Learning Objectives• Utilize knowledge regarding the specific disease pathways for

PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors.

• Evaluate patients for comorbid conditions to determine the relative risk for PAH.

• Use evidence-based guidelines to select the most appropriate treatment.

• Apply determinants of risk to assess a patient’s prognosis and recognize when therapy needs to be augmented.

• Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring.

Overview of PAH

• US prevalence = estimates up to 50,000 to 100,000– 15,000 to 25,000 diagnosed and treated

• Disease of small pulmonary arteries characterized by vascular narrowing and increased vascular resistance– Vasoconstriction

– Cell proliferation and pulmonary vascular remodeling

– Thrombosis in situ

• Common cause of death:

Right ventricular (RV) failure

Humbert, et al. J Am Coll Cardiol. 2004;43:13S-24S.

Mechanisms of Pathology for PAH

Humbert, et al. N Engl J Med. 2004;351:1425-1436.

Nitric oxide

cGMP

Vasodilatation and antiproliferation

Endothelial cells

Nitric oxide pathway

Preproendothelin ProendothelinL-arginine

NOS

Arachidonic acid Prostaglandin I2

Prostaglandin I2

cAMPVasodilatation and

antiproliferationVasoconstriction and

proliferation

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

Pathophysiology of PAH

Genetic Predisposition

Other Risk Factors

(CTD, CHD, toxins, etc.)

Altered Pathways And Mediators

Vasoconstriction

Cell Proliferation

Thrombosis

VascularRemodeling}

Genetic Mutations in PAH

• Mutations in the gene that codes for BMPR2– BMPR2 mutations are

identified in ~ 70% of patients with heritable PAH

– BMPR2 mutations are also found in ~ 20% of patients with I-PAH

» Clinical course – poor response to acute vasodilator testing and treatment with calcium channel blockers

• Mutations in the gene that codes for: – Activin receptor-like kinase type

1 (ALK1)

– Endoglin (ENG)

» Cause hereditary hemorrhagic telangiectasia (HHT) and may lead to the development of PAH

Machado, et al. J Am Coll Cardiol. 2009;54:S32-42.

Vasoconstriction in PAH

Impaired Vasodilation↓ Prostacyclin↓ Nitric oxide↓ Nitric oxide synthase

Vasodilation

Vasoconstriction

Enhanced Vasoconstriction↑ Endothelin↑ Serotonin (5-HT)↑ Thromboxane↓ Potassium channel expression/activity

Cell Proliferation in PAH

High PVR• Proliferative / angiogenic / apoptosis resistant

– ↑ Endothelin, serotonin (5-HT), VEGF, BMPR2 and ALK1 mutations

– ↓ Potassium channel expression/activity

Vascular Remodeling in PAH

• Poorly understood• PAH cells are pro-proliferative• Many factors implicated in pro-proliferative phenotype• Proliferative and obstructive remodeling of the pulmonary

vessel wall• Some new therapies aimed at controlling cell growth• Several potential mediators

– Alterations in gene expression in growth-controlling pathways– Growth factors– Inflammatory mediators

Galie, et al. Eur Heart J. 2009;30:2493-2537.Galie, et al. Eur Heart J. 2009;30:2493-2537.

Revised Classification ofPulmonary Hypertension

Group 1: Pulmonary Arterial Hypertension (PAH)

Criteria• mPAP ≥ 25 mm Hg• PCWP 15 mm Hg• No significant:

– Obstructive/Restrictive lung disease

– Left heart disease– Thromboembolic disease

Types• Idiopathic PAH• Heritable PAH

– BMPR2, ALK1, Endoglin• Drug- and toxin-induced• Associated with:

– Connective tissue disease– HIV– Portal pulmonary– Congenital heart diseases– Schistosomiasis– Chronic hemolytic anemia

• Persistent pulmonary hypertension of the newborn

Simonneau, et al. J Am Coll Cardiol. 2009;54:S43-54.

Differential Diagnosis of PAH

• Clinical presentation• Electrocardiogram (ECG)• Chest radiograph• Pulmonary function tests and arterial blood gases• ECHO (right heart hemodynamics)• Ventilation / perfusion lung scan• High-resolution CT, contrast CT, pulmonary angiography• Cardiac MRI• Blood tests and immunology• Abdominal ultrasound scan• Right heart catheterization and vasoreactivity

Galie, et al. Eur Heart J. 2009;30:2493-2537.

Invasive DiagnosticTesting for PAH

Right heart catheterization– Mandatory for all patients being tested for PAH– Pulmonary arterial pressure (PAP)– Cardiac output (CO)– Right atrial pressure (RAP)– Pulmonary arterial wedge pressure (PAWP)

Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

Prevalence of PAH in Associated Conditions4th World Symposium on PH (2008)

Associated Condition Prevalence of PAHSystemic sclerosis 7-12 %

HIV infection 0.46-0.5 %

Portal hypertension 2-6 %

Congenital heart disease 1.6-12.5 per million in those with congenital systemic-to-pulmonary shunts → 25-50 % affected by Eisenmenger syndrome

Schistosomiasis 4.6 % in those with hepatosplenic disease

Chronic hemolytic anemia Highly variable; currently being studied

Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.

Patient Evaluation

Confirm presence of PHConfirm presence of PH

Determine type of PH present (PAH?)Determine type of PH present (PAH?)

Gauge functional capacityGauge functional capacity

Estimate prognosis (survival)Estimate prognosis (survival)

Determine treatment and monitoring planDetermine treatment and monitoring plan

NYHA/WHO FunctionalClassification for PAH

Class I No limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope.

Class II Slight limitation of physical activity; no discomfort at rest. Ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope.

Class III Marked limitation of physical activity; no discomfort at rest. Less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope.

Class IV Inability to perform any physical activity without symptoms; signs of right ventricular failure or syncope; dyspnea and/or fatigue may be present at rest; discomfort is increased by any physical activity.

Taichman, et al. Clin Chest Med. 2007;28:1-22.

Predicting Survival in PAH

• Hemodynamics• Response to acute vasodilator therapy

(calcium channel blockers, CCB)• Exercise capacity • NYHA/WHO functional class• Biomarkers (i.e., BNP levels)

Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

Years

Long-term CCB responders(~50% of acute respondersor ≤ 6% of IPAH patients)

Long-term CCB non-responders

38 33 30 22 13 8 3 3 2 1

19 12 7 4 0

Patientsat risk (N)

Cum

ulat

ive

Sur

viva

l

Long-term CCBresponders

Long-term CCBnon-responders

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18

Sitbon, et al. Circulation. 2005;111:3105-11.

P = 0.0007

Response to CCB Therapy andSurvival in Patients with PAH

Impact of Delay in Treatmenton Patient Survival

0

20

40

60

80

100

0 12 24 36 48 52

Ambrisentan

Placebo -Ambrisentan

ABSTRACT: McLaughlin, et al. Am J Respir Crit Care Med. 2008;177:A697.ABSTRACT: McLaughlin, et al. Am J Respir Crit Care Med. 2008;177:A697.

N = 251 242 226 209 195 AmbrisentanN = 122 110 100 94 95 Placebo → AmbrisentanN = 251 242 226 209 195 AmbrisentanN = 122 110 100 94 95 Placebo → Ambrisentan

Eve

nt-F

ree

Sur

viva

l (%

Pat

ient

s)E

vent

-Fre

e S

urvi

val (

% P

atie

nts) 86%86%

96%96%

84%84%

76%76%↑Transition placebogroup to ambrisentan

↑Transition placebogroup to ambrisentan

WeeksWeeks

Goals for Patients with PAH

• Ultimate goals– Feel better– Do more– Live longer

• Gap in understanding →? Promote vasorelaxation

? Suppress cellular proliferation

? Induce apoptosis within pulmonary artery wall

Archer, et al. N Engl J Med. 2009;361:1864-71.Archer, et al. N Engl J Med. 2009;361:1864-71.

Amlodipine, diltiazem, nifedipine (B)

YES

ACUTE RESPONDER

WHO Class I-IVAmlodipine, diltiazem,

nifedipine (B)

Sustained response (WHO I-II)

Atrial septostomy (E/B) and/orlung transplant (E/A)

INADEQUATE CLINICAL RESPONSE

NO

PAH Evidence-Based Treatment Algorithm

Acute vasoreactivity test (A for IPAH)(E/C for APAH)

Expert referral (E/A)

Supportive therapy and general measures Avoid excessive physical exertion (E/A)Birth control (E/A)Psychosocial support (E/C)Infection prevention (E/A)

Oral anticoagulants (E/B) – IPAH/HPAHDiuretics (E/A)Oxygen (E/A)Digoxin (E/C)Supervised rehabilitation (E/B)

Strength of Recommendation WHO Class II WHO Class III WHO Class IV

AAmbrisentan, Bosentan, Sildenafil

Ambrisentan, Bosentan,Epoprostenol IV, Iloprost inh, Sildenafil

Epoprostenol IV

B Sitaxsentan, Tadalafil Sitaxsentan, Tadalafil, Treprostinil SC

Iloprost inh

C Beraprost Treprostinil SC

E/BIloprost IV, Treprostinil IV Iloprost IV, Treprostinil IV

Initial combination therapy (see below)

E/CAmbrisentan, Bosentan, Sildenafil, Sitaxsentan, Tadalafil

Not approved Treprostinil inh Treprostinil inh

Sequential combination therapy

PDE-5 I ERA + (B)

+ (B)+ (B)Prostanoids

NON-RESPONDER

4th World Symposium on PH. Dana Point, CA. 2008.Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.

INADEQUATE CLINICAL RESPONSE

Acute Vasoreactivity Test for PAH

• Calcium Channel Blockers (CCB)

– Acute vasoreactive response =

– Positive response in < 10% of patients with IPAH

– Responders are on higher than ordinary doses of CCB:

amlodipine 10 mg twice daily; diltiazem 360 mg twice daily

– Moderate recommendation based on scientific evidence

Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.

Reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased CO with acute pulmonary vasodilator challenge with either inhaled NO or IV epoprostenol

Reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased CO with acute pulmonary vasodilator challenge with either inhaled NO or IV epoprostenol

FDA-Approved Agents for theTreatment of PAH

• Prostacyclin analogs (PA)– Epoprostenol– Iloprost– Treprostinil

• Endothelin-receptor antagonists (ERA)– Ambrisentan– Bosentan

• Phosphodiesterase-5 inhibitors (PDE-I)– Sildenafil– Tadalafil

Comparison of Agents

AgentRoute of

Administration Adverse Events

Epoprostenol Continuous IV infusion

Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain

Iloprost Inhalation Headache, cough, flushing, jaw pain

Treprostinil » Subcutaneous

» IV

» Inhalation*

» Pain and erythema at injection site, headache, nausea, diarrhea, rash

» Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain

» Cough, headache, flushing, throat irritation, nausea

Ambrisentan Oral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 2.8%), peripheral edema

Bosentan Oral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 11%), peripheral edema, anemia

Sildenafil Oral Headache, flushing, dyspepsia, epistaxis

Tadalafil Oral Headache, dyspepsia, back pain, myalgia, flushing

Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. *Benza, et al. ATS. San Diego, CA. May 15-20, 2009. Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

CADD pump Central line

Epoprostenol for PAH

• Prostacyclin analog• Indication – WHO group I -

functional class III, IV• Administration – continuous

IV infusion via central venous catheter

• Dosage – 20-40 ng/kg/min• Storage – must keep

medication cold with ice packs (stable for 8 hours at room temp)

100

80

60

40

20

0Weeks

Epoprostenol (N=41)

0 2 4 6 8 1210

Conventional therapy (N = 40)

Epoprostenol for IPAHPatient Survival

Pat

ient

Sur

viva

l (%

)

P = 0.003P = 0.003

Barst, et al. N Engl J Med. 1996;334:296-301.

• Prostacyclin analog

• Indication – WHO group I - functional class III, IV

• Administration– Ultrasonic nebulizer

– Dosage = 2.5 to 5 g, 6 to 9 times daily; maximum daily dosage evaluated in clinical studies = 45 g

– Administration in well-ventilated areas

• Theoretical advantage of selectivity – Pulmonary vs systemic administration

Iloprost for PAH

Iloprost for PAHComposite Primary Endpoint at Week 12

43

2625

84

13

19

40

5

10

15

20

25

30

35

40

45

10% Improvementin 6-MWD

Improvement inFunctional Class

Death or ClinicalWorsening

Composite PrimaryEndpoint

Iloprost

Placebo

Olschewski, et al. N Engl J Med. 2002;347:322-9.

Res

pond

ers

(% P

atie

nts)

P = 0.0033

N = 203

Treprostinil for PAH

• Prostacyclin analog

• Indication – WHO group I -functional class II, III, IV

• Dosage – 1.25 – 40 ng/kg/min

• Administration– Subcutaneous

– IV

– Inhalation

Infusion site reaction

Treprostinil SC for PAH Change in 6-MWD (from Baseline to Week 12)

0

5

10

15

20

25

30

35

40

< 5.0ng/kg/min

5.0 - 8.1ng/kg/min

8.2 – 13.8ng/kg/min

> 13.8 ng/kg/min

3.31.4

20

36.1

Cha

nge

from

Bas

elin

e (m

eter

s)

P = 0.03

Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.

N = 470

Treprostinil IV for PAHChange from Baseline to Week 12

400375

315

0

50

100

150

200

250

300

350

400

450

0 6 12

0 0

4

011

9

13

0

2

4

6

8

10

12

14

l ll lll lV l ll lll lV

Change in 6-MWD

Cha

nge

from

Bas

elin

e (m

eter

s)

Tapson, et al. Chest. 2006;129:683-8.

Weeks

Num

ber

of

Pat

ien

ts

Change in Functional Class

12 WeeksBaseline

N = 14

Treprostinil Inhalation for PAH:TRIUMPH-1 Clinical Trial

Treprostinil inhalation FDA approval – July, 2009 Administered four times daily

Study design – phase lll, randomized, double-blind, placebo-controlled, 12-week study

Combination with bosentan or sildenafil Open-label extension for 24 months N= 206 Adverse events – cough, headache,

nausea, diarrhea, flushing, throat irritation

50

3431

0

10

20

30

40

50

60

12 18 24MonthsMonths

Change in 6-MWD from Baseline (meters)Change in 6-MWD from Baseline (meters)

ABSTRACT: Benza, et al. ATS. San Diego, CA. May 15-20, 2009. ABSTRACT: Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

Endothelin Receptor AntagonistsComparison of Agents

Source: FDA-approved product labeling for individual agents. Source: FDA-approved product labeling for individual agents.

Bosentan Ambrisentan

Use in pregnancy Pregnancy category X (non-hormonal birth control method required)

Pregnancy category X (non-hormonal birth control method required)

LFT elevation Monthly LFT monitoring required; ≥ 3x ULN in ~ 11% patients (pooled data from 16-week studies)

Monthly LFT monitoring required; ≥ 3x ULN in 0.8% patients in 12-week studies, 2.8% patients in 1-year studies

Peripheral edema 1.7% patients (placebo-adjusted; fluid retention/edema)

6% patients (placebo-adjusted)

Additional adverse events

Respiratory tract infections, headache, fainting, flushing, low blood pressure, sinusitis, joint pain, irregular heartbeat

Nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, constipation

Endothelin Receptor AntagonistsComparison of Drug-Drug Interactions

Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S78-84. 2) Galie, et al. Eur Heart J. 2009;30:2493-2537. 3) Spence, et al. ATS. San Diego, CA. May 15-20, 2009. 4) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009. Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S78-84. 2) Galie, et al. Eur Heart J. 2009;30:2493-2537. 3) Spence, et al. ATS. San Diego, CA. May 15-20, 2009. 4) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009.

Bosentan AmbrisentanRitonavir

Rifampin

Cyclosporine A

Hormonal contraceptives

Sildenafil

Tadalafil1

Glyburide

Simvastatin (+ other CYP3A-metabolized statins)

CYP2C9 inhibitors (fluconazole, amiodarone)

CYP3A inhibitors (ketoconazole, itraconazole, amprenavir, erythromycin, fluconazole, diltiazem)

Tacrolimus

Phenytoin2

Warfarin2

Ritonavir

Rifampin

Cyclosporine A

Hormonal contraceptives3

Omeprazole4

Ketoconazole2,4

Bosentan for PAH

• Endothelin receptor antagonist (ETA/ETB non selective)

• Indication – WHO group I - functional class II, III, IV• Dosage – 62.5 mg oral twice daily for 4 weeks then

125 mg oral twice daily

62.5 mg bid 125 or 250 mg bid Bosentan

-40

-20

0

20

40

60

80

Bosentan (N= 144)

Placebo (N= 69)

Baseline Week 4 Week 8 Week 16

P = 0.0002

Cha

nge

from

Bas

elin

e (m

eter

s)

Rubin, et al. N Engl J Med. 2002;346:896-903.

Bosentan for PAH:BREATHE Clinical Trial

Change in 6-MWD (from Baseline to Week 16)

Bosentan for PAHComparison of 6-MWD in 6-Month, Open-Label Study

406

360

434

416

394

394

439 442

426435 430

300

350

400

450

500

Baselinecontrolled study

Baseline open-label study

1 month 6 months

Former placebopatients

Former bosentanpatientsCombined group(all bosentan)

Sitbon, et al. Chest. 2003;124:247-54.

Six-month, open-label study of bosentan (125 mg bid) aftera double-blind, placebo-controlled, four-month study

Delay in treatment in former placebo patients → less robust improvement in 6-MWD during open-label extension

N= 29

Cha

nge

from

Bas

elin

e (m

eter

s)

Bosentan for PAH:EARLY Clinical Trial

107.5

83.2

0

20

40

60

80

100

120

Placebo (N= 88)

Bosentan (N= 80)

Change in PVR (from Baseline to Week 24)

Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

% o

f B

asel

ine

PV

R a

t W

eek

24(g

eom

etric

me

ans)

P < 0.0001

Decrease in PVR:Surrogate marker for delaying disease progression

Treatment effect =- 22.6%

Treatment effect =- 22.6%

Bosentan for PAH:EARLY Clinical Trial

10

5

0

5

10

15

20

12 24 weeks

Placebo (N= 91)

Bosentan (N= 86)P = 0.076

25

20

15

Change in 6-MWD (from Baseline to Week 24)

Treatment effect =+ 19.1 meters

Treatment effect =+ 19.1 meters

Cha

nge

in 6

-MW

D (

met

ers)

Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

11.2

- 7.9

weeks

Bosentan for PAH:EARLY Clinical Trial

100

80

60

40

20

00 4 8 12 16 20 2824 32

92 90 89 86 84 83 1877 993 92 87 85 84 83 2780 15

Eve

nt-F

ree

Pat

ient

s (%

)

Patients at risk (N)

Placebo

Bosentan

P < 0.02

Time to Clinical Worsening (from Baseline to Week 32)

weeksweeks

Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

Ambrisentan for PAH

• Endothelin receptor antagonist (ETA selective)

• Indication – WHO group I - functional class II, III• Dosage – 5 mg and 10 mg oral daily

Ambrisentan for PAHChange in 6-MWD (from Baseline to Week 12)

Galie, et al. Circulation. 2008;117:3010-9.

-25

0

25

50

4 8 12 weeks

10 mg:+43.6 m

5 mg:+22.8 m

Placebo:-7.8 m

N= 202

4 8 12 weeks

5 mg:+49.4 m

2.5 mg+22.2 m

Placebo:-10.1 m

-20

0

20

40

60N=192

Cha

nge

from

Bas

elin

e (m

eter

s)

ARIES 1 ARIES 2

Placebo-adjusted change at week 12:Ambrisentan 5 mg = 31 m; 10 mg = 51 m

Placebo-adjusted change at week 12:Ambrisentan 2.5 mg = 32 m; 5 mg = 59 m

Ambrisentan for PAH:ARIES 1 and 2 Clinical Trials

Time to Clinical Worsening

--- Placebo--- 2.5 mg (P = 0.03)--- 5 mg (P = 0.005)--- 10 mg (P = 0.03)

70

80

90

100

0 4 8 12 Weeks

Eve

nt-F

ree

Pat

ient

s (%

)

Ambrisentan → 71% relative risk reduction

Galie, et al. Circulation. 2008;117:3010-9.

Ambrisentan for PAH:ARIES-E

Change in 6-MWD (from Baseline to 24 Months)

Mean ± 95% CI; LOCF for missing data

Cha

nge

from

Bas

elin

e (m

eter

s)

2.5 mg (N = 93)5 mg (N = 186)10 mg (N = 96)

Years

-20

-100

1020

3040

50

60

0.0 0.25 0.5 1.0 1.5 2.0

70

7 m

23 m28 m

Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.

Ambrisentan for PAH:ARIES-E

Change in WHO Functional Class

40

20

0

20

40

60

80

100

0.0 0.25 0.5 1.0 1.5 2.0

Years

Pat

ient

s (%

)

Ma

inta

ine

d o

r Im

pro

ved

Wo

rsen

ed

2.5 mg (N= 94)5 mg (N = 187)10 mg (N = 96)

LOCF for missing data

79%86%90%

10%14%21%

Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.

Phosphodiesterase-5 InhibitorsComparison of Drug-Drug Interactions

Sildenafil TadalafilNitrates

Alpha blockers

Amlodipine

Ritonavir

Bosentan1

HMG CoA reductase inhibitors1

Phenytoin1

Erythromycin1

Ketoconazole1

Cimetidine1

Rifampin1

Phenobarbital1

Carbamazepine1

Nitrates

Alpha blockers

Antihypertensive agents

Ketoconazole

Rifampin

Ritonavir

Bosentan1

Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:2493-2537.Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:2493-2537.

Sildenafil for PAH

• PDE-5 inhibitor• Indication – to increase exercise capacity,

decrease clinical worsening in patients with WHO group I – functional class II, III, IV

• Dosage – 20 mg oral three times daily• IV formulation

– Approved December, 2009– Dosage – 10 mg three times daily

Sildenafil for PAH:SUPER Clinical Trial

Change in WHO Functional Class (from Baseline to Week 12)

Placebo (N= 70) Sildenafil (N= 203)

Pat

ient

s (%

)

0%

20%

40%

60%

80%

100%

Baseline Week 12 Baseline Week 12

Class I Class II Class III Class IV

Galie, et al. N Engl J Med. 2005;353:2148-57.

Sildenafil for PAH:Long-Term Extension of SUPER Clinical Trial

Change in 6-MWD (from Baseline)

48

51

40

45

50

55

12 weeks 12 months

Cha

nge

from

Bas

elin

e (m

eter

s)

(N= 222)(N= 273)

Galie, et al. N Engl J Med. 2005;353:2148-57.

Sildenafil for PAH:SUPER 2 Clinical Trial

• Study design– Open-label, long-term extension of SUPER clinical trial

• Patients– N= 259 enrolled; 180 completed 3 years of follow-up

• Dosage = 20-80 mg three times daily• Study results at 3 years

– Functional class – improved in 30%; unchanged in 31%– Kaplan-Meier estimated survival = 79%– Patient disposition – 53 patients died (29%); 44 discontinued therapy (24%)– Combination therapy – 20%– Adverse effects – mild/moderate in severity

ABSTRACT: Rubin, et al. CHEST. Philadelphia, PA. Oct. 25-30, 2008.

Tadalafil for PAH

• FDA approval – May, 2009• PDE-5 inhibitor• Indication – to increase exercise capacity, decrease

clinical worsening in patients with WHO group I – functional class II, III, IV

• Dosage – 40 mg oral daily

Tadalafil for PAH:PHIRST Clinical Trial

Subgroup analysis: Study design – phase lll, double-

blind, placebo-controlled, multicenter, 16-week study

Comparison of tadalafil monotherapy (N= 189) to combination therapy with bosentan 125 mg twice daily (N= 216)

Dosage of tadalafil = 20 mg and 40 mg

Study resultsNo greater improvement in 6-MWD with combination therapy compared to monotherapy

32

44

23 23

05

101520

253035

4045

Week 16

Monotherapy 20 mg

Monotherapy 40 mg

Combination therapy 20 mg

Combination therapy 40 mgABSTRACT: Barst, et al. ATS. San Diego, CA. May 15-20, 2009.Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.ABSTRACT: Barst, et al. ATS. San Diego, CA. May 15-20, 2009.Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.

Change in 6-MWD from Baseline (meters)Change in 6-MWD from Baseline (meters)

Tadalafil for PAH:PHIRST Clinical Trial

Study Results• Efficacy

– Greater improvement in 6-MWD in treatment-naïve patients compared to patients with background bosentan

– Significant improvements in quality of life and time to and incidence of clinical worsening (68% relative risk reduction)

• Safety– Most common adverse events were headache, myalgia, and flushing

which were mild to moderate in severity

Galie, et al. Circulation. 2009;Epub May 26.Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.Galie, et al. Circulation. 2009;Epub May 26.Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.

Tadalafil for PAH:PHIRST Clinical Trial

-1

7

3

13

1.5

10

-2

8

-1

7

-3.5

9

-4

-2

0

2

4

6

8

10

12

14

PhysicalFunctioning

Role-Physical

Bodily Pain GeneralHealth

Vitality SocialFunctioning

Placebo

Tadalafil 40 mg

Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.

P< 0.01 vs Placebo

Mea

n C

han

ge f

rom

Ba

selin

e to

Wee

k 16

Short Form 36 (SF-36) Domains

Quality of life measure:Higher scores reflect better functioning and health status

Tadalafil for PAH:Long-Term Extension of PHIRST

Study design – phase lll, double-blind, placebo-controlled study (16 weeks) → long-term extension study (44 weeks)

Dosage = 20 mg and 40 mg N = 241 Study results

Efficacy6-MWD: sustained improvement over 44 weeksSafety62 patients withdrew from study including: 17 due to PAH progression; 12 due to adverse events; 11 due to death

37

38

30

35

40

16 44

ABSTRACT: Oudiz, et al. ATS. San Diego, CA. May 15-20, 2009.ABSTRACT: Oudiz, et al. ERS. Vienna, Austria. September 14, 2009.ABSTRACT: Oudiz, et al. ATS. San Diego, CA. May 15-20, 2009.ABSTRACT: Oudiz, et al. ERS. Vienna, Austria. September 14, 2009.

Change in 6-MWD from Baseline (meters)Change in 6-MWD from Baseline (meters)

WeeksWeeks

Low Risk Determinants of Risk High Risk

No Clinical evidence of RV failure Yes

Gradual Disease progression Rapid

II, III WHO functional class IV

Longer (> 400 meters) 6-MWD Shorter (< 300 meters)

Peak VO2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO2 < 10.4 mL/kg/min

Minimally elevated and stable BNP/NT-proBNP Significantly elevated

PaCO2 > 34 mm Hg Blood gasses PaCO2 < 32 mm Hg

Minimal RV dysfunction ECHO findingsPericardial effusion, RV dysfunction,

RA enlargement

RAP < 10 mm Hg;

CI > 2.5 L/min/m2Hemodynamics

RAP > 20 mm Hg;

CI < 2 L/min/m2

McLaughlin, et al. Circulation. 2006;114:1417-31.McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.

PAH Determinants of Patient RiskACC/AHA Expert Consensus

Combination Therapy for PAH

• To target multiple disease pathways– Endothelin pathway (endothelin receptor antagonists)– Nitric oxide pathway (PDE-5 inhibitors)– Prostacyclin pathway (prostacyclin analogs)

• Used clinically with little evidence to date• Used when therapy needs to be augmented because patient

response to monotherapy is inadequate• Must consider the drug interaction potential of agents to be

combined (risk-benefit analysis)– Drug interaction between bosentan and sildenafil– Drug interaction between bosentan and tadalafil

Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.

Combination Therapy for PAH

TTCW = time to clinical worsening; NSS = non-statistically significant; SS = statistically significant1) Humbert, et al. Eur Respir J. 2004;24:353-9. 2) McLaughlin, et al. Am J Respir Crit Care Med. 2006;174:1257-63. 3) Hoeper, et al. Eur Respir J. 2006;28:691-4. 4) Simonneau, et al. Ann Intern Med. 2008;149:521-30. 5) Galie, et al. Circulation. 2009;119(22):2894-903.

Clinical Study Agents Study Design N Study Endpoints Statistical Significance

Humbert, et al1 Epoprostenol

Bosentan

Randomized, double-blind, placebo-controlled; 16 weeks

33 Hemodynamics, exercise capacity, functional class

NSS findings

McLaughlin, et al2 Iloprost

Bosentan

Randomized, double-blind, placebo-controlled, multicenter; 12 weeks

67 Hemodynamics, exercise capacity, functional class, TTCW

SS improvement in parameters

Hoeper, et al3 Iloprost

Bosentan

Randomized, placebo-controlled, multicenter; 12 weeks

40 Exercise capacity, functional class, TTCW

NSS findings

Simonneau, et al4 Epoprostenol

Sildenafil

Randomized, double-blind, placebo-controlled, multicenter; 16 weeks

256 Hemodynamics, exercise capacity, TTCW

SS improvement in exercise capacity, TTCW

Galie, et al5 Bosentan

Tadalafil

Randomized, double-blind, placebo-controlled; 16 weeks

405 Hemodynamics, exercise capacity, functional class, TTCW, quality of life

SS improvement in all parameters, except functional class

Monitoring Schedule forPatients with PAH

Parameter Baseline (pretreatment)

Every 3-6 months

3-4 Months after start or change in therapy

If clinical worsening

Clinical assessment

WHO functional class

ECG

X X X X

6-MWD X X X XCardiopulmonary exercise testing

X X X

BNP/NT-proBNP X X X XECHO X X X

Right heart catheterization X X X

Galie, et al. Eur Heart J. 2009;30:2493-2537.Galie, et al. Eur Heart J. 2009;30:2493-2537.

Summary

• Comprehensive management of PAH involves optimizing multiple supportive therapies

• Early, evidence-based treatment of PAH is associated with improved patient outcomes

• Agents for the treatment of PAH vary with regard to:– Indication, administration, adverse effect profile, drug-drug

interactions, clinical study data

• Therefore, a comparison of the risk-benefit ratio of available agents is needed to guide PAH treatment selection