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![Page 1: Therapeutic Options for PAH ADAANI FROST, MD Director, Pulmonary Hypertension Center Professor of Medicine Baylor College of Medicine Houston, Texas.](https://reader036.fdocuments.in/reader036/viewer/2022062421/56649cc45503460f9498d85c/html5/thumbnails/1.jpg)
Therapeutic Options for PAH
ADAANI FROST, MDADAANI FROST, MD
Director, Pulmonary Hypertension CenterProfessor of Medicine
Baylor College of MedicineHouston, Texas
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Learning Objectives (CME, CE, CPE)
● At the completion of this educational activity, participants should be able to:
- Discuss the improvements made in PAH-specific therapies over the past decade
- Discuss data regarding the efficacy, safety, and tolerability of the major classes of PAH-specific therapies
- Identify major class-related adverse effects associated with PAH-specific therapies
- Identify issues related to drug-drug interactions and other aspects of clinical pharmacology that impact on patient care
- List the major points of difference between the individual agents used to treat PAH
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Introduction
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PAH:Definition on Right Heart Catheterization
Gaine SP, et al. Lancet. 1998;352:719-725.
Increased mean pulmonary arterial pressure (mPAP)
>25 mm Hg at restor
>30 mm Hg during exercise
Normal pulmonary artery wedge pressure (PAWP)
<15 mm Hg
Increased pulmonary vascular resistance (PVR)
>3 Wood units
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5
Goals of Management of PAH
● Improve survival
● Prevent worsening
● Improve hemodynamics
● Maintain or improve functional class
● Improve exercise capacity
● Improve daily functioning and quality of life
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General Measures
● Recommend regular cautious supervised exercise
- Maintain skeletal muscle conditioning
- Know the pre-determined stopping points (eg, significant
dyspnea, chest pain, dizziness)
● Provide prophylaxis for pulmonary infections
- Influenza and pneumococcal vaccines
● Maintain hemoglobin levels
- Aggressive evaluation for anemia
- Monitor for hyperviscosity syndromes in patients with congenital heart disease (eg, Eisenmenger syndrome)
• Phlebotomy may be indicated in patients with high hematocrit (>63) or with signs of neurologic symptoms
Galie N, et al. Eur Heart J. 2004;25:2243-2278.
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7
General Measures
● Counsel on avoiding pregnancy
- High rate of mortality in patients with PAH
- Caution with hormonal birth control methods when on bosentan
• It renders oral contraceptive less effective, so must add barrier method
• Ambrisentan does not interfere with oral contraceptives
- Bosentan and ambrisentan are pregnancy category X
Galie N, et al. Eur Heart J. 2004;25:2243-2278.
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General Medical Care for PH
● Oxygen supplementation
- Maintain O2 saturation >90% at rest, with supervised exercise, and during sleep
- Unless PAH is severe, most patients are only mildly hypoxemic in the absence of intracardiac shunt or concomitant lung disease
• O2 supplementation may not alleviate PAH symptoms associated with shunts
- Supplemental O2 for air travel, if indicated
- Avoid altitudes above 5000 feet
Badesch DB, et al. Chest. 2004;126:35S-62S.Galie N, et al. Eur Heart J. 2004;25:2243-2278.
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Considerations forSelecting Initial Therapy for PAH
● Severity of symptoms/functional class
● Physical examination (right-heart failure?)
● Rate of progression
● Echocardiogram (RV size and function)
● Cardiopulmonary hemodynamics
● 6-minute walk distance/exercise capacity
● BNP/NT-pro-BNP
● Capability of patient to handle parenteral therapy
- Parenteral therapy is first choice in very advanced patients
● Other issues
- Drug-drug interactions, adverse events, comorbid conditions (eg, diabetes), route of administration, dosing intervals, cost
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Mechanisms of Action ofTherapies for PH
Humbert M, et al. N Engl J Med. 2004;351:1425-1436.
Nitric oxide
cGMP
Vasodilation and antiproliferation
Endothelial cells
Nitric oxide pathway
Preproendothelin ProendothelinL-arginine
NOS
Arachidonic acid Prostaglandin I2
Prostaglandin I2
cAMPVasodilation and antiproliferation
Vasoconstriction and antiproliferation
Endothelin-receptor A Endothelin-
receptor B
Endothelin pathway Prostacyclin pathway
Endothelin-1
Endothelin-receptor
antagonists
Exogenous nitric oxide
Prostacyclinderivates
Phosphodiesterase type 5 inhibitor
Phosphodiesterase type 5
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Commonly ReportedClinical Trial Outcomes in PAH
● 6-minute walk distance
- Primary endpoint in many clinical trials
- Easy to administer
- Correlates with other outcomes
● Change in NYHA/WHO functional class
- Secondary endpoint in many trials
● Improvement in hemodynamics
- Requires repeat catheterization
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Commonly ReportedClinical Trial Outcomes in PAH
● Time to clinical worsening
- Combined endpoint being used more frequently
- Variation in definition depending on study
● Mortality
- Placebo-controlled survival studies not feasible/ethical with modern PAH therapies
- Survival data available based on open-label long-term extension studies of placebo-controlled trials
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Pharmacotherapy for PAH: Routes of Delivery
● Oral therapy
- Endothelin receptor antagonists (ERAs)
- PDE5 inhibitors
- Calcium channel blockers (small minority of patients)
● Inhaled therapy
- Prostanoids
● Intravenous/subcutaneous therapy
- Prostanoids
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Treatment Options for Patients Failing Acute Vasoreactivity Testing by NYHA Functional Class
FunctionalClass II
FunctionalClass III
FunctionalClass IV
SildenafilAmbrisentan*Treprostinil scTreprostinil iv
Bosentan†
Bosentan‡ Ambrisentan*‡
Sildenafil‡Epoprostenol iv
Iloprost (inhaled)Treprostinil scTreprostinil iv
Epoprostenol ivBosentan
Iloprost (inhaled)Sildenafil
Treprostinil scTreprostinil iv
Badesch DB, et al. Chest. 2007;131:1917-1928.Galie N, et al. Presented at ESC 2007.
*Ambrisentan approved after development of updated guidelines.†Inclusion based on data presented at ESC 2007.‡Not necessarily in order of preference.
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Options for Patients Failing to Improve or Deteriorating Under Initial Therapy
Badesch DB, et al. Chest. 2007;131:1917-1928.
Functional Class III or IV
Atrial septostomy and/or
Lung transplantation
Combination Therapy(?)Prostanoids
EndothelinReceptor
Antagonists
PDE5Inhibitors
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Management of PAH Therapy
● Up to 100% of PAH patients will report 1 or more adverse effects of PAH therapy
● Most adverse effects should be managed conservatively
● Since there are limited agents and alternatives, patient risk from adverse event needs to be judged against reduced efficacy of PAH therapy
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PAH Therapies inTreatment-Naïve Patients
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Calcium Channel Blockers
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Oral Calcium Channel Blockers in IPAH
● Favorable acute response to vasodilator challenge
- Decrease in mPAP of at least 10 mmHg to <40 mm Hg
- Increased or unchanged cardiac output
● Patients who fail acute vasodilator challenge should not be treated with calcium channel blockers
Badesch DB, et al. Chest. 2004;126:35S-62S.
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French Registry:Response to Acute Vasodilator Challenge
0
2
4
6
8
10
12
Res
po
nse
(%
)
Idiopathic
n=649.Challenge with vasodilator at time of right heart catheterization.
10.3%
Humbert M, et al. Am J Respir Crit Care Med. 2006;173:1023-1030.
0%
2.6%
0% 0%
3.3%
1.6%
6.8%
Familial ConnectiveTissue
CongenitalHeart
PortalHypertension
Anorexigens HIV >2 Factors
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Long-Term Response to Calcium Channel Blocker Therapy in IPAH
● Long-term responders to calcium channel blocker therapy (at least 1 year)
- Less severe disease at baseline
- More pronounced decrease in mPAP during acute challenge
- Long-term responders
• 54% of acute responders
• 6.8% (95% CI, 4.7% to 8.9%) of patient sample
- 5-year survival rate of calcium channel blocker therapy failures: 48%
0
2
4
6
8
10
12
14
16
18
20
Responders
Pat
ien
ts (
%)
AcuteVasodilatorChallenge
Long-TermCalcium ChannelBlocker Therapy
12.6%
6.8%
Sitbon O, et al. Circulation. 2005;111:3105-3111.
n=557.
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Survival onOral Calcium Channel Blocker Therapy
Sitbon O, et al. Circulation. 2005;111:3105-3111.
Survival endpoint included those who received transplants or were lost to follow-up.
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14 16 18
38 33 30 22 13 8 3 3 2 1
Years
Failures
Cu
mu
lati
ve S
urv
ival Responders
19 12 7 4 0Subjectsat Risk (n)
RespondersFailures
Long-Term Calcium Channel Blocker Therapy
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Prostanoids
Intravenous/Subcutaneous Therapy
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Prostanoid Intravenous/Subcutaneous Therapy for PAH
● Requires expertise as numerous complications and risks are associated with therapy
- Adequate coordinator support for associated problems
• Adequate patient support for medication preparation
Epoprostenol
● First PAH-specific therapy
● Requires continuous intravenous infusion
Treprostinil
● Available both as continuous subcutaneous injection or continuous intravenous infusion
● Longer half-life and more chemically stable than epoprostenol
Barst RJ, et al. N Engl J Med. 1996;334:296-302.Simonneau G, et al. Am J Respir Crit Care Med. 2002;165:800-804.
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Improved SurvivalWith Epoprostenol for IPAH
P=0.003 versus conventional therapy (anticoagulants, oral vasodilators, diuretic agents, cardiac glycosides, and supplemental oxygen).
Barst RJ, et al. N Engl J Med. 1996;334:296-302.
100
80
60
40
20
00 2 4 6 8 10 12
Epoprostenol (n=41)Conventional therapy (n=40)
Weeks
Su
rviv
al (
%)
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Intravenous Epoprostenol forSevere PAH: 3-Year Survival
n=162 consecutive patients with IPAH in NYHA Class III or IV. 3-year survival with IV epoprostenol compared with expected survival from historical controls. *P<0.001 at all time points.
McLaughlin VV, et al. Circulation. 2002;106:1477-1482.
0 6 12 18 24 30 36Months
20
40
60
80
100
Su
rviv
al (
%)
*
*
*
ObservedExpected
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Hemodynamic VariablesImproved With Epoprostenol Therapy
McLaughlin VV, et al. Circulation. 2002;106:1477-1482.
mPAP mRAP
Cl PVR
Ch
ang
e (
mm
Hg
)C
han
ge
(L
/min
/m2
)
Ch
ang
e (
Wo
od
un
its
)C
han
ge
(m
m H
g)
-8
-21.0
-16.0
-11.0
-6.0
-1.0
4.0
Epoprostenol
-3
-10.0
-8.0
-6.0
-4.0
-2.0
0.0
2.0
Epoprostenol
-13.0
-11.0
-9.0
-7.0
-5.0
-3.0
-1.0
1.0
-6.5
1
-3.0
-2.0
-1.0
0.0
1.0
2.0
3.0
Epoprostenol
Epoprostenol
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Subcutaneous Treprostinil: Week-12 Change From Baseline in 6-Minute Walk Distance by Dose Quartile
Simonneau G, et al. Am J Respir Crit Care Med. 2002;165:800-804.
0
10
20
30
40
Mea
n C
han
ge
in 6
-Min
ute
Wal
k D
ista
nce
(m
eter
s)
<5.0 5.0 - <8.2
n=470. Chronic study drug infusion initiated at 1.25 ng/ kg/min. At Week 12, the maximum allowable dose was 22.5 ng/kg/min. *P=0.006 for all doses of treprostinil versus placebo.
8.2 - <13.8 >13.8
Dose Quartile (ng/kg/min)
3.31.4
20
36.1
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Long-Term OutcomesWith Subcutaneous Treprostinil
Barst RJ, et al. Eur Respir J. 2006;28:1195-1203.
0
10
20
30
Pat
ien
ts (
%)
Discontinue forDeterioration
Death
n=860.Patients followed for up to 4 years.
SwitchTherapy
AddTherapy
Discontinue forAdverse Events
14%16%
11%
15%
23%
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SC Treprostinil as Naïve,Add-On, and Transition Therapy
Soto FJ, et al. Am J Respir Crit Care Med. 2008;177:A966.
Changes in 6-Minute Walk Distance: >1 Year Follow-Up
n=52.*P=0.0009; †P=0.01; ‡P=0.02 versus baseline for each group.
Ch
ang
e fr
om
bas
elin
e6-
MW
D (
m)
Naïve(n=25)
Add-On(n=15)
Transition(n=13)
0
50
100
150
200
120* 128†
76‡
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Intravenous Treprostinil:Impact on 6-Minute Walk Distance
0
50
100
150
200
250
300
350
400
450
Baseline
n=16.*P=0.008 and †P=0.001 versus baseline.
Week 6 Week 12
Tapson VF, et al. Chest. 2006;129:683-688.
319
378*400†
To
tal 6
-Min
ute
Wal
kD
ista
nce
(m
eter
s)
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Intravenous Treprostinil: Hemodynamic Changes at 12 Weeks
mPAP mRAP
Cl PVR
Ch
ang
e (
mm
Hg
)C
han
ge
(L
/min
/m2
)
Ch
ang
e (
Wo
od
un
its
)C
han
ge
(m
m H
g)
-4.2
Treprostinil
-0.8
Treprostinil
-13.0
-11.0
-9.0
-7.0
-5.0
-3.0
-1.0
1.0
-9.4
Treprostinil
Tapson VF, et al. Chest. 2006;129:683-688.
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
-7.0
-6.0
-5.0
-4.0
-3.0
-2.0
-1.0
0.0
0.47
Treprostinil
-0.2
0.0
0.1
0.2
0.3
0.4
0.5
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Epoprostenol Pharmacokinetics
Half life 2.7 minutes
Bioavailability 100%
Metabolism Spontaneous and enzymatic degradation
Excretion Urinary
CYP interactions None
Stability Unstable at room temperature; requires refrigeration
Epoprostenol full prescribing information. 2008.
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Treprostinil Pharmacokinetics
Half life 4 hours
Bioavailability ~100%
Metabolism Hepatic
Excretion Urinary
CYP interactions None known
Treprostinil full prescribing information. 2006.
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Adverse Events Associated With Prostanoid Injection Therapy
● Common adverse events
- Adverse events associated with therapy should be expected (incidence rates >80%)
• Most adverse events associated with vasodilation
- Headache, jaw pain, flushing/skin rash, diarrhea, nausea and vomiting
- Catheter infections and injection site reactions (treprostinil)
Epoprostenol full prescribing information. 2002.Treprostinil full prescribing information. 2006.
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Epoprostenol and Treprostinil: Epoprostenol and Treprostinil: Common Adverse EffectsCommon Adverse Effects
● FlushingFlushing
● HeadacheHeadache
● Diarrhea, nausea, vomitingDiarrhea, nausea, vomiting
● Jaw painJaw pain
● MyalgiaMyalgia
● HypotensionHypotension
● Anxiety, nervousness, Anxiety, nervousness, agitationagitation
● Chest painChest pain
● DizzinessDizziness
● BradycardiaBradycardia
● Abdominal painAbdominal pain
● DyspneaDyspnea
● Back painBack pain
● SweatingSweating
● DyspepsiaDyspepsia
● ParesthesiaParesthesia
● TachycardiaTachycardia
● Delivery site complicationsDelivery site complications
Epoprostenol full prescribing information. 2002.Treprostinil full prescribing information. 2006.
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Thrombocytopenia Correlated With Epoprostenol Dose and With RAP
Chin KM, et al. Am J Respir Crit Care Med. 2008;177:A260.
n=54 current and former epoprostenol-treated patients.
100
50
0
150
200
250
300
400
350
RAP <10 mmHg
RAP 11-14 mmHg
RAP >15 mmHg
Pla
tele
t C
ou
nt
(100
0s)
Epoprostenol Dose (ng.kg/min)300 15 45 60 75 90 105 120
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Epoprostenol-Related Thrombocytopenia
Platelet Count Drop >50,000 Noted in Red
Platelet Countat Baseline
Platelet Count2-4 Months
Platelet Countat 8-12 Months
450
400
350
300
250
200
150
100
50
0
Jacob S. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.
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Catheter Infections Associated With Intravenous Prostacyclins
● Infection rates range from 0.43 to 1.13 infections per 1000 treatment days
● IV treprostinil associated with slightly higher infection rates compared with epoprostenol
- Treprostinil also associated with higher incidence of Gram-negative bacteria
● Exposure to Gram-negative pathogens may occur during bathing or showering
● A closed-hub system may decrease bacterial contamination of the hub
Doran AK, et al. Int J Clin Pract. 2008;62(suppl 160):5-9.
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Preventing and ManagingCatheter Infections
● Complete guidelines available at www.phassociation.org
● Use a cuffed and tunneled CVC
● No submersion of catheter in water
● Remove catheter if bacterial infection is documented
- Do not use “clear the line” approach
● Use of gloves does not eliminate hand hygiene need
● Do not use topical antibiotics or creams on insertion sites
Doran AK, et al. Int J Clin Pract. 2008;62(suppl 160):5-9.
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Treprostinil SC Infusion Site Pain and Reaction
● Infusion site pain and infusion site reaction (redness and swelling) occur in the majority of patients
● These symptoms were often severe and could lead to treatment with narcotics or discontinuation of treprostinil
● Infusion site pain is not related to dose
● Site pain varies by patient as well as by infusion site
● There are sometimes simply “good” sites and “bad” sites
● Site pain is often the worst 2 to 5 days into a new injection site
Treprostinil full prescribing information. 2006.
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Treprostinil Site Pain Care: Nonpharmacologic Approaches
● Encourage patients to change a “bad” site right away
● Allow patients to maintain a “good” site for several days
● Try alternative sites such as upper buttocks or backs of upper arms
● Remove any medication droplets on the end of the needle after priming
● For frequent topical medication application, apply thin DuoDERM® prior to catheter insertion
● Try dry catheter preplacement method before initiating medication
● Change to a more concentrated solution to allow for less volume infusion per hour
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Prostanoids
Inhalation Therapy
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Prostanoid Mechanisms of Action
Humbert M, et al. N Engl J Med. 2004;351:1425-1436.Newman JH, et al. Circulation. 2004;109:2947-2952.
cAMP
Vasodilation and antiproliferation
Arachidonic acid
Prostaglandin I2
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Inhaled Prostanoid Therapy for PAH: Iloprost
● Stable prostacyclin analogue
● Effect on PVR approximately equivalent to inhaled NO or oral sildenafil during acute testing
● 6 to 9 inhalations daily required
- Half-life of 20 to 30 minutes
Olschewski H, et al. N Engl J Med. 2002;347:322-329.Ghofrani HA, et al. J Am Coll Cardiol. 2004;43:68S-72S.Rubin LJ, et al. Proc Am Thorac Soc. 2006;3:111-115.
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Inhaled Iloprost for Severe PAH: Combined Endpoint Analysis
0
5
10
15
20
25
Pat
ien
ts (
%)
All
16.8%*
Non-IPAH
4.9%
20.8%
12.5%
n=203. *P=0.07 versus placebo. Non-IPAH group included patients with chronic thromboembolic pulmonary hypertension (n=57).
IloprostPlacebo
Olschewski H, et al. N Engl J Med. 2002;347:322-329.
5.5%4.3%
IPAH
Improvement of 1 NYHA Class and >10% Increase in 6-Minute Walk Distance
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Inhaled Iloprost Pharmacokinetics
Half life 20 to 30 minutes
Bioavailability Undetermined
Metabolism Hepatic
Excretion Urinary
CYP interactions None known
Iloprost full prescribing information. 2006.
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Safety and TolerabilityConsiderations With Inhaled Iloprost
● Adverse events
- Flushing, headache, jaw pain typical of prostanoid therapy
- Cough associated with route of delivery
● Warnings and precautions
- Risk of hypotension in patients with low systemic blood pressure
Iloprost full prescribing information. 2006.