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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.

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Learning objectives l.jpg

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 l.jpg

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.


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Mechanisms of Pathology for PAH

Endothelinpathway

Prostacyclinpathway

Nitricoxidepathway

Endothelial cells

L-arginine

Preproendothelin

Proendothelin

Arachidonicacid

Prostaglandin I2

NOS

Nitric oxide

Prostaglandin I2

Endothelin-1

Endothelin-receptor A

Endothelin-receptor B

Exogenous nitric oxide

Prostacyclinderivates

cGMP

Endothelin-receptor antagonists

cAMP

Phosphodiesterase type 5

Vasodilatation and antiproliferation

Vasodilatation and antiproliferation

Vasoconstriction and proliferation

Phosphodiesterase type 5 inhibitor

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


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Pathophysiology of PAH

Genetic

Predisposition

}

Vasoconstriction

Cell Proliferation

Thrombosis

Vascular

Remodeling

Other Risk

Factors

(CTD, CHD, toxins, etc.)

Altered Pathways

And Mediators


Genetic mutations in pah l.jpg

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

Genetic Mutations in PAH

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


Vasoconstriction in pah l.jpg

Vasoconstriction in PAH

Vasoconstriction

Vasodilation

Enhanced Vasoconstriction

↑ Endothelin

↑ Serotonin (5-HT)

↑ Thromboxane

↓ Potassium channel

expression/activity

Impaired Vasodilation

↓ Prostacyclin

↓ Nitric oxide

↓ Nitric oxide synthase


Cell proliferation in pah l.jpg

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 l.jpg

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.


Revised classification of pulmonary hypertension group 1 pulmonary arterial hypertension pah l.jpg

Revised Classification ofPulmonary HypertensionGroup 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.


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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.


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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 conditions 4 th world symposium on ph 2008 l.jpg

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

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


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Patient Evaluation

Confirm presence of PH

Determine type of PH present (PAH?)

Gauge functional capacity

Estimate prognosis (survival)

Determine treatment and monitoring plan


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NYHA/WHO FunctionalClassification for PAH

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


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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.


Response to ccb therapy and survival in patients with pah l.jpg

1.0

0.8

0.6

0.4

0.2

0.0

0

2

4

6

8

10

12

14

16

18

Response to CCB Therapy andSurvival in Patients with PAH

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

P = 0.0007

Cumulative Survival

Long-term CCB non-responders

Years

Long-term CCBresponders

38

33

30

22

13

8

3

3

2

1

Patientsat risk (N)

19

12

7

4

0

Long-term CCBnon-responders

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


Impact of delay in treatment on patient survival l.jpg

Impact of Delay in Treatmenton Patient Survival

96%

84%

86%

↑Transition placebo

group to ambrisentan

76%

Event-Free Survival (% Patients)

Weeks

N = 251 242226 209 195Ambrisentan

N = 122 110100 94 95Placebo → Ambrisentan

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


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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.


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Oral anticoagulants (E/B) – IPAH/HPAH

Diuretics (E/A)

Oxygen (E/A)

Digoxin (E/C)

Supervised rehabilitation (E/B)

Supportive therapy and general measures

Avoid excessive physical exertion (E/A)

Birth control (E/A)

Psychosocial support (E/C)

Infection prevention(E/A)

Expert referral (E/A)

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

NO

Prostanoids

+ (B)

+ (B)

PDE-5 I

+ (B)

ERA

PAH Evidence-Based Treatment Algorithm

ACUTE RESPONDER

NON-RESPONDER

WHO Class I-IV

Amlodipine, diltiazem, nifedipine (B)

Sustained response

(WHO I-II)

YES

Amlodipine, diltiazem, nifedipine(B)

INADEQUATE CLINICAL RESPONSE

Sequential combination therapy

INADEQUATE CLINICAL RESPONSE

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

4th World Symposium on PH. Dana Point, CA. 2008.

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


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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

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

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


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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


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Comparison of Agents

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


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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)

CADD pump

Central line


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100

80

60

40

20

0

0

2

4

6

8

10

12

Epoprostenol for IPAH

Patient Survival

Epoprostenol (N=41)

P = 0.003

Conventional therapy (N = 40)

Patient Survival (%)

Weeks

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


Iloprost for pah l.jpg

Prostacyclin analog

Indication – WHO group I - functional class III, IV

Administration

Ultrasonic nebulizer

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

Administration in well-ventilated areas

Theoretical advantage of selectivity

Pulmonary vs systemic administration

Iloprost for PAH


Iloprost for pah composite primary endpoint at week 12 l.jpg

Iloprost for PAHComposite Primary Endpoint at Week 12

P = 0.0033

Responders (% Patients)

N = 203

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


Treprostinil for pah l.jpg

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 l.jpg

40

35

30

25

20

15

10

5

0

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

36.1

P = 0.03

20

Change from Baseline (meters)

N = 470

3.3

1.4

< 5.0

ng/kg/min

8.2 – 13.8ng/kg/min

> 13.8 ng/kg/min

5.0 - 8.1ng/kg/min

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


Treprostinil iv for pah change from baseline to week 12 l.jpg

Treprostinil IV for PAHChange from Baseline to Week 12

Change in Functional Class

Change in 6-MWD

N = 14

Number of Patients

Change from Baseline (meters)

Weeks

Baseline

12 Weeks

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


Treprostinil inhalation for pah triumph 1 clinical trial l.jpg

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

Change in 6-MWD from Baseline (meters)

Months

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


Endothelin receptor antagonists comparison of agents l.jpg

Endothelin Receptor AntagonistsComparison of Agents

Source: FDA-approved product labeling for individual agents.


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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.


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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


Bosentan for pah breathe clinical trial change in 6 mwd from baseline to week 16 l.jpg

80

60

40

20

0

-20

-40

Bosentan for PAH:BREATHE Clinical TrialChange in 6-MWD (from Baseline to Week 16)

Bosentan (N= 144)

P = 0.0002

Change from Baseline (meters)

Placebo (N= 69)

Baseline

Week 4

Week 8

Week 16

125 or 250 mg bid Bosentan

62.5 mg bid

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


Bosentan for pah comparison of 6 mwd in 6 month open label study l.jpg

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

N= 29

Change from Baseline (meters)

Six-month, open-label study of bosentan (125 mg bid) after

a double-blind, placebo-controlled, four-month study

Delay in treatment in former placebo patients → less robust

improvement in 6-MWD during open-label extension

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


Bosentan for pah early clinical trial l.jpg

Bosentan for PAH:EARLY Clinical Trial

Change in PVR (from Baseline to Week 24)

Decrease in PVR:

Surrogate marker for delaying disease progression

P < 0.0001

% of Baseline PVR at Week 24(geometric means)

Treatment effect =

- 22.6%

Galie, et al. Lancet. 2008.371(9630):2093-100.

Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.


Bosentan for pah early clinical trial38 l.jpg

Bosentan for PAH:EARLY Clinical Trial

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

25

20

15

11.2

Placebo (N= 91)

10

Bosentan (N= 86)

P = 0.076

5

Change in 6-MWD (meters)

0

12

24

weeks

weeks

5

10

- 7.9

15

Treatment effect =

+ 19.1 meters

20

Galie, et al. Lancet. 2008.371(9630):2093-100.

Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.


Bosentan for pah early clinical trial39 l.jpg

Bosentan for PAH:EARLY Clinical Trial

92

93

90

92

89

87

85

86

84

84

83

83

77

80

27

18

15

9

Time to Clinical Worsening (from Baseline to Week 32)

100

P < 0.02

80

Placebo

60

Bosentan

Event-Free Patients (%)

40

20

0

0

4

8

12

16

20

24

28

32

weeks

Patients at risk (N)

Galie, et al. Lancet. 2008.371(9630):2093-100.

Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.


Ambrisentan for pah l.jpg

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 pah change in 6 mwd from baseline to week 12 l.jpg

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

ARIES 1

ARIES 2

60

50

N=192

N= 202

10 mg:

+43.6 m

5 mg:

+49.4 m

40

25

5 mg:

+22.8 m

2.5 mg

+22.2 m

20

Change from Baseline (meters)

0

0

Placebo:

-7.8 m

Placebo:

-10.1 m

-20

8

12 weeks

4

12 weeks

4

8

-25

Placebo-adjusted change at week 12:

Ambrisentan 2.5 mg = 32 m; 5 mg = 59 m

Placebo-adjusted change at week 12:

Ambrisentan 5 mg = 31 m; 10 mg = 51 m

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


Ambrisentan for pah aries 1 and 2 clinical trials time to clinical worsening l.jpg

Ambrisentan for PAH:ARIES 1 and 2 Clinical TrialsTime to Clinical Worsening

100

--- Placebo

--- 2.5 mg (P = 0.03)

--- 5 mg (P = 0.005)

--- 10 mg (P = 0.03)

90

Event-Free Patients (%)

80

70

0

4

8

12

Weeks

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 l.jpg

Ambrisentan for PAH:ARIES-EChange in 6-MWD (from Baseline to 24 Months)

2.5 mg (N = 93)

5 mg (N = 186)

10 mg (N = 96)

70

60

50

40

28 m

30

Change from Baseline (meters)

23 m

20

10

7 m

0

-10

-20

0.25

1.0

1.5

2.0

0.0

0.5

Years

Mean ± 95% CI; LOCF for missing data

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


Ambrisentan for pah aries e change in who functional class l.jpg

Ambrisentan for PAH:ARIES-EChange in WHO Functional Class

100

90%

86%

80

79%

Maintained or Improved

60

2.5 mg (N= 94)

5 mg (N = 187)

10 mg (N = 96)

40

20

Patients (%)

0

10%

14%

20

Worsened

21%

40

1.5

0.0

0.25

0.5

1.0

2.0

Years

LOCF for missing data

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


Phosphodiesterase 5 inhibitors comparison of drug drug interactions l.jpg

Phosphodiesterase-5 InhibitorsComparison of Drug-Drug Interactions

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


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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 l.jpg

Sildenafil for PAH:SUPER Clinical TrialChange in WHO Functional Class (from Baseline to Week 12)

Placebo (N= 70)

Sildenafil (N= 203)

100%

80%

60%

Patients (%)

40%

20%

0%

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 l.jpg

Sildenafil for PAH:Long-Term Extension of SUPER Clinical TrialChange in 6-MWD (from Baseline)

Change from Baseline (meters)

(N= 222)

(N= 273)

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


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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.


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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 l.jpg

Tadalafil for PAH:PHIRST Clinical Trial

Change in 6-MWD from Baseline (meters)

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 results

    No greater improvement in 6-MWD with combination therapy compared to monotherapy

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.


Tadalafil for pah phirst clinical trial52 l.jpg

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.


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Tadalafil for PAH:PHIRST Clinical Trial

Short Form 36 (SF-36) Domains

Mean Change from Baseline to Week 16

Quality of life measure:

Higher scores reflect better functioning and health status

P< 0.01 vs Placebo

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


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Tadalafil for PAH:Long-Term Extension of PHIRST

Change in 6-MWD from Baseline (meters)

  • 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

    Efficacy

    6-MWD: sustained improvement over 44 weeks

    Safety

    62 patients withdrew from study including: 17 due to PAH progression; 12 due to adverse events; 11 due to death

Weeks

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

ABSTRACT: Oudiz, et al. ERS. Vienna, Austria. September 14, 2009.


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PAH Determinants of Patient RiskACC/AHA Expert Consensus

McLaughlin, et al. Circulation. 2006;114:1417-31.

McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.


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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.


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Combination Therapy for PAH

TTCW = time to clinical worsening; NSS = non-statistically significant; SS = statistically significant

1) 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.


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Monitoring Schedule forPatients with PAH

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


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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


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