Pulmonary Arterial Hypertension: Disease State and Treatment Options Dr. William Harvey Director Pulmonary Artery Hypertension Clinic IU Health North Hospital

Pulmonary Arterial Hypertension: Disease State and Treatment Options

Dr. William HarveyDirector Pulmonary Artery

Hypertension ClinicIU Health North Hospital

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Presentation Outline

Definition of PAH

Pathophysiology

Epidemiology

Clinical classification

Natural history

Signs and symptoms

Diagnosis

Treatment of PAH

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Pulmonary Arterial Hypertension: Definition and Histological Characteristics

Mean PA pressure >25 mm Hg or 30 mm Hg with exercise (PCWP ≤15 mm Hg)

PVR >3 Wood units

Increased pressure load on RV

Eventual right-sided heart failure and death

lumen

media

intima

adventitia

Normal pulmonary arteriole

Plexiform lesion

Pulmonary arteriole in PAH

Barst et al. J Am Coll Cardiol. 2004;43:40S-47S.

PathophysiologyPulmonary Artery Hypertension

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Pathogenesis of PAH: Vasoconstriction

Decreased NO synthaseProstacyclinNO Increased

EndothelinSerotoninThromboxane

Vasodilation

Vasoconstriction

Mechanisms of Pathology for PAH

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

Nitric oxide

cGMPVasodilatation 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

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Epidemiology/ClassificationPulmonary Artery Hypertension

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Epidemiology of PAH (WHO Group I)1

Idiopathic PAH2

– Incidence is approximately 2 to 5 per million per year

– 2 to 3 times more prevalent in women

– Mean age of 37 years at diagnosis3

Familial PAH

– Observed in about 6% to 10% of PAH cases3

Associated PAH

– Approximately 27% of patients with CTD (scleroderma or mixed CTD) have PAH4

Equally high prevalence in limited and diffuse disease5

– Each year, 0.5% of patients with HIV develop PAH6

– Prevalence of portopulmonary hypertension is 4% to 15% among patients undergoing evaluation for liver transplantation7-8

– 15% to 30% of all patients with congenital heart disease have PAH9

1. Simonneau et al. J Am Coll Cardiol. 2004;43(12 suppl):5S-12S. 2. Gaine and Rubin. Lancet. 1998;352:719-725. 3. Rich et al. Ann Intern Med. 1987;107:216-223. 4. Wigley et al. Arthritis Rheum. 2005;52:2125-2132. 5. Launay et al. J Rheumatol. 2007;34:1005-1011. 6. Limsukon et al. Mt Sinai J Med. 2006;73:1037-1044. 7. Colle et al. Hepatology. 2003;37:401-409. 8. Kuo et al. Chest. 1997;112:980-986. 9. Landzberg. Clin Chest Med. 2007;28:243-253.

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Epidemiology of PAH

Rare disease (orphan designation) of the pulmonary microvasculature affecting 50,000 to 100,000 people in the United States1

– Affects all ages and races

– Most prevalent in 4th and 5th decades of life

– Higher prevalence in females

True incidence and prevalence may be underestimated

– Due to under diagnosis (e.g., in patients with HIV) and misdiagnosis (e.g., asthma)2

Prevalence of PAH may increase because of demographic trends in associated conditions

1. Rubin. Chest. 1993;104:236-250. 2. Ghamra and Dweik. Cleve Clin J Med. 2003;70:S2-S8.

2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1

Idiopathic (IPAH) Heritable (PAH)

– BMPR2

– ALK1

– Endoglin (with or without hereditary hemorrhagic telangiectasia)

– Unknown

Drugs and Toxins induced Associated with

– Connective Tissue Diseases

– HIV Infection

– Portal Hypertension

– Congenital Heart Diseases

– Schistosomiasis

– Chronic hemolytic anemia

Persistent pulmonary hypertension of the newborn

Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.


Pulmonary hypertension owing to left heart disease

– Systolic dysfunction

– Diastolic dysfunction

– Valvular disease



Pulmonary hypertension owing to lung diseases and/or hypoxia

– Chronic obstructive pulmonary disease

– Interstitial lung disease

– Other pulmonary diseases with mixed restrictive and obstructive pattern

– Sleep-disordered breathing

– Alveolar hypoventilation disorders

– Chronic exposure to high altitude

– Developmental abnormalities



Chronic thromboembolic pulmonary hypertension (CTEPH)



Pulmonary hypertension with unclear multifactorial mechanisms

Hematologic disorders: myeloproliferative disorders, splenectomy

Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis

Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis


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NYHA Functional Classification

Rich, ed. Executive summary from the World Symposium on Primary Pulmonary Hypertension, Evian, France, 1998:6-10.

NYHA Definition

Class I No symptoms with ordinary physical activity

Class II Some symptoms with ordinary activity and slight limitation of physical activity

Class III Symptoms with less than ordinary activity and increased limitation of physical activity

Class IV Symptoms with any activity, possibly even while at rest

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WHO Functional Classification

WHO Definition

Class I No limitation of physical activity; no symptoms with ordinary physical activity

Class II Slight limitation of physical activity; ordinary physical activity causes PAH symptoms

Class III Marked limitation of physical activity; less than ordinary physical activity causes PAH symptoms

Class IV PAH symptoms with any physical activity and even at rest; discomfort with any physical activity; signs of right heart failure

Rubin. Chest. 2004;126(suppl 1):7S-10S.

Natural HistoryPulmonary Artery Hypertension

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Natural History of PAH: NIH Registry1,2

NIH = National Institutes of Health.Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3, and 4 years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years, respectively. *Patients with primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension.

1. Rich et al. Ann Intern Med. 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med. 1991;115:343-349.

Predicted survival*

69%

56%

46%

38%

Predicted survivalPer

cent

sur

viva

l

Years

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Survival by PAH Etiology

CHD = congenital heart disease; CVD = collagen vascular disease; HIV = human immunodeficiency virus; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PoPH = portopulmonary hypertension.McLaughlin et al. Chest. 2004;126:78S-92S.

0

20

40

60

80

100

0 1 2 3 4 5 6

CHD

CVD

HIV

PPH

PoPH

Years

Per

cent

sur

viva

l

Prognosis in Mixed Treated/Untreated Cohorts

PAH/SSc Progresses Even More Rapidly

Koh, et al. Br J Rheumatol 1996

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Years from Diagnosis of Pulmonary Hypertension

Per

cen

t S

urv

ival

PAH

Lung Involvement without PAH

No Lung involvement

Signs/Symptoms Pulmonary Artery Hypertension

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Symptoms of PAH

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

Shortness of breath (dyspnea)

Chest pain (angina)

Swollen ankles and legs (edema)

Dizziness and/or fainting (syncope)

Feeling tired or worn out (fatigue)

See slides 33-39 for Important Safety Information about Remodulin and refer to the Full Prescribing Information provided.

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REVEAL Database: Most Frequent Symptoms at Diagnosis

Elliott EG, et al. Chest. 2007;132(suppl 4):631S.

Dyspnea at rest

Cough

Dizzy/lightheaded

Presyncope/syncope

Edema

Chest pain/discomfort

Other

Fatigue

Dyspnea on exertion84%

26%

24%

23%

21%

23%

16%

13%

11%

83%

29%

27%

20%

20%

20%

14%

13%

11%

0 25 50 75 100 Incidence (%)

IPAHAPAH

N=1479.

Abstract

Abstract

Implications of Syncope in Patients with PAH

Le RJ, et al. Chest. 2010;138:927A.

N=475 adults with Group 1 PAH completing standardized symptom assessment at time of diagnosis.P<0.01. Hazard ratio 2.56 [95% CI, 1.26, 4.84].

100

80

60

40

20

00 1 2 3 4 5

P<0.01

Syncopal at diagnosisNon-syncopal at diagnosis

Su

rviv

al, %

Follow-up, years

Diagnosis of PAH

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Diagnosis of PAH*

Diagnostic OutcomesHistory and physical† Evaluate signs and symptoms, family history,

associated diseases, ANAsChest x-ray† Assess for RV enlargement, peripheral hypovascularity

(pruning), and prominent pulmonary arteriesEchocardiogram Assess for RV and RA enlargement, RV

dysfunction, TR velocity to measure RVSPElectrocardiogram Evaluate for right heart enlargement and strain, cardiac

rhythmCardiac catheterization†

Evaluate for CHD; measure wedge pressure or LVEDP;

establish severity and prognosis; test vasodilator therapy

PFTs Assess obstructive and restrictive airway disease

VQ scan Rule out thromboembolic disease

*Additional tests may be ordered to rule out possible causes of PAH (pulmonary arteriography, blood tests [HIV, hepatic disease, scleroderma], polysomnography [sleep-disordered breathing]). †Required for referral.

ANA = antinuclear antibody; CHD = congenital heart disease; LVEDP = left ventricular end-diastolic pressure; PFT = pulmonary function test; RA = right atrial; RV = right ventricular; RVSP = right ventricular systolic pressure; TR = tricuspid regurgitation; VQ = ventilation-perfusion.

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Chest X-Ray Consistent With PH

Image courtesy of Vallerie McLaughlin, MD

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Signs of PAH on Echocardiogram with Doppler Apical Four Chamber

Increased sPAP or TR jet

Right atrial and ventricular hypertrophy

Flattening of intraventricular septum

Small LV dimension

Dilated PA

LVRV

LARA

IVS

McGoon, et al. Chest 2004

Echocardiogram:Parasternal Short Axis


Echocardiogram: Apical Four Chamber


Echocardiogram: Tricuspid Regurgitation

Modified Bernoulli’s Equation:4 x (V)² + RAP = RVSP (PASP)

V=tricuspid jet velocity (m/s); RAP= right atrial pressure; RVSP=right ventricular systolic pressure; PASP=pulmonary artery systolic pressure.


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Accuracy of PH Diagnosis by Echocardiography in Advanced Lung Disease

Cohort study of lung transplant patients (n=374)

All patients

– Doppler echo 24 to 48 hours prior to RHC

Prevalence of PH: 25%

Echo frequently inaccurate leading to over diagnosis of pulmonary hypertension in patients with advanced lung disease

Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5):735-740.

0

10

20

30

40

50

60

70

Diagnosis of PH

Stu

die

s (%

)

OverestimationAccurateUnderestimation

NoPulmonary

Hypertension

PulmonaryHypertension

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Actual Diagnoses of Patients Referred to PH Specialty Clinic

Moghbelli MH, et al. Am J Respir Crit Care Med. 2008;177:A923.

Interstitial Lung Disease

Venous Thromboembolism

Other

Structural Heart Disease

Obstructive Sleep Apnea

LV Dysfunction

Obstructive Lung Disease

All Alternative Diagnoses 85.0%

24.0%

22.0%

19%

13.0%

12.0%

5.0%

5.0%

Abstract

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Vasodilator Agents

Nitric Oxide:

– Inhaled gas, short half life, prospective studies, 20-80ppm for 3- 5 minutes

Flolan:

– 2-10 ng/kg/min

– Increase by 2ng/kg/min q 15 minutes until goal

– SE: headache, flushing nausea

Response: mean PAP <40mmHg, 10 mmHg average drop , maintain CO

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Treatment of Pulmonary Arterial Hypertension

Supportive Therapy and General Measures in PAH

Oral anticoagulants (IPAH/HPAH)

– Favorable data primarily from retrospective trials

Diuretics

– Standard of care for right-heart failure

– Clinician preference on choice of agents

Oxygen

– Low-flow supplemental O2 improved outcome in clinical case series; maintain SaO2 >92%

• Not evaluated in randomized controlled trial

Digoxin

– Modest increase in cardiac output

– No data available on long-term management

Supervised exercise program rehabilitation

Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

Additional General and Supportive Measures in PAH

Avoid excessive exertion Avoid pregnancy Avoid constipation Encourage smoking cessation Appropriately refer to ensure psychological and social

support Provide appropriate training and counseling on infection

prevention– Including, but not limited to, infections related to

infusion/injection-based PAH therapy

– Pneumococcal and flu vaccines


When to Initiate PAH-specific Therapy

No data support “wait-and-see” approach to diagnosed PAH

Data suggests that patients assigned to placebo in randomized controlled trials may fail to “catch-up” when enrolled into long-term observational arms

In FC II patients, bosentan improved outcomes consistent with usefulness of early intervention


PAH-specific Therapies Approved for Use in the US

Endothelin Receptor Antagonists

Phosphodiesterase-type 5 Inhibitors

Prostanoids – Prostacyclin Analogs

Ambrisentan (PO) Sildenafil (PO) Epoprostenol (IV)

Bosentan (PO) Tadalafil (PO) Iloprost (inhaled)

Treprostinil (IV, SC, and inhaled)

FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.

Updated Guidelines: PAH-Specific Therapies Available in the US

Adapted from Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

Strength of Recommendation

WHO Class II WHO Class III WHO Class IV

A Ambrisentan, bosentan, sildenafil

Ambrisentan, bosentan, epoprostenol IV, iloprost inh, sildenafil

Epoprostenol IV

B Tadalafil Tadalafil, treprostinil SC

Iloprost inh

C Treprostinil SC

E/B Treprostinil IV Treprostinil IV, initial combo tx

E/C Ambrisentan, bosentan, sildenafil, tadalafil

Recently approved Treprostinil inh Treprostinil inh

Choice of Initial PAH-specific Therapy

Dependent on many factors

– Disease severity

– Approval status

– Route of administration

– Side-effect profile

– Patient preference

– Physician experience and clinical judgment


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Determinants of Disease Severity

BNP = brain natriuretic peptide; CI = cardiac index; RAP = right artery pressure; RV = right ventricular. McLaughlin and McGoon. Circulation. 2006;114:1417-1431.

Determinants of risk Lower risk Higher risk

Clinical evidence of RV failure No Yes

Progression Gradual Rapid

WHO functional class II, III IV

6MWD Longer (>400 m) Shorter (<300 m)

BNP Minimally elevated Very elevated

Echocardiographic findings Minimal RV dysfunction Significant RV dysfunction, pericardial effusion

Hemodynamics Normal/near normal RAP and CI

High RAP, low CI

From McLaughlin and McGoon. With permission.

Comparison of Agents

AgentRoute of

Administration

Adverse Events

Epoprostenol Continuous IV infusion

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

Iloprost Adaptive aerosol device

Headache, cough, flushing, jaw pain

Treprostinil » Subcutaneous

» IV

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

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

Ambrisentan Oral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 2%), lower extremity edema

Bosentan Oral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 10%), lower extremity edema, anemia

Sildenafil Oral Headache, flushing, dyspepsia, epistaxis

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

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

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Pulmonary Arterial Hypertension Treatment Options*

Flolan is a registered trademark of GlaxoSmithKline. Ventavis and Tracleer are registered trademarks of Actelion Pharmaceuticals US, Inc. Letairis is a trademark of Gilead Sciences, Inc. Revatio is a trademark of Pfizer Inc. Remodulin is a registered trademark of United Therapeutics Corp.

Product Delivery Frequency Indicated population

PDE-5 inhibitor

Revatio™ (sildenafil citrate) Oral t.i.d. WHO group I

Endothelin receptor antagonists

Letairis™ (ambrisentan) Oral q.d. WHO class II-III

Tracleer® (bosentan) Oral b.i.d. WHO class III-IV

Prostacyclins

Flolan® (epoprostenol sodium) Injection

IV Continuous NYHA FC III-IV

Remodulin® IV (treprostinil sodium) Injection

IV Continuous NYHA FC II-IV

Remodulin® SC (treprostinil sodium) Injection

SC Continuous NYHA FC II-IV

Ventavis® (iloprost) Inhalation Solution

Inhaled 6-9 x daily NYHA III-IV

*It is important to note that peer-reviewed, head-to-head analyses of the effectiveness of these products have never been conducted. Only a healthcare provider can determine the proper PAH therapy for each patient.

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Treatment Guidelines: Algorithm

CCB = calcium channel blocker; ETRA = endothelin receptor antagonist; PDE-5 = phosphodiesterase type-5.McLaughlin and McGoon. Circulation. 2006;114:1417-1431.

General careOral anticoagulants ± diuretics ± oxygen ± digoxin

Acute vasoreactivity testing

Oral CCB Lower risk Higher risk

Sustained response

Continue CCB

ETRAs or PDE-5 inhibitors (oral)

Epoprostenol or treprostinil (IV)Iloprost (inhaled)Treprostinil (SC)

Epoprostenol or treprostinil (IV)Iloprost (inhaled)

ETRAs or PDE-5 inhibitors (oral)Treprostinil (SC)

AtrioseptostomyLung transplantation

Clinical reassessment: consider additional therapy if goals are not met

Investigational protocolsCombination regimens

PositiveNegative

YesNo

From McLaughlin and McGoon. With permission.

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Calcium Channel Blocker Therapy

Indicated for IPAH patients who respond to acute vasodilator* testing at the time of cardiac catheterization

– Response defined by reduction in mPAP ≥10 mm Hg to a mPAP ≤40 mm Hg, with an unchanged or increased CO1

Approximately 12.8% of patients respond to acute vasodilator testing2

– Only 6.8% had a favorable clinical response to chronic CCB therapy at 1 year

Other PAH treatments should be evaluated if patient does not improve to FC I or II

CO = cardiac output; mPAP = mean pulmonary arterial pressure. *Inhaled nitric oxide, adenosine, or epoprostenol.1. Badesch et al. Chest. 2007;131:1917-1928. 2. Sitbon et al. Circulation. 2005;111:3105-3111.

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Key Treatment Goals

Improve quality of life and survival

Improve to FC I or II

Improve 6MWD to ≥380 m

Improve hemodynamics

Alleviate symptoms

McLaughlin and McGoon. Circulation. 2006;114:1417-1431.

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Treatment Algorithm According to Risk

ETRA = endothelin receptor antagonist; PDE-5 = phosphodiesterase type-5.

McLaughlin and McGoon. Circulation. 2006;114:1417-1431.

LOWER-RISK PATIENTS*

ETRAsPDE-5

inhibitors

ORAL MED

IntravenousInhaled

Subcutaneous

PROSTACYCLIN

HIGHER-RISK PATIENTS†

IntravenousInhaled

Subcutaneous

PROSTACYCLIN

*Important characteristics of lower risk include WHO FC II and III, 6MWD >400 m, and minimal RV dysfunction. †Key characteristics of higher risk include WHO FC IV, 6MWD <300 m, and significant RV dysfunction.

Updated Guidelines: Inadequate Clinical Response to Initial PAH Therapy

Atrial septostomy and/or

Lung transplantation


Failure to show improvement or deterioration with monotherapy

Sequential Combination Therapy

Prostanoids

EndothelinReceptor

Antagonists

PDE5Inhibitors

Conclusions

Recognize potential for PH based on signs and symptoms

Identify etiology of PH and treat reversible causes

Use right heart cath to confirm dx, and help risk stratify

Once start therapy have close clinical f/u to follow response

Decide on treatment goals

Consider referral to PAH center or clinic

Future may be combination therapy

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Documents

Pulmonary Arterial Hypertension: Disease State and Treatment Options Dr. William Harvey Director Pulmonary Artery Hypertension Clinic IU Health North Hospital