Pulmonary Hypertension

Khuram Ameen Oregon Lung Specialists

No Relevant Disclosures

Definition OF Pulmonary Arterial Hypertension

Mean Pulmonary artery pressure of 25 mm or greater at rest and 30 or greater with exercise

Pulmonary capillary wedge pressure (PCWP) <15 mmHg

Pulmonary vascular resistance (PVR) >120 dynes/sec/cm5

WHO Classification

Group 1. Pulmonary arterial hypertension (PAH)

Group 2. Pulmonary hypertension with left heart disease

Group 3. Pulmonary hypertension associated with lung diseases and/or hypoxemia

Group 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease

Group 5. Miscellaneous

PAH Is Difficult to Diagnose

Early symptoms of PAH are subtle and nonspecific Symptoms include dyspnea, fatigue, angina, syncope, among

others1,2

Idiopathic pulmonary arterial hypertension (IPAH) is a diagnosis of exclusion Diagnosis typically takes 2 to 3 years3

1. Peacock AJ et al, eds. Pulmonary Circulation: Diseases and Their Treatment. 2nd ed. Arnold; 2004. 2. National Institutes of Health. National Heart, Lung, and Blood Institute diseases and conditions index. What is pulmonary arterial hypertension? Available at:

http://www.nhlbi.nih.gov/health/dci/Diseases/pah/pah_what.html. Accessed October 18, 2005. 3. Rich S et al. Ann Intern Med. 1987;107:216-223.

Clinical Presentation

Common Initial Symptoms (N =187)

Patients (%)

Dyspnea 60

Fatigue 19

Syncope or near syncope 13

Chest pain 7

Palpitations 5

Leg edema 3

Diagnosis Of Pulmonary Hypertension

Patients suspected of having PH generally

undergo extensive diagnostic testing, which is aimed at confirming its presence and identifying its cause.

The goal of diagnostic testing is to confirm that PH exists and to identify its underlying cause.

Diagnosis of Pulmonary Hypertension

Pulmonary function tests It is usually severe interstitial lung disease (with lung volumes below 50 percent of predicted) or obstructive lung disease that produces PH. In most circumstances, PH should not be attributed to lung disease if the PFTs are only mildly abnormal since PH itself can cause PFT abnormalities

Chest radiograph enlargement of the central pulmonary arteries with attenuation of the peripheral vessels, Right ventricular enlargement

Electrocardiography signs of right ventricular hypertrophy or strain Most ECG signs are not sensitive

Diagnosis of Pulmonary Hypertension

Overnight oximetry Overnight oximetry can be used to screen patients for Obstructive Sleep Apnea-Hypopnea (OSAH)-related nocturnal oxyhemoglobin desaturation, although it is not an acceptable diagnostic test for OSAH. Polysomnography is the gold standard diagnostic test for OSAH and should be considered when the clinical suspicion for OSAH is high

V/Q scan Ventilation-perfusion (V/Q) scanning is used to evaluate patients for thromboembolic disease. A normal V/Q scan accurately excludes chronic thromboembolic disease with a sensitivity of 90 to 100 percent and a specificity of 94 to 100 percent

Diagnosis of Pulmonary Hypertension

Echocardiography Echocardiography is performed to estimate the pulmonary artery systolic pressure and to assess right ventricular size, thickness, and function. In addition, echocardiography can evaluate right atrial size, left ventricular systolic and diastolic function, and valve function, while detecting pericardial effusions and intracardiac shunts

Diagnosis of Pulmonary Hypertension

Right heart catheterization Right heart catheterization is necessary to confirm the

diagnosis of PH and accurately determine the severity of the hemodynamic derangements

The presence and/or severity of a congenital or acquired left-to-right shunt can be confirmed when noninvasive studies are not definitive

A vasoreactivity test is necessary for reasons other than the initiation of advanced therapy

Is there a reason to suspect PAH? Clinical history, Exam, CXR, ECG

No further evaluation necessary

Is PAH Likely? Echocardiogram

No

Is PAH due to LH Disease? Echo

Measure RVSP, RVE, RAE, RV dysfunction

Dx LV systolic; diastolic dysfunction; valvular dysfunction. Appropriate treatment and further evaluation if necessary

Yes

Is PAH due to CHD? Echo with contrast

Rationale

Dx abnormal morphology; shunt surgery; medical treatment of PAH or evaluation for further definition or contributing causes

Yes

ACCP Diagnostic Guidelines

McGoon, et al. Chest 2004

ACCP Diagnostic Guidelines (cont.)

Is PAH due to CTD, HIV? Serologies

Is chronic PE suspected? V/Q scan

Dx scleroderma, SLE, other CTD, HIV. Medical treatment for PAH and further evaluation for contributing causes

Is chronic PE confirmed and operable? Pulmonary angiogram

Yes

Is PAH due to lung disease or hypoxemia? PFT’s, arterial saturation

Yes

Thromboendarterectomy if appropriate or medical treatment

No

Yes

Dx parenchymal lung disease, hypoxemia or sleep disorder. Medical treatment, oxygen, positive pressure breathing, and further evaluation for other contributing causes

Yes

McGoon, et al. Chest 2004

ACCP Diagnostic Guidelines (cont.)

McGoon, et al. Chest 2004

What limitations are caused by the PAH?

FC, 6 MWT

What are the precise hemodynamics?

RHC

Document PA and RA pressures, PCWP (LV or LA pressure if PCWP unobtainable or uncertain), transpulmonary gradient, CO,PVR,SvO2,response to vasodilators: Confirm PAH , or IPAH if no other cause identified. Discuss genetic testing and counseling of IPAH family

Document exercise capacity regardless of cause of PH: Establish baseline, prognosis and document progression/response to treatment with serial re-assessment

Classification of PAH Group One (ACCP 2004)

1.1 Idiopathic (iPAH)

1.2 Familial

1.3 Associated with Collagen vascular disease

Congenital systemic to pulmonary shunts

Portal hypertension

HIV infection

Drugs and Toxins

Other (hemoglobinopathy, glycogen storage diseases etc.)

1.4 Associated with significant venous or capillary involvement 1.5 Persistent pulmonary hypertension of the newborn

At-Risk Populations for PAH

Populations Prevalence/Incidence

IPAH1 1-2/million

CTD 2

Systemic Sclerosis CREST syndrome UNCOVER 3

30% 50%

27% (11% newly identified)

CHD 4 Up to 50% of patients with large VSDs develop Eisenmenger syndrome, often associated with PAH

HIV 5 1/200

SCD 6 20-40%

Drugs/Toxins 7 Direct relationship with anorexigens (amphetamines, cocaine); L-tryptophan may also be associated with PAH

1 Rich, et al. Chest 1989; 2 Braunwald, et al. Heart Disease, 6th ed.; 3 Wigley, et al. Arthritis Rheum 2005; 4 Simmoneau, et al. J Am Coll Cardiol 2004; 5 Speich, et al. Chest 1991; 6 Lin, et al. Curr Hematol Rep 2005; 7 Rich, et al. Chest 2000.

Increased Pulmonary Resistance and Pressure

Pre-Symptomatic Symptomatic Severely Symptomatic

High flow, low resistance vessel Low flow, high resistance vessel

Adapted from Gaine, et al. JAMA 2000.

As PAH Progresses Cardiac Output Declines

Time

PAP PVR

CO

Pre-symptomatic/ Compensated

Symptomatic/ Decompensating

Symptom Threshold

Right Heart Dysfunction

Declining/ Decompensated

IPAH: Rapid Progression and Poor Survival

Adapted from: D’Alonzo, et al. Ann Intern Med 1991.

PAH Survival

0

20

40

60

80

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years of Followup

Surv

ival

(%)

68%

48% 34%

PAH Survival

0

20

40

60

80

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years of Followup

Surv

ival

(%)

68%

48% 34%

PAH: Survival Based on Etiology1

1. Adapted from McLaughlin VV et al. Chest. 2004;126:78-92.

1 2 3 4 5 Years

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0

Survival in PAH

CHD CVD HIV IPAH Portopulm

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

Perc

ent S

urvi

val

PAH

Lung Involvement without PAH

No Lung involvement

PAH Treatment: Targeting Known Pathophysiological Pathways

1. Kaplan NM. Systemic hypertension: mechanisms and diagnosis. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Saunders; 2005:959-987. 2. Spieker LE et al. J Am Coll Cardiol. 2001;37:1493-1505. 3. Badesch DB. Chest. 2004;126:35-62.

Prostacyclins Epoprostenol

Treprostinil IV/SQ?Oral Iloprost, inhaled

PDE-5 inhibitors

Sildenafil Tadalafil

Endothelin receptor antagonists Bosentan

*Sitaxsentan *Ambosertan

Pathways Involved in PAH

ET-1 binds to ETA and ETB receptors on smooth muscle and endothelial cells1

NO stimulates the cGMP pathway2

PGI2 stimulates the cAMP pathway2

Stimuli such as decreased blood flow, hypoxia, or shear stress induce the overproduction of ET-1 and decrease NO production3-5

Chronic imbalance of ET-1, NO, and PGI2 levels lead to pathophysiological changes3-8:

Vasoconstriction Increased vascular tone Smooth muscle cell proliferation

Vascular remodeling Right-heart hypertrophy

Endothelin Is 1 of 3 Main Pathways in PAH1-3

1. Peacock AJ et al, eds. Pulmonary Circulation: Diseases and Their Treatment. 2nd ed. Arnold; 2004. 2. Kaplan NM. In: Zipes DP et al. Braunwald�s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Elsevier Saunders; 2005:959-987. 3. Spieker LE et al. J Am Coll Cardiol. 2001;37:1493-1505.

Endothelial Dysfunction Primarily Drives PAH

Two hallmarks of PAH are vasoconstriction and vascular remodeling1 Vasoconstriction and cellular proliferation are driven by

ET-12 Vasodilation is driven by nitric oxide (NO) and

prostacyclin (PGI2), which are antiproliferative in nature3

Disease severity is associated with excess circulating ET-1 levels4

1. Jeffery TK et al. Pharmacol Ther. 2001;92:1-20. 2. Peacock AJ et al, eds. Pulmonary Circulation: Diseases and Their Treatment. 2nd ed. Arnold; 2004. 3. Hankins SR et al. Curr Cardiol Rep. 2000;2:244-251. 4. Rubens C et al. Chest. 2001;120:1562-1569.

Prostacyclins

Therapeutic Class 2001-2003

2004-2005 2006 1990s-2000

PDE-5 inhibitors

Endothelin receptor antagonists

PAH Treatment: Timeline of Recent Advances1-3

Epoprostenol

Treprostinil

Iloprost

Bosentan

Sitaxsentan*

Sildenafil

*Late stage clinical development 1. Humbert M et al. N Engl J Med. 2004;351:1425-1436. 2. CDER Priority Drug and Biologic Approvals in Calendar Year 2004. Available at http://www.fda.gov/cder/rdmt/NDAPriority04.htm. Accessed on April 10, 2006. 3. CDER Priority Drug and Biologic Approvals in Calendar Year 2005. Available at http://www.fda.gov/cder/rdmt/InternetPriority05.htm. Accessed on April 10, 2006.

WHO Functional Class of PAH Class I Patients with PH but without resulting limitation of physical activity.

Ordinary physical activity does not cause undue dyspnea, chest pain, or near syncope.

Class II Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.

Class III Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.

Class IV Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

Rubin. Chest 2004

PAH: Conventional Therapy

• Includes1

– Supplemental oxygen to treat chronic hypoxemia – Diuretics – Anticoagulants – Digoxin

• Some patients benefit from high-dose calcium channel blockers1

– Can alleviate pulmonary vasoconstriction and increase survival2

– Hypotension and edema can result in poor tolerance of required doses3

– Candidates identified by acute vasodilator challenge1,2

1. Humbert M et al. N Engl J Med. 2004;351:1425-1436. 2. Nauser TD, Stites SW. Am Fam Physician. 2001;63:1789-1798, 1800. 3. Mehta S. Chest. 2003;124:2045-2049.

PAH: Prostacyclin Therapy

• Epoprostenol (Flolan®)1

• Indicated for IPAH and for PAH patients associated with scleroderma – Class III-IV

• Given by continuous infusion – Requires in-dwelling central venous catheter

• Common dose-limiting adverse events: nausea, vomiting, headache, hypotension, and flushing

• Abrupt withdrawal can result in rebound PAH symptoms • Must keep reconstituted solution between 2° and 8°C

1. Flolan prescribing information. GlaxoSmithKline, 2002.

PAH: Prostacyclin Therapy (cont)

• Treprostinil (Remodulin®)1

• Indicated for PAH patients – Class II-IV

• Given via subcutaneous or intravenous infusion • Longer half-life than epoprostenol

– Reduces risk of rebound worsening • Common adverse events: pain (85%) or reaction (83%) at

infusion site • Stable at room temperature

1. Remodulin prescribing information. United Therapeutics Corporation, 2006.

PAH: Prostacyclin Therapy (cont)

• Inhaled iloprost (Ventavis®)1

• Indicated for PAH patients (WHO Group I) – Class III-IV

• Given via nebulizer – Short duration of action2

– 6 to 9 inhalations per day • Common adverse events: flushing, cough, headache

1. Ventavis prescribing information. CoTherix, Inc., 2005. 2. Humbert M et al. N Engl J Med. 2004;351:1425-1436.

PAH: Phosphodiesterase-5 Inhibitor Therapy

• Sildenafil (Revatio™)1

• Indicated for PAH patients (WHO Group I) • Oral

– Recommended dose 20 mg three times per day • Common adverse events: headache, dyspepsia, flushing

1. Revatio prescribing information. Pfizer, Inc., 2005.

PAH: Endothelin Receptor Antagonist Therapy

• Bosentan (Tracleer®)1

• Indicated for PAH patients (WHO Group I) – Class III-IV

• Oral – Initial dose: 62.5 mg bid x 4 weeks – Maintenance dose: 125 mg bid

• Liver enzymes measured prior to initiating treatment and then monthly

• Common adverse events: headache, flushing, abnormal hepatic function, leg edema, anemia

• Pregnancy must be excluded before start of treatment; monthly pregnancy tests required

1. Tracleer prescribing information. Actelion Pharmaceuticals US, Inc. 2005.

Significant Change in 6MWD BREATHE-1

Tracleer 125/250 mg bid (n=144)

Treatment Effect: 44 m (p<0.001)

Rubin, et al. N Engl J Med 2002

-10

20

40

0 4 8 16 12 Weeks

62.5 mg bid 125 or 250 mg bid

Placebo (n=69)

0

Cha

nge

in 6

MW

D (m

)

Data are mean ± SEM. Walk distance was somewhat greater with 250 mg BID, but the potential for increased liver injury causes this dose not to be recommended [125 mg BID (n=74) change in walk distance (m): 27 ± 75, 250 mg BID (n=70) change in walk distance (m): 46 ± 62].

PAH: Class II/III/IV Treatment Algorithm1

1. Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.

Continue calcium- channel blockers

Atrial septostomy or

Lung transplantation

Pulmonary arterial hypertension (WHO functional class II, III, or IV)

Conventional therapy (oral anticoagulant ± diuretics ± oxygen)

Yes No

Acute vasodilator response

Endothelin-receptor antagonist or

PDE5 Inhibitor or

Prostacyclin analogues or

Intravenous prostacyclin

Intravenous prostacyclin or

Endothelin-receptor antagonist or

Prostacyclin analogues or

PDE5 Inhibitor

Class II Oral calcium-channel blockers

Sustained Response PDE5 Inhibitor or

Prostacyclin analogue Endothelian-receptor

antagonists

Class IV Class III

No improvement or deterioration

Yes No