chest. 2011;140:19-26. 21 Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Case: Electrocardiogram
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Signs of PAH on Chest X-ray
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Checklist for Echocardiographic Assessments When PH Is Suspected
. Estimate pulmonary artery systolic pressure . Evaluate severity of TR . Evaluate right heart size and function . Exclude left heart valvular disease and systolic dysfunction . Exclude congenital heart disease . Differentiate PAH from PH due to LHD . Estimate RA pressure . Evaluate for pericardial effusion
24 Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2015;65:1976-1997.
ProCE, LLC www.ProCE.com 12 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
Echocardiographic Characteristics of PAH
Apical 4-chamber view
LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
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Echocardiographic Findings That Help Differentiate PAH From PH Due to LHD
PAH Parameter PH Due to LHD Enlarged RV size May be enlarged Small LA size Large Increased RA/LA size ratio Normal (LA>RA) Bows from right Interatrial Bows from left to to left septum right Common RVOT notching Rare <<1 E/A ratio >1 Normal Lateral e’ Decreased <8 Lateral E/e’ >10
26 Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2015;65:1976-1997.
ProCE, LLC www.ProCE.com 13 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
Pulmonary Function Testing in PAH
. To exclude/characterize underlying airway or parenchymal disease . Decreased DLco and mild-to-moderate reduction in lung volumes common in PAH . DLco • Reduction in DLco in a patient with scleroderma and normal lung volumes is suggestive of PAH . It is recommended that SSc patients should have annual PFTs in additions to annuals echocardiogram
3/2/2021
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V/Q Scan to Exclude Chronic Thromboembolic Pulmonary Hypertension (CTEPH) . V/Q scan should be performed to exclude CTEPH . >1 segmental-sized or larger mismatched perfusion defects seen with CTEPH . Normal V/Q scan rules out CTEPH
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Blood Tests to Detect Potential Underlying Disease in PAH
. Antinuclear antibody (ANA) . Antiphospholipid antibodies • Lupus anticoagulant, anticardiolipin antibodies . HIV serology . CBC with platelets . Liver function test . Thyroid function test . Hemoglobin electrophoresis, if indicated
Barst RJ et al. J Am Coll Cardiol. 2004; 43(1Suppl):40S-47S. 29 ESC/ERS Task Force. Eur Heart J, 2009; 30:2493-2537.
Functional Capacity: 6- Minute Walk Test
. Helps to determine baseline prognosis and assess response to treatment and/or disease progression. . Simple, inexpensive, reproducible, and well standardized. . Measured distance patient can walk on a flat, hard surface in 6 minutes. . Patient area asked to cover as much ground as they can in 6 minutes. Patient can stop/rest during test but the clock keeps running.
McGoon M et al. Chest, 2004; 126(1 Suppl):14S-34S. ATS Committee on Proficiency on Proficiency Standards for 30 Clinical Pulmonary Function Laboratories. Am J Respir Crit Care Med, 2002;166:111-117.
ProCE, LLC www.ProCE.com 15 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
Diagnosis of PAH Requires Right Heart Catheterization
RIGHT HEART ESSENTIAL COMPONENTS OF INVASIVE CATHETERIZATION HEMODYNAMIC ASSESSMENT
• Required to confirm diagnosis, • O2 Saturations (SVC, IVC, RV, PA, SA) calculate resistance, guide • RAP therapy • PAP, Systolic, diastolic, mean • Excludes other etiologies of PH — Intracardiac or extracardiac • PAWP, or LVEDP shunts • CO/CI — Left-heart-disease • PVR • Measures degree of right-heart dysfunction • Vasodilator challenge should be performed — RAP in patients with idiopathic, heritable, and — CO PAH associated with drugs and toxins.
McGoon M et al. Chest, 2004; 126:14S-34S. McLaughlin VV et al. J Am Coll Cardiol, 2009; 53:1573-1619. 31 Galiè N et al. EurRespirJ. 2019 Jan 24;53(1).
Summary
. High index of suspicion-multiple causes of pulmonary hypertension . Thorough diagnostic evaluation . Exclude thromboembolic disease . Evaluate potential causes/contributing issues . RHC required prior to initiating PAH therapy . Baseline functional evaluation . Integrate diagnostic data for final diagnosis and risk assessment
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ProCE, LLC www.ProCE.com 16 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
James C. Coons, PharmD, FCCP, BCCP
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Pharmacotherapy Timeline
1980 1960-1980 Oral anticoagulants, 1995 2001 Empiric/various calcium channel vasodilators blockers, lung/heart Epoprostenol Bosentan transplantation
2004 2002 2005 2007 Treprostinil IV, Treprostinil SQ Sildenafil Ambrisentan iloprost
2013 2009 2010 Riociguat, Tadalafil, 2015 Thermostable macitentan, treprostinil epoprostenol treprostinil Selexipag inhaled oral
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ProCE, LLC www.ProCE.com 17 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
Treatment Guidelines: General Approach
35 Eur Heart J 2019;53:1801889.
Acute Vasoreactivity Testing
• Typically used for patients with idiopathic, heritable, or drug-induced PAH • Favorable response:
Reduction of mean PAP ≥ 10 mm Medication Dosage Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or Amlodipine 20 - 30 mg/day increased CO by means of an acute pulmonary vasodilator Nifedipine 180 - 240 mg/day challenge using either inhaled nitric oxide, IV epoprostenol, or Diltiazem 720 – 960 mg/day IV adenosine • Positive response in <10% of patients with idiopathic PAH
J Am Coll Cardiol 2009;54:S78-84. Am Heart J 2011;162:201-13. 36 Circulation 2005;111:3105-11.
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Long-term Response to Calcium Channel Blockers
• WHO FC I/II with sustained hemodynamic improvement (same or better than with acute testing) after ≥ 1 year on CCB therapy only • These patients are recognized as a distinct clinical phenotype
37 Eur Heart J 2019;53:1801913.
Oral Therapies
• Phosphodiesterase type-5 (PDE-5) Inhibitors
• Endothelin receptor antagonists (ERAs)
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ProCE, LLC www.ProCE.com 19 Interprofessional Considerations in the Management of Pulmonary Arterial Hypertension
PDE-5 Inhibitors
Medication Indication Dosing Improves exercise 20 mg PO tid Sildenafil ability in early (Revatio®) 10 mg IV tid (short-term use in stage PAH patients unable to take PO) 40 mg PO daily – Initiate 20 mg if renal/hepatic Tadalafil Improves exercise impairment or concurrent (Adcirca®) ability ritonavir – Avoid if CrCL <30 mL/min
tid = three times daily; PO = by mouth; CrCL = creatinine clearance. Revatio [package insert]. New York, NY: Pfizer Labs; 2014. 39 Adcirca [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015.
Endothelin Receptor Antagonists Pharmacologic Properties and Other Medication Indication Dosing Special Considerations
Improves exercise - Dual antagonist of ET-1A & 1B receptors 62.5 mg PO bid, Bosentan ability and decrease ® then 125 mg PO - Tracleer and Bosentan Access Programs (Tracleer®) rate of clinical bid after (REMS: LFTs at baseline and monthly; worsening in WHO 4 weeks pregnancy testing at baseline and FC III-IV monthly) - Selective ET-1 antagonist Ambrisentan A WHO FC II-III 10 mg PO daily ® (Letairis®) -Letairisand Ambrisentan Access Programs (REMS: pregnancy testing at baseline and monthly) - Tissue selective - Lipophilic Macitentan Delays progression 10 mg PO daily - Dual antagonist of ET-1A & 1B receptors (Opsumit®) of PAH -Opsumit® Access Program (REMS: pregnancy testing at baseline and monthly)
bid = twice daily; REMS = risk evaluation and mitigation strategy; Hb = hemoglobin; LFTs = liver function tests; Hb=hemoglobin. 40 Tracleer [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2016. Letairis [package insert]. Foster City, CA: Gilead Sciences; 2015. Opsumit [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2016.
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Audience Which statement regarding the prostacyclin and Response selective IP receptor agonist classes is most accurate?
A. Iloprost is an oral prostacyclin B. Treprostinil is available in multiple formulations C. There is no maximum dose of selexipag D.Treprostinil diolamine is only given twice daily
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Prostacyclins
. Epoprostenol
. Treprostinil
. Iloprost
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Parenteral Prostacyclins
Pharmacologic Properties and Other Special Medication Indication Dosing Considerations - Half-life 4-6 minutes - Back-up cassette/pump 2 ng/kg/min titrated to - Protect from light Epoprostenol IV WHO FC dose-limiting - Ice pack (Flolan® only) (Flolan®, Veletri®) III-IV adverse effects - Requires reconstitution and further dilution (usual range, (0.9% saline or sterile water: Veletri®; sterile 20-40 ng/kg/min) diluent or pH 12 sterile diluent: Flolan®) - Every 24-hour cassette change WHO FC - Half-life 4 hours Treprostinil SC II-IV - Back-up pump (Remodulin®) 1.25 ng/kg/min titrated to - Stable at room temperature dose-limiting - SQ: Undiluted, every 72-hour syringe change adverse effects - IV: Requires further dilution, every Treprostinil IV WHO FC (usual range, 48-hour cassette change (Remodulin®) II-IV 40-80 ng/kg/min) - High pH diluent associated with lower risk of bloodstream infections
Flolan [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2016. Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2014. Veletri [package insert]. 43 South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2016. Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2014. CHEST 2012; 141(1):36–42.
Inhaled Prostacyclins
Medication Indication Dosing Other Special Considerations
2.5-5 mcg - Only administered via I-neb® given AAD® System Iloprost WHO FC 6 to 9 times - Use higher concentration ampule (Ventavis®) III-IV per day (20 mcg/mL) for patients with (maximum, 45 extended treatment time or at 5- mcg/d) mcg dose
-3 breaths QID Increases -Titrate by Treprostinil walk 3 breaths - Only administered via Tyvaso® (Tyvaso®) distance in every Inhalation System WHO FC III 1-2 weeks up to 9 breaths QID
QID = four times daily. Ventavis [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2013. 44 Tyvaso [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2016.
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Newer Oral Therapies
. Riociguat (Adempas®)
. Oral treprostinil diolamine extended release (Orenitram®)
. Selexipag (Uptravi®)
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Riociguat
. Soluble guanylate cyclase (sGC) stimulator . Nitric oxide (NO) binds to sGC . sGC catalyzes synthesis of cyclic guanosine monophosphate (cGMP) . cGMP signaling influences vascular tone, proliferation, fibrosis, and inflammation . Riociguat has a dual mechanism: • Sensitizes sGC to NO • Directly stimulates sGC, independent of NO
46 Adempas [package insert]. Whippany, NJ: Bayer Healthcare Pharmaceuticals Inc; 2017.
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Riociguat (cont’d)
. Indicated to improve exercise capacity, WHO FC, and delay clinical worsening in patients with: • PAH • Persistent/recurrent chronic thromboembolic pulmonary hypertension (after surgery or for inoperable disease) . Initiate 1 mg PO tid, titrate in 0.5-mg increments every 2 weeks up to 2.5 mg PO tid • Start 0.5 mg PO tid if risk for hypotension or with concomitant strong CYP and P-gp inhibitors • Avoid if CrCL <15 mL/min or if on hemodialysis . Adempas® REMS program (teratogenicity)
CYP = cytochrome P450; P-gp = p-glycoprotein. Adempas [package insert]. Whippany, NJ: Bayer Healthcare Pharmaceuticals Inc; 2017. 47
Treprostinil Diolamine Extended Release
. First oral prostacyclin . Approved to delay disease progression and to improve exercise capacity . Initiate 0.125 mg PO tid or 0.25 mg PO bid with food . Titrate by 0.125 mg tid or by 0.25 mg bid, every 3 to 4 days or longer . Three-times daily dosing preferred due to tolerability . Carefully selected, lower-risk patients may be considered for transition from parenteral or inhaled therapy to oral treprostinil
Orenitram [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2016. Circulation 2013;127:624-33. Chest 2013;144:952-8. J Heart Lung Transplant 48 2017;36:193-201. Am J Respir Crit Care Med 2019;DOI: 10.1164/rccm.201908-1640OC.
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Selexipag
. Selective IP receptor agonist . Type of prostanoid receptor found in lungs (regulates vascular tone, platelet activity, immunologic responses) . Similar mode of action to prostacyclin, but a non-prostanoid . Approved to delay disease progression and reduce risk of hospitalization for PAH . Initiate 200 mcg PO bid and up-titrate weekly as tolerated to maximum of 1600 mcg PO bid
49 Uptravi [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2015. N Engl J Med 2015;373:2522-33.
Adverse Reactions
Medication/Class Adverse Effects
Headache, dyspepsia, flushing, epistaxis, insomnia, PDE5i hypotension, visual changes Headache, dizziness, dyspepsia, gastroesophageal reflux, Riociguat nausea, diarrhea, vomiting, hypotension, anemia, constipation, teratogenicity
Headache, flushing, peripheral edema, nasal congestion, ERAs sinusitis, transaminitis, liver injury, anemia, teratogenicity
Nausea, vomiting, diarrhea, flushing, jaw pain, headache, Prostacyclins rash, erythema, hypotension, leg pain – Inhaled: Cough, throat irritation Headache, diarrhea, jaw pain, nausea, myalgia, vomiting, Selexipag extremity pain, flushing
PDE5i = phosphodiesterase-5 inhibitor; ERA = endothelin receptor antagonist. 50 Eur Heart J 2016;37:67-119.
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Audience Which medication is most likely to interact Response with a PDE5 inhibitor?
A. Gemfibrozil B. Glyburide C. Clopidogrel D.Isosorbide
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Drug Interactions
Medication/Class Interactions
Strong CYP3A4 inhibitors/inducers, nitrates, PDE5i alpha-blockers, alcohol Strong CYP and P-gp inhibitors/inducers, PDE5is, Riociguat non-specific PDE inhibitors (eg, theophylline, dipyridamole), nitrates, antacids, smoking Strong CYP3A4 and CYP2C19 inhibitors/inducers, ERAs warfarin, oral contraceptives – Bosentan: Cyclosporine, glyburide Prostacyclins Vasodilators, antiplatelets, anticoagulants – Treprostinil: Gemfibrozil, rifampin Selexipag Strong CYP2C8 inhibitors, clopidogrel
CYP = cytochrome P450; P-gp = p-glycoprotein. 52 Eur Heart J 2016;37:67-119.
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Affordability/Accessibility
. Annual medication costs: • PDE5 inhibitors: $10,000-$15,000 • ERAs: $50,000-$60,000 • Prostacyclins: $95,000-$200,000
. Seeking prior authorization . Addressing high co-pays & uninsured . Collaboration with specialty pharmacies
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Video #2
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Treatment Guidelines
55 Eur Heart J 2019;53:1801889.
Initial Combination Therapy
Class and Level of Recommendation Treatment WHO FC II WHO FC III WHO FC IV Ambrisentan + tadalafil IB IB IIb, C Other ERA + PDE5i IIa, C IIa, C IIb, C Bosentan + sildenafil + IV IIa, C IIa, C epoprostenol Bosentan + IV IIa, C IIa, C epoprostenol Other ERA or PDE5i + SC IIb, C IIb, C treprostinil Other ERA or PDE5i + IIb, C IIb, C other IV prostacyclin analogues
Eur Heart J 2015;46:903-975. 56 Eur Heart J 2019;53:1801889.
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Residual Role for Initial Monotherapy
. Long-term response to CCBs . Long-term-treated patients with stable, low-risk profile on monotherapy . IPAH and > 75 yrs old with multiple risk factors for HFpEF . Suspected PVOD or PCH . HIV, portal hypertension, or uncorrected congenital heart disease . Mild disease (WHO FC I, PVR 3-4 WU, mPAP < 30 mm Hg, normal RV) . Combination therapy not available or contraindicated
57 Eur Heart J 2015;46:903-975.
Treatment Guidelines
58 Eur Heart J 2019;53:1801889.
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Sequential Therapy
. Combinations with most evidence • Macitentan and sildenafil • Riociguat and bosentan • Selexipag and ERA and/or PDE5i
. Consider prostacyclins
Eur Respir J 2019;53:1801889. N Engl J Med 2013;369:330-40. 59 N Engl J Med 2013;369:809-18. N Engl J Med 2015;373:2522-33.
Summary Points
• Multiple drug options target different pathways and are used in combination to improve outcome for patients with PAH • Guidelines direct treatment approach based on multiparametric risk stratification • Treatment escalation is critical for patients not achieving low-risk status
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Martha Kingman, DNP, FNP-C
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Methods to Improve Quality of Life in PAH
- Careful Medication Titration - Side Effect Management - Management of central line infections
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Video #3
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Prostacyclin Side Effects
• Jaw pain • Headache • Flushing/erythema • Nausea • Diarrhea • Anorexia • Thrombocytopenia
Complications of Delivery system: • Line sepsis • Epoprostenol: Interruption (3 -6 min)
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Treprostinil (Remodulin®) Pump Options Intravenous Subcutaneous
CADD-Legacy
CADD-MS 3 Awaiting FDA approval: Implantable pump for treprostinil
CADD-MS is a trademark and CADD-Legacy is a registered trademark 65 of Smiths Medical System. Cane Crono Five is manufactured by Canè Medical Technology.
Audience All the following are important key concepts Response when titrating prostacyclin therapies except:
A. Side effects are more common during the titration phase B. Patient education is key due to complex titration schemes C. Selexipag titrated to highest tolerated dose or 1600mcg BID D.The faster you can reach a high dose the better E. Dosing is individualized for IV and SQ
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Goal of Continuous Infusion Dosing
Possible Dose Adjustments Over Time • No set dose No set dose
Dosing individualized
Titrate to optimize dose while minimizing side effects • Dosing individualized based on the patient
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Managing Side Effects of Prostacyclin Pathway Therapies – Dosing and Titration
. Initiated at low doses and up-titrated slowly, as tolerated, until a maintenance dose is achieved1 . Side effects more common during the titration phase than in maintenance phase2 . Patient education of potential side effects is very important . Most patients find the symptomatic benefit received is worth the side effects . Patients receiving prostacyclin therapies have shown improvement in QoL3
1. McLaughlin VV, Palevsky HI. Parenteral and inhaled prostanoid therapy in the treatment of pulmonary arterial hypertension. Clin Chest Med. 2013;34(4):825-40. 2. Skoro-Sajer N, Lang IM. Selexipag for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother.2014;15(3):429-36 68 3. O’Connell C, Amar D, Boucly A, et al. Comparative safety and tolerability of prostacyclins in pulmonary hypertension. Drug Saf. 2016;39(4):287-94
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Case
• Patient was discharged from the hospital on 6ng/kg/amin of IV epoprostenol with a schedule to: ─ Increase by 1ng/kg/min every 3 days to goal of 20ng/kg/min ─ Once she reached 10ng/kg/min she contacted the office with complaints of mild nausea and diarrhea. ─ Ondansetron was prescribed for nausea and patient advised to use Imodium for diarrhea. Follow up telehealth appointment in 3 days to re-assess.
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Managing GI side effects when using prostacyclins
Side Intervention Side Effect Intervention Effect Nausea/Vomiting Take with food, eat small frequent meals, Diarrhea ginger based foods (ginger ale) Loperamide Anti-emetics: Ondansetron Slow up titration of PC or decrease For inhaled therapies, swish and spit after each treatment session, temporarily dose decrease by 1 breath 4 times a day Dietary changes: increase fiber, gluten Rule out pregnancy free, low fat, BRAT diet Refer to gastroenterologist Probiotic Slow titration or decrease dose Loss of Appetite/Weight Dietary consult Rule out other causes, such as C. Loss Increase caloric content, small frequent difficile meals, nutritional supplement Refer to GI Evaluate for other metabolic causes of weight loss
Kingman M, Archer-Chicko C, Bartlett M, et al. Management of Prostacyclin Side Effects in Adult Patients with Pulmonary Arterial Hypertension. Pulmonary 70 Therapy, 2017; submitted
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Managing Prostacyclin Associated Pain
Side Effect Intervention Consideration/Rationale
Leg Pain Screen for iron deficiency. Gabapentin Decreased RBC oxygen carrying capacity, may be a more successful analgesic for with reduced circulation in lower leg pain extremities
Jaw Pain Usually no interventions needed. Not a dose limiting side effect, loss of jaw Reassure patient that this will get better pain may indicate need for up-titration with time
Take slow bites or sips of water, suck on Jaw pain is intermittent and generally saltine cracker or hard candy, chew gum occurs with first bite of the meal before eating
Kingman M, Archer-Chicko C, Bartlett M, et al. Management of Prostacyclin Side Effects in Adult Patients with 71 Pulmonary Arterial Hypertension. Pulmonary Therapy, 2017; submitted
Case
• Telehealth visit revealed patient feeling better but still had worsened nausea after increasing to 12ng/kg/min. • Plan: Dose reduced to 10ng/kg/min and held there for one week with change in titration schedule to increase by 1n/kg/min every 6 days, rather than every 3 days and continue to goal of 20nng/kg/min.
• Patient called 2 weeks later to report doing well on this new approach with only occasional use of anti-emetics.
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Case
. Patient reached her goal of 20ng/kg/min and was feeling better. 3 months later she called the office with fever of 101.6 and advised to go to the emergency room for possible central line infection.
. Upon arrival to the ED, blood cultures are drawn, and the pulmonary hypertension expert is contacted to admit patient. Her central line is removed and a PICC line is placed for her Veletri and IV antibiotics.
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Audience All the following are true regarding prevention Response and treatment of central line infections except:
A. Use a cuffed and tunneled central venous catheter B. Apply antibiotic ointment to the insertion site C. Neg blood culture required before placing a new central line D.Do not use a clear the line approach E. Never infuse anything in the prostacyclin line
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Managing Central line Catheter Infections
. Use a cuffed and tunneled central venous catheter . Remove catheter if bacterial infection is documented/ suspected • Do not use “clear the line” approach • Place a PICC line to use for IV prostacyclin and as well as a lumen for IV antibiotics • Once patient stable, they can be discharged to finish IV antibiotics at home . Do not use topical antibiotics or creams on insertion sites • Once repeat blood cultures are negative, new central line can be placed . Complete guidelines available at: www.phassociation.org
Doran AK, Ivy DD, Barst RJ, et al. Guidelines for the prevention of central venous catheter-related blood stream infections with prostanoid therapy for 75 pulmonary arterial hypertension. Int J Clin Pract Suppl. 2008;160:5-9.
Conclusions
• PAH is a disease characterized by vascular proliferation, and vasoconstriction, leading to right ventricular failure.
• The revised treatment algorithm includes regular risk-assessment and early referral to an expert PH center.
• Endothelin, prostacyclin and nitric oxide are thought to be key mediators in PAH with14 FDA approved therapies targeting these pathways
• Careful titration and side effect management can improve patient quality of life.
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