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.