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Therapeutic Options for PAH
ADAANI FROST, MDADAANI FROST, MD
Director, Pulmonary Hypertension CenterProfessor of Medicine
Baylor College of MedicineHouston, Texas
2
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
Introduction
4
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
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
6
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.
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.
8
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.
9
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
10
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
11
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
12
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
13
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
14
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.
15
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
16
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
PAH Therapies inTreatment-Naïve Patients
Calcium Channel Blockers
19
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.
20
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
21
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.
22
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
Prostanoids
Intravenous/Subcutaneous Therapy
24
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.
25
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 (
%)
26
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
27
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
28
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
29
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%
30
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‡
31
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)
32
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
33
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.
34
Treprostinil Pharmacokinetics
Half life 4 hours
Bioavailability ~100%
Metabolism Hepatic
Excretion Urinary
CYP interactions None known
Treprostinil full prescribing information. 2006.
35
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.
36
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.
37
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
38
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.
39
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.
40
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.
41
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.
42
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
Prostanoids
Inhalation Therapy
44
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
45
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.
46
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
47
Inhaled Iloprost Pharmacokinetics
Half life 20 to 30 minutes
Bioavailability Undetermined
Metabolism Hepatic
Excretion Urinary
CYP interactions None known
Iloprost full prescribing information. 2006.
48
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.