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Slide1
a
Interprofessional Considerations in the Management of Pulmonary Arterial 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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Slide5a
Interprofessional Considerations in the Management of Pulmonary Arterial 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.
Slide6CME/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 EducationCCO 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.
Slide7Target 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 patientsFunding:This activity is supported by an educational grant from Actelion Pharmaceuticals US, Inc., a Janssen Pharmaceutical Company of Johnson & Johnson.
CME/CE Activity Information & Accreditation
(continued)
Slide8Disclosures
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.Potential conflicts of interest were resolved with a peer review process provided by Daniel Thibodeau, MHP, PA-C, DFAAPA.
Slide9Disclosures
(continued)Disclosure of Unlabeled UseThis 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.DisclaimerParticipants 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.
Slide10Faculty
10
James C. Coons, PharmD, FCCP, BCCP
Associate Professor
University of Pittsburgh School of Pharmacy
Clinical Pharmacist, Cardiology
University of Pittsburgh Medical Center-Presbyterian HospitalPGY2 Cardiology Residency Program Director
Pittsburgh, Pennsylvania
Martha Kingman, DNP, FNP-C
Nurse Practitioner
Pulmonary Hypertension Program
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas
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
Slide11Vallerie V. McLaughlin, MD, FACC, FAHA, FCCP
Pulmonary Hypertension:Sorting out the Cause
Slide12What is the most common presenting symptom of pulmonary hypertension?SyncopeChest PainDyspnea
Lower extremity edemaCough
Slide13The diagnostic work up for PAH includes all of the following tests except:EchocardiogramVentilation Perfusion ScanRight Heart Catheterization
Left Heart CatheterizationPFT’s
Slide146th World Symposium on PH: Proposed Hemodynamic Definition of PH/PAH
Adapted from Simonneau G et al. Eur Resp J. 2019; 53: 1801913 [https://doi.org/10.1183/13993003.01913-2018.DefinitionsCharacteristicsClinical Groups
Pre-capillary PH
mPAP >20 mmHg
PAWP ⩽15 mmHg
PVR ⩾3WU
1, 3, 4, 5Isolated post-capillary PHmPAP >20 mmHgPAWP >15 mmHg PVR <3 WU2, 5Combined pre- and post-capillary PHmPAP >20 mmHg
PAWP >15 mmHg
PVR ⩾3WU
2, 5
Slide15NO: -
ET-1: +
Endothelial
cell
SMCs
PGI2: -
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
Adapted from: Humbert M
et al.
Circulation
2014
Slide16Mechanisms of Action of Approved Therapies for PAH
Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.
cGMP
cAMP
Vasoconstriction and proliferation
Endothelinreceptor A
Endothelin-receptor antagonists
Endothelinreceptor B
Phosphodiesterase type 5 inhibitor
Vasodilation
and antiproliferation
Phosphodiesterase type 5
Vasodilation
and antiproliferation
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I
2
L-citrulline
Nitric Oxide
Pathway
Endothelin
Pathway
Prostacyclin
Pathway
Endothelial cells
Proendothelin
Endothelial
cells
Arachidonic
acid
Smooth muscle cells
Prostacyclin
(prostaglandin I
2
)
Smooth muscle cells
Exogenous
nitric oxide
sGC stimulator
Prostacyclin derivatives
IP receptor agonists
Slide17Video #1
Slide18Common Symptoms of PAH
Adapted from Rich S et al. Ann Intern Med, 1987; 107:216-223.
Adapted fromBrown LM et al. Chest
, 2011; 140:19-26.
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
Slide19Adapted from McLaughlin VV et al.
J Am Coll
Cardiol
. 2009;53:1573-1619.
ACCF/AHA Diagnostic Algorithm
Slide20History and Physical Exam Findings Are Insensitive Unless Advanced Disease/RV Failure Present
HistoryExam (PH)
Exam (RV Failure)
Dyspnea (86%)
Fatigue (27%)
Chest pain (22%)
Edema (22%)
Syncope (17%)
Dizziness (15%)
Cough (14%)
Palpitations (13%)
Loud P2
RV lift
Systolic murmur (TR; inspiratory augmentation)
Early systolic click
Midsystolic ejection murmur
Diastolic murmur (PR)
JVD; increased A wave, V wave; hepatojugular reflex
RV S3, S4
Pulsatile liver
Hepatomegaly
Edema
Ascites
Low BP, low PP, cool extremities
REVEAL. Brown LM et al.
Chest.
2011;140:19-26.
Adapted from McLaughlin VV et al.
J Am Coll Cardiol
. 2009;53:1573-1619.
Slide21Case: Electrocardiogram
Slide22Signs of PAH on Chest X-ray
Slide23Checklist for Echocardiographic Assessments When PH Is SuspectedEstimate pulmonary artery systolic pressureEvaluate severity of TR
Evaluate right heart size and functionExclude left heart valvular disease and systolic dysfunction Exclude congenital heart diseaseDifferentiate PAH from PH due to LHDEstimate RA pressureEvaluate for pericardial effusionAdapted from McLaughlin VV et al. J Am Coll Cardiol. 2015;65:1976-1997.
Slide24Echocardiographic Characteristics of PAH
LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
Apical
4-chamber view
Slide25Echocardiographic Findings That Help Differentiate PAH From PH Due to LHD
PAHParameterPH Due to LHDEnlargedRV sizeMay be enlargedSmallLA sizeLarge
IncreasedRA/LA size ratio
Normal
(LA>RA)
Bows
from right to leftInteratrialseptumBows from left to rightCommonRVOT notchingRare<<1
E/A
ratio
>1
Normal
Lateral e’
Decreased
<8
Lateral E/e’
>10
Adapted from McLaughlin VV et al.
J Am Coll Cardiol
. 2015;65:1976-1997
.
Slide26Pulmonary Function Testing in PAHTo exclude/characterize underlying airway or parenchymal disease
Decreased DLco and mild-to-moderate reduction in lung volumes common in PAHDLcoReduction in DLco in a patient with scleroderma and normal lung volumes is suggestive of PAHIt is recommended that SSc patients should have annual PFTs in additions to annuals echocardiogram
3/2/2021
Slide27V/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 CTEPHNormal V/Q scan rules out CTEPH
Slide28Blood Tests to Detect Potential Underlying Disease in PAH
Antinuclear antibody (ANA)Antiphospholipid antibodiesLupus anticoagulant, anticardiolipin antibodiesHIV serologyCBC with plateletsLiver function testThyroid function testHemoglobin electrophoresis, if indicated
Barst RJ et al.
J Am Coll Cardiol
. 2004; 43(1Suppl):40S-47S.
ESC/ERS Task Force.
Eur Heart J, 2009; 30:2493-2537.
Slide29Functional Capacity: 6- Minute Walk TestHelps 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 Clinical Pulmonary Function Laboratories. Am J Respir Crit Care Med, 2002;166:111-117.
Slide30Diagnosis of PAH Requires Right Heart Catheterization
RIGHT HEART CATHETERIZATION
ESSENTIAL COMPONENTS OF INVASIVE
HEMODYNAMIC ASSESSMENT
Required to confirm diagnosis, calculate resistance, guide therapy
Excludes other etiologies of PH
Intracardiac or extracardiac shunts
Left-heart-disease
Measures degree of right-heart dysfunction
RAP
CO
O
2
Saturations (SVC, IVC, RV, PA, SA)
RAP
PAP, Systolic, diastolic, mean
PAWP, or LVEDP
CO/CI
PVR
Vasodilator challenge should be performed in patients with idiopathic, heritable, and 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.
Galiè
N et al.
Eur
Respir
J.
2019 Jan 24;53(1).
Slide31SummaryHigh index of suspicion-multiple causes of pulmonary hypertensionThorough diagnostic evaluationExclude thromboembolic disease
Evaluate potential causes/contributing issuesRHC required prior to initiating PAH therapyBaseline functional evaluationIntegrate diagnostic data for final diagnosis and risk assessment
Slide32James C. Coons, PharmD, FCCP, BCCP
Slide33Pharmacotherapy Timeline
Slide34Treatment Guidelines: General Approach
Eur Heart J 2019;53:1801889.
Slide35Acute Vasoreactivity TestingTypically used for patients with idiopathic, heritable, or drug-induced PAH
Favorable response:Positive response in <10% of patients with idiopathic PAHJ Am Coll Cardiol 2009;54:S78-84. Am Heart J 2011;162:201-13. Circulation 2005;111:3105-11.
Reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased CO by means of an acute pulmonary vasodilator challenge using either inhaled nitric oxide, IV epoprostenol, or IV adenosine
Medication
Dosage
Amlodipine
20 - 30 mg/day
Nifedipine
180 - 240 mg/day
Diltiazem
720 – 960 mg/day
Slide36Long-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 onlyThese patients are recognized as a distinct clinical phenotypeEur Heart J 2019;53:1801913.
Slide37Oral TherapiesPhosphodiesterase type-5 (PDE-5) Inhibitors
Endothelin receptor antagonists (ERAs)
Slide38PDE-5 Inhibitors
Medication
Indication
Dosing
Sildenafil
(Revatio®)
Improves exercise ability in
early stage PAH
20 mg PO tid
10 mg IV tid
(short-term
use in patients unable to take PO)
Tadalafil
(Adcirca®)
Improves
exercise ability
40 mg PO daily
– Initiate
20 mg if renal/hepatic
impairment or concurrent
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.
Adcirca [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015.
Slide39Endothelin Receptor Antagonists
Medication
Indication
Dosing
Pharmacologic Properties
and Other
Special Considerations
Bosentan
(Tracleer®)
Improves exercise ability and decrease rate of clinical worsening in
WHO FC III-IV
62.5 mg
PO bid, then 125 mg PO bid after
4 weeks
Dual antagonist of ET-1
A
& 1
B
receptors
Tracleer
®
and
Bosentan
Access Programs (REMS: LFTs at baseline and monthly; pregnancy testing at baseline and monthly)
Ambrisentan
(Letairis®)
WHO FC II-III
10 mg PO
daily
Selective
ET-1
A
antagonist
Letairis
®
and
Ambrisentan
Access Programs (REMS:
pregnancy testing at baseline and monthly)
Macitentan
(Opsumit®)
Delays progression of PAH
10 mg PO
daily
Tissue selective
Lipophilic
Dual antagonist of ET-1
A
& 1
B
receptors
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.
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.
Slide40Which statement regarding the prostacyclin and selective IP receptor agonist classes is most accurate?Iloprost is an oral prostacyclin
Treprostinil is available in multiple formulationsThere is no maximum dose of selexipagTreprostinil diolamine is only given twice daily
Slide41EpoprostenolTreprostinilIloprostProstacyclins
Slide42Parenteral Prostacyclins
Medication
Indication
Dosing
Pharmacologic Properties
and Other
Special Considerations
Epoprostenol IV
(Flolan®,
Veletri®)
WHO FC
III-IV
2 ng/kg/min titrated to
dose-limiting adverse effects (usual range,
20-40 ng/kg/min)
Half-life 4-6 minutes
Back-up cassette/pump
Protect from light
Ice pack (Flolan
®
only)
Requires reconstitution and further dilution (0.9% saline or sterile water: Veletri
®
;
sterile diluent or pH 12 sterile diluent: Flolan
®
)
Every 24-hour cassette change
Treprostinil SC
(Remodulin®)
WHO FC
II-IV
1.25 ng/kg/min titrated to
dose-limiting adverse effects (usual range,
40-80 ng/kg/min)
Half-life 4 hours
Back-up pump
Stable at room temperature
SQ: Undiluted, every 72-hour syringe change
IV: Requires further dilution, every
48-hour cassette change
High pH
diluent associated with lower risk of bloodstream infections
Treprostinil IV
(Remodulin®)
WHO FC
II-IV
Flolan [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2016. Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2014. Veletri [package insert]. 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.
Slide43Inhaled Prostacyclins
Medication
Indication
Dosing
Other
Special Considerations
Iloprost
(Ventavis®)
WHO FC
III-IV
2.5-5 mcg given
6 to 9 times per day (maximum, 45 mcg/d)
Only administered via I-neb
®
AAD
®
System
Use higher concentration ampule
(20 mcg/mL) for patients with extended treatment time or at
5-mcg dose
Treprostinil
(Tyvaso®)
Increases walk distance in WHO FC III
3 breaths QID
Titrate by
3 breaths every
1-2 weeks up to 9 breaths QID
Only administered via Tyvaso
®
Inhalation System
QID = four times daily.
Ventavis [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2013.
Tyvaso [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2016.
Slide44Riociguat (Adempas®)Oral treprostinil diolamine extended release (Orenitram®)Selexipag (Uptravi®)Newer Oral Therapies
Slide45RiociguatSoluble guanylate cyclase (sGC) stimulatorNitric oxide (NO) binds to sGCsGC catalyzes synthesis of cyclic guanosine monophosphate (cGMP)cGMP signaling influences vascular tone, proliferation, fibrosis, and inflammation
Riociguat has a dual mechanism:Sensitizes sGC to NODirectly stimulates sGC, independent of NOAdempas [package insert]. Whippany, NJ: Bayer Healthcare Pharmaceuticals Inc; 2017.
Slide46Indicated to improve exercise capacity, WHO FC, and delay clinical worsening in patients with:PAHPersistent/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 tidStart 0.5 mg PO tid if risk for hypotension or with concomitant strong CYP and P-gp inhibitorsAvoid if CrCL <15 mL/min or if on hemodialysisAdempas® REMS program (teratogenicity)Riociguat (cont’d)
CYP = cytochrome P450; P-gp = p-glycoprotein.
Adempas [package insert]. Whippany, NJ: Bayer Healthcare Pharmaceuticals Inc; 2017.
Slide47First oral prostacyclin Approved to delay disease progression and to improve exercise capacityInitiate 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 longerThree-times daily dosing preferred due to tolerabilityCarefully selected, lower-risk patients may be considered for transition from parenteral or inhaled therapy to oral treprostinilTreprostinil Diolamine Extended Release
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 2017;36:193-201. Am J Respir
Crit
Care Med 2019;DOI: 10.1164/rccm.201908-1640OC.
Slide48Selective IP receptor agonistType of prostanoid receptor found in lungs (regulates vascular tone, platelet activity, immunologic responses)Similar mode of action to prostacyclin, but a
non-prostanoidApproved to delay disease progression and reduce risk of hospitalization for PAHInitiate 200 mcg PO bid and up-titrate weekly as tolerated to maximum of 1600 mcg PO bidSelexipag
Uptravi [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2015. N Engl J Med 2015;373:2522-33.
Slide49Adverse Reactions
Medication/Class
Adverse Effects
PDE5i
Headache, dyspepsia, flushing, epistaxis, insomnia, hypotension, visual changes
Riociguat
Headache, dizziness, dyspepsia, gastroesophageal reflux, nausea, diarrhea, vomiting, hypotension, anemia, constipation, teratogenicity
ERAs
Headache, flushing, peripheral edema, nasal congestion, sinusitis, transaminitis,
liver injury,
anemia, teratogenicity
Prostacyclins
Nausea, vomiting, diarrhea, flushing, jaw pain, headache, rash, erythema, hypotension, leg pain
–
Inhaled: Cough, throat irritation
Selexipag
Headache, diarrhea, jaw pain, nausea, myalgia, vomiting, extremity pain, flushing
PDE5i = phosphodiesterase-5 inhibitor; ERA = endothelin receptor antagonist.
Eur Heart J 2016;37:67-119.
Slide50Which medication is most likely to interact with a PDE5 inhibitor?GemfibrozilGlyburideClopidogrel
Isosorbide
Slide51Drug Interactions
Medication/Class
Interactions
PDE5i
Strong CYP3A4 inhibitors/inducers, nitrates,
alpha-blockers, alcohol
Riociguat
Strong CYP and P-gp inhibitors/inducers, PDE5is,
non-specific PDE inhibitors
(eg, theophylline, dipyridamole), nitrates, antacids, smoking
ERAs
Strong CYP3A4 and CYP2C19 inhibitors/inducers, 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.
Eur Heart J 2016;37:67-119.
Slide52Affordability/Accessibility
Annual medication costs:PDE5 inhibitors: $10,000-$15,000ERAs: $50,000-$60,000Prostacyclins: $95,000-$200,000Seeking prior authorizationAddressing high co-pays & uninsuredCollaboration with specialty pharmacies52
Slide53Video #2
Slide54Treatment Guidelines
Eur Heart J 2019;53:1801889.
Slide55Initial Combination Therapy
TreatmentWHO FC IIWHO FC IIIWHO FC IVAmbrisentan + tadalafilIBIBIIb, COther ERA + PDE5i
IIa, CIIa
, C
IIb, C
Bosentan
+ sildenafil + IV epoprostenolIIa, CIIa, CBosentan + IV epoprostenol
IIa
, C
IIa
, C
Other ERA or PDE5i + SC
treprostinil
IIb, C
IIb, C
Other ERA or PDE5i + other IV prostacyclin analogues
IIb, C
IIb, C
Class and Level of Recommendation
Eur Heart J 2015;46:903-975.
Eur Heart J 2019;53:1801889.
Slide56Long-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 HFpEFSuspected PVOD or PCH
HIV, portal hypertension, or uncorrected congenital heart diseaseMild disease (WHO FC I, PVR 3-4 WU, mPAP < 30 mm Hg, normal RV)Combination therapy not available or contraindicatedResidual Role for Initial Monotherapy
Eur Heart J 2015;46:903-975.
Slide57Treatment Guidelines
Eur Heart J 2019;53:1801889.
Slide58Sequential TherapyCombinations with most evidence
Macitentan and sildenafilRiociguat and bosentanSelexipag and ERA and/or PDE5iConsider prostacyclins
Eur Respir J 2019;53:1801889. N
Engl
J Med 2013;369:330-40.
N
Engl J Med 2013;369:809-18. N Engl J Med 2015;373:2522-33.
Slide59Summary PointsMultiple 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 stratificationTreatment escalation is critical for patients not achieving low-risk status
Slide60Martha Kingman, DNP, FNP-C
Slide61Methods to Improve Quality of Life in PAH
- Careful Medication Titration - Side Effect Management - Management of central line infections
Slide62Video #3
Slide63Prostacyclin Side Effects
Jaw painHeadacheFlushing/erythemaNauseaDiarrheaAnorexiaThrombocytopeniaComplications of Delivery system:Line sepsisEpoprostenol: Interruption (3 -6 min)
Slide64Treprostinil
(Remodulin®)Pump Options Subcutaneous
Intravenous
CADD-MS 3
CADD-Legacy
CADD-MS is a trademark and CADD-Legacy is a registered trademark of Smiths Medical System. Cane
Crono
Five is manufactured by
Canè
Medical Technology.
Awaiting FDA approval
: Implantable pump for
treprostinil
Slide65All the following are important key concepts when titrating prostacyclin therapies except:
Side effects are more common during the titration phasePatient education is key due to complex titration schemesSelexipag titrated to highest tolerated dose or 1600mcg BIDThe faster you can reach a high dose the betterDosing is individualized for IV and SQ
Slide66Possible Dose Adjustments
Over TimeNo set dose No set doseDosing individualized
Titrate to optimize dose while minimizing side effectsDosing individualized based on the patient
Goal of Continuous Infusion Dosing
Slide67Initiated 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 phase2Patient 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 QoL3McLaughlin VV, Palevsky HI. Parenteral and inhaled prostanoid therapy in the treatment of pulmonary arterial hypertension. Clin Chest Med. 2013;34(4):825-40.Skoro-Sajer
N, Lang IM. Selexipag for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother.2014;15(3):429-36
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 Managing Side Effects of Prostacyclin Pathway Therapies – Dosing and Titration
Slide68Case 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/minOnce 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.
Slide69Side Effect
InterventionDiarrhea
Loperamide
Slow up titration of PC or decrease dose
Dietary changes: increase fiber, gluten free, low fat, BRAT diet
Probiotic
Rule out other causes, such as
C.
difficile
Refer to GI
Kingman M, Archer-
Chicko
C, Bartlett M, et al. Management of Prostacyclin Side Effects in Adult Patients with Pulmonary Arterial Hypertension. Pulmonary Therapy, 2017; submitted
Side Effect
Intervention
Nausea/Vomiting
Take with food, eat small frequent meals,
ginger based foods (ginger ale)
Anti-emetics: Ondansetron
For inhaled therapies, swish and spit after
each treatment session, temporarily decrease by 1 breath 4 times a day
Rule out pregnancy
Refer to gastroenterologist
Slow titration or decrease dose
Loss of Appetite/Weight Loss
Dietary consult
Increase caloric content, small frequent
meals, nutritional supplement
Evaluate for other metabolic causes of
weight loss
Managing GI side effects when using
prostacyclins
Slide70Side Effect
InterventionConsideration/RationaleLeg Pain
Screen for iron deficiency. Gabapentin may be a more successful analgesic for leg pain
Decreased RBC oxygen carrying capacity, with reduced circulation in lower extremities
Jaw Pain
Usually no interventions needed. Reassure patient that this will get better with time
Not a dose limiting side effect, loss of jaw pain may indicate need for up-titration
Take slow bites or sips of water, suck on saltine cracker or hard candy, chew gum before eating
Jaw pain is intermittent and generally occurs with first bite of the meal
Kingman M, Archer-
Chicko
C, Bartlett M, et al. Management of Prostacyclin Side Effects in Adult Patients with Pulmonary Arterial Hypertension. Pulmonary Therapy, 2017; submitted
Managing Prostacyclin Associated Pain
Slide71Case 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.
Slide72Patient 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.Case
Slide73All the following are true regarding prevention and treatment of central line infections except:
Use a cuffed and tunneled central venous catheterApply antibiotic ointment to the insertion siteNeg blood culture required before placing a new central lineDo not use a clear the line approachNever infuse anything in the prostacyclin line
Slide74Use a cuffed and tunneled central venous catheterRemove catheter if bacterial infection is documented/ suspectedDo not use “clear the line” approachPlace a PICC line to use for IV prostacyclin and as well as a lumen for IV antibioticsOnce patient stable, they can be discharged to finish IV antibiotics at home
Do not use topical antibiotics or creams on insertion sitesOnce repeat blood cultures are negative, new central line can be placedComplete guidelines available at: www.phassociation.orgDoran AK, Ivy DD, Barst RJ, et al. Guidelines for the prevention of central venous catheter-related blood stream infections with prostanoid therapy for pulmonary arterial hypertension. Int J Clin Pract Suppl. 2008;160:5-9.Managing Central line Catheter Infections
Slide75Conclusions
75
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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