PULMONARY ARTERIAL

HYPERTENSIONChristina Migliore, MD, FCCP

Pulmonary Arterial Hypertension: Definition

Pulmonary arterial hypertension (PAH) is a progressive, incurable disease of the small pulmonary arteries characterized by vascular cell proliferation, aberrant remodeling, and thrombosis in situ

PAH is defined as a combination of1 Sustained elevation of mean pulmonary arterial pressure of

> 25 mm Hg at rest or > 30 mm Hg with exercise Mean pulmonary-capillary wedge pressure and left

ventricular end-diastolic pressure < 15 mm Hg

Pulmonary vascular resistance (PVR = mPAP-PCW/CO)> 3 Wood units1. Farber HW, et al. N Engl J Med. 2004;351:1655-1665.

Pulmonary Hypertension:5th World Symposium Classification

Simonneau G, et al. J Am Coll Cardiol. 2013;

1. Pulmonary Arterial Hypertension• Idiopathic (IPAH)• Familial (FPAH)• Associated with (APAH):

− Collagen vascular disease− Congenital systemic-to-pulmonary shunt− Portal hypertension− HIV infection− Drugs and toxins − Anorectic agents (appetite suppressants)− Others

• Associated with significant venous or capillary involvement− Pulmonary veno-occlusive disease− Pulmonary capillary hemangiomatosis

• Persistent pulmonary hypertension of the newborn

2. Pulmonary With Left Heart Disease• Left-sided atrial or ventricular heart disease• Left-sided valvular heart disease • left-heart inflow/outflow obstructive lesions• congenital cardiomyopathies

3. Pulmonary Hypertension Associated With Lung Diseases and/or Hypoxemia

• Chronic obstructive pulmonary disease• Interstitial lung disease• Sleep-disordered breathing • Alveolar hypoventilation disorders • Chronic exposure to high altitude• Developmental Abnormalities

4. Pulmonary Hypertension Due To Chronic Thrombotic and/or Embolic Disease

• Thromboembolic obstruction of proximal pulmonary arteries

• Thromboembolic obstruction of distal pulmonary arteries

• Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)

5. Pulmonary Hypertension Resulting From Disorders Directly Affecting the Pulmonary Vasculature

• Inflammatory conditions• Schistosomiasis• Sarcoidosis • chronic hemolytic anemia

Survival in Pulmonary Arterial Hypertension

Median survival was ~2.8 years in patients with IPAH prior to the discovery of effective pharmacologic interventions1

Survival rates (patients with IPAH) at 1, 3, and 5 years were 68%, 48%, and 34%, respectively1

PAH mortality attributed to1 Right heart failure 47% Sudden death 26% Other (pneumonia, bleeding) 27%

Although new treatments have improved mortality rates, there is little evidence to support reversal of aberrant remodeling.IPAH = Idiopathic pulmonary arterial hypertension.

1. D’Alonzo GE, et al. Ann Intern Med. 1991;115:343-349.

Survival in Pulmonary Arterial Hypertension Varies by Etiology

Reproduced from McLaughlin VV et al, 2004 with permission from the American College of Chest Physicians. Copyright 2004.

Classifying Disease Severity in PH: WHO Functional Class

Class I: Patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.

Class II: Patients with PH resulting in slight limitation of physical activity. Comfortable at rest, but ordinary physical activity causes dyspnea or fatigue, chest pain, or near syncope.

Class III: Patients with PH resulting in marked limitation of physical activity. Still comfortable at rest, but less-than-ordinary physical activity causes dyspnea or fatigue, chest pain, or near syncope.

Class IV: Patients with PH resulting in inability to perform any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present at rest, and discomfort is increased by any physical activity.

WHO = World health organization.Adapted with permission from McGoon M, et al. Chest. 2004;126:14S-34S.

PULMONARY ARTERIAL HYPERTENSION

Pathogenesis

Pathogenesis of PH

Unclear, but at least 3 processes believed to contribute to arterial narrowing

Vasoconstriction

Vascular remodeling

Thrombosis in situ

Frost A, 2002

Pulmonary Artery Wall Changes in Pulmonary Arterial Hypertension

Normal Wall thickening Fibrous, scarred tissue

Disease progression

PAH: Pathogenesis

NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE

Gaine S. JAMA. 2000;284:3160-3168.

Mediators of Pulmonary Vascular Responses in Pulmonary Arterial Hypertension

Vasoconstriction Cell Proliferation Thrombosis

Increased TxA2 Increased VEGF Increased TxA2

Decreased PGI2 Decreased PGI2 Decreased PGI2

Decreased NO Decreased NO Decreased NO

Increased ET-1 Increased ET-1 —

Increased 5-HT Increased 5-HT Increased 5-HT

Decreased VIP Decreased VIP Decreased VIP

ET-1 = Endothelin-1; NO = Nitric oxide; PGI2 = Prostaglandin I2; 5-HT= Serotonin; TxA2 = Thromboxane A2; VEGF = Vascular endothelial growth factor; VIP = Vasoactive intestinal peptide. Reproduced with permission from Farber H, et al. N Engl J Med. 2004;351:1655-1665.Copyright © 2004. Massachusetts Medical Society. All rights reserved.

Disease Pathways in Pulmonary Arterial Hypertension

Reproduced with permission from Humbert M, et al. N Engl J Med. 2004;351:1425-1436. Copyright © 1993. Massachusetts Medical Society. All rights reserved.

PULMONARY ARTERIAL HYPERTENSION

Diagnosis

Clinical Symptoms and Signs ofPulmonary Arterial HypertensionClinical Symptoms Dyspnea on exertion Fatigue and lethargy Syncope with exertion Chest pain Dizziness Edema Cough Hemoptysis Hoarseness Anorexia Right upper quadrant

discomfort

Clinical Signs Right ventricular

hypertrophy Tricuspid valvular

regurgitation Right ventricular failure Right-sided third heart

sound (S3) Elevated jugular venous

pressure Jugular vein distention Hepatomegaly Peripheral edema EKG screeningGaine SP, Rubin LJ. Lancet. 1998;352:719-725.

Nauser TD, et al. Am Fam Physician. 2001;63:1789-1798. McGoon M, et al. Chest. 2004;126:14S-34S.

Chest Radiograph of Pulmonary Arterial Hypertension

Blue arrows indicate peripheral pruning; red arrow indicates enlargement of central pulmonary arteries; green arrow indicates reduction in retrosternal air space.McLaughlin VV and McGoon M. Circulation. 2006;114:1417-1431.Adapted and reproduced with permission from Circulation. © 2006.

Assessment of PAH:Echocardiography

• Estimated RV systolic pressure• RV size and function• RA size• TR, PI…?PS• Dilation, flow reversal of IVC• PA size• Lack of left sided chamber and valve

abnormalities

Echocardiogram-Severe iPAH

Pulmonary Arterial Hypertension:Definition by RHC

Mean PA pressure > 25 mmHg with PCW <15 mmHg(NIH Registry on PPH, 1987)

PVR ≥ 3 Units

??Exercise mean PA pressure > 30 mmHg

PVR = TPG/CO

TPG = PAM-PCW

Vasoreactivity Testing

During right heart catheterization (RHC) a vasoreactivity test might be performed with epoprostenol, Nitric Oxide.

A positive vasodilator challenge is one with drop in PAM of ≥10mm Hg and a reduction of the PAM to ≤40mm Hg with no change in CO

Patient with a + vasodilator challenge are candidates for calcium channel blocker therapy

Patient with a cardiac index of ≤2.4, unstable B/P (SBP <90mm Hg), hemodynamically unstable, or symptoms of RHF will not undergo a vasoreactivity challenge

10% or less of patients have + vasoreactivity test

Algorithm for Diagnosis of Pulmonary Arterial Hypertension

McLaughlin V, and McGoon M. Circulation. 2006; 114:1417-1431.Reprinted with permission from Circulation. © 2006.

• Patient exam

Case Presentation

HL is a 43 year old mother of three who presented 2 years ago with dyspnea on exertion attributed to obesity at that time. She reports a 1 year usage of fenfluramine prior to symptom onset. She now presents with severe dyspnea on exertion with syncope. States her mother had PAH.

History and physical exam- HR 80, BP 120/80, slight JVD

ECG, chest x-ray, echo- Moderate right atrial and ventricular enlargement, normal left

PFTs, VQ scan, sleep study- normal LFTs, HIV, Autoantibody testing- normal 6 Minute walk distance (6MWD) 240m

Case Study- RHC Results

PAH is defined as a combination of1 Sustained elevation of mean pulmonary arterial pressure of

> 25 mm Hg at rest or > 30 mm Hg with exercise Mean pulmonary-capillary wedge pressure and left ventricular

end-diastolic pressure < 15 mm Hg Pulmonary vascular resistance (PVR = mPAP-PCW/CO)

> 3 Wood units Right heart catheterization- right atrial pressure (RAP) = 8 mean Pulmonary artery pressure (mPAP) = 55 Pulmonary-capillary wedge pressure (PCW)= 6 Cardiac output (CO)= 4.5 L/min Cardiac index (CI) = 3 L/min/m2 , Pulmonary vascular resistance (PVR)= 10.8 Wood units. No change with inhaled nitric oxide

PULMONARY ARTERIAL HYPERTENSION

Treatment

Evolution of Pulmonary Arterial Hypertension Management—Market Introductions* and

Clinical Milestones

*Based on US approvals.

Iloprost

Ventavis®

Bosentan

Tracleer®

Epoprostenol

Flolan®

Combination regimens

Conventional therapy

IV prostanoids extend survival

Treprostinil

Remodulin®

1980s 1990s 2000+

SildenafilRevatio™

Digoxin, diuretics, anticoagulants, andCCBs

Ambrisentan

Letairis™

Therapeutic Interventions in PAH

Reproduced with permission from Farber HW, Loscalzo J. N Engl J Med. 2004;351:1655-1665. Copyright © 2004 Massachusetts Medical Society. All rights reserved.

PAH Determinants of Risk

McLaughlin and McGoon. Circulation 2006;114:1417-31

Lower RiskDeterminants of

Risk Higher Risk

NoClinical evidence

ofRV failure

Yes

GradualProgression of

Symptoms Rapid

II, III WHO class IV

Longer (>400 m) 6MW distance Shorter (<300 m)

Peak VO2 >10.4 ml/kg/min CPET

Peak VO2 <10.4 ml/kg/min

Minimally elevated BNP Very elevated

Minimal RV dysfunction

Echocardiographic findings

Pericardial effusion,significant RV

dysfunction; RA enlargement

Normal/near normal

RAP <10 and CI >2.5

HemodynamicsHigh RAP > 20,

low CI <2.0

Pulmonary Arterial HypertensionTreatment Algorithm

Conventional therapy(oral anticoagulant ± diuretics ± oxygen)

Yes No

Acute vasodilator response

Oral calcium channelblockers

Sustained response

Yes No

Class II/III

Endothelin receptor antagonistor

Prostacyclin analoguesor

Intravenous prostacyclin

Class IV

Intravenous prostacyclin or

Endothelin receptor antagonistor

Prostacyclin analogues

Continue calciumchannel blockers PDE5 inhibitors

Atrial septostomyor

Lung transplantation

No change

NYHA = New York Heart Association. Reprinted with permission from Humbert M, et al. N Engl J Med. 2004;351:1425-1436. Copyright © 2004 Massachusetts Medical Society. All rights reserved.

• COMBINATION THERAPY?

Pulmonary Arterial Hypertension Treatment Options

Product Delivery Indicated population

PDE-5 inhibitor

Adcirca™ (tadalafil) Oral WHO group I

Revatio™ (sildenafil citrate) Oral WHO group I

Endothelin receptor antagonists

Letairis™ (ambrisentan) Oral WHO class II-III

Tracleer® (bosentan) Oral WHO class II-IV

Prostacyclins

Flolan®/ Veletri (epoprostenol sodium) Injection IV NYHA FC III-IV

Remodulin® IV (treprostinil sodium) Injection IV NYHA FC II-IV

Remodulin SC (treprostinil sodium) Injection SC NYHA FC II-IV

Tyvaso® (treprostinil) Inhalation Solution Inhaled NYHA FC III

Ventavis® (iloprost) Inhalation SolutionOrenitram

InhaledOral

NYHA FC III-IV

ORAL THERAPY

Endothelin Receptor Antagonists• Bosentan (Tracleer)

• Mixed ETA/ETB antagonist

• FDA approved for class II-IV PAH

• Oral, well-tolerated

• LFTs, pregnancy concerns

• Ambrisentan (Letairis)

• ETA specificity (unclear clinical significance)

• Once daily dosing

• Pregnancy concerns, NO more LFT’s required by the FDA

Opsumit (macitentan) Mixed ETA/ETB antagonist Dose 10mg Daily No LFT’s monitoring required, but check

baseline REM’s Program required for all female

patients Pregnancy Class X Monthly pregnancy test

PDE 5 inhibitors

o Sildenafil (Revatio) FDA approved for class II-IV PAH Oral, well-tolerated- TID Most common side effect: Headache, stuffy nose,

reflux, myalgias Do not give Nitrates

o Tadalafil (Adcirca) FDA approved for class II-IV PAH Oral, well-tolerated- Once daily Most common side effect: Headaches, stuffy nose,

reflux, myalgias Do not give Nitrates

Orenitram ( oral treprostinil) Contraindications:

Severe Liver impairment (Child Pugh Class C)

Concomitant administration with CYP2C8 inhibitor [eg. gemfibrozil (Lopid®)]

Side Effects: Hypotension Bleeding HA Diarrhea Nausea

Warnings Do not crush pills Pills should be intact Do not stop abruptly Careful use with

patients with diverticulitis

No alcohol If patient misses 2 or

ore doses restart at base dose and re-titrate

If unable to take PO transition to SQ or IV treprostinil

INHALED PROSTANOIDS

Ventavis® (iloprost) Inhalation Solution: Dosage and Administration

6-9 inhalations daily during waking hours-No more than once every two hours

Dose: maximum of 2.5 or 5 mcg per treatment Dosed via I-neb AAD system Set up medication with each dose

AAD system can be monitored for compliance

Adverse effects include flushing, cough, headache, trismus (lockjaw), insomnia, hypotension, vomiting, increased alkaline phosphatase

Tyvaso ™ (treprostinil)

4 inhalations per day 6mcg per inhalation

with up 9 breaths 4 times/day

Medication delivered by special inhalation system

Adverse effect cough, flushing, headache, hypotension

Once a day set up of drug

CONTINUOUS INFUSION PROSTANOIDS

Epoprostenol – Flolan, Veletri (IV only)

Treprostinil- Remodulin (SC or IV)

Epoprostenol (Flolan® & generic, Veletri®) Therapy in PAH

Continuous IV Rx, half life of 3 minutes

FDA-approved for IPAH, APAH

NYHA Class III-IV

Mix only with manufacturers diluent

Significant adverse effects - GI, Musc - skel., hypotension, jaw pain

Flolan Requires ICE packs

Weight base dose

Solution stable for up to 8hrs at room temperature, 48 hrs when refrigerated and 24 hrs if kept cold

Veletri®- RTS up to 77°F

Treprostinil (Remodulin®) Therapy in PAH

Continuous IV or SC Rx, half life of 4-6 hours

NYHA Class III-IV

Can be mixed with 0.9% NS or Sterile water for inj

Significant adverse effects - GI, Musc - skel., jaw pain

Does not require ICE packs

Weight based

Solution bag stable for up to 48hrs

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

What about Lung Transplant?

“Official” Lung Transplant IndicationsJ Heart Lung Transplant 2006;25:745–55.

• General candidate guidelines• Referral & transplant timing guidelines for PAH

Pulmonary Arterial Hypertension

Refer Symptomatic, progressive illness with NYHA class III-IV w/optimal Rx and/or rapidly progressive disease

Transplant when: persisting NYHA class III-IV on therapy declining 6MWD (or <350m) cardiac index <2 L/min/m2 Right atrial pressure >15 mm HG “failing therapy w/ IV epoprostenol or

equivalent”

J Heart Lung Transplant 2006;25:745–55.

.

ADULT LUNG TRANSPLANTATIONKaplan-Meier Survival By Diagnosis (Transplants: January 1994 – June 2003)

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10Years

Su

rviv

al (

%)

ALPHA-1 (N=1,127) CF (N= 1,934)COPD (N= 4,888) IPF (N= 2,058)PPH (N= 533) SARCOIDOSIS (N = 314)

HALF-LIFE Alpha-1: 5.1 Years; CF: 5.8 Years; COPD: 4.8 Years; IPF: 3.7 Years; PPH: 4.3 Years; Sarcoidosis: 4.0 Years

Survival comparisonsCOPD vs. IPF: p < 0.0001Alpha-1 vs. CF: p = 0.0248Alpha-1 vs. IPF: p < 0.0001Alpha-1 vs. PPH: p = 0.0021CF vs. COPD: p = 0.0006CF vs. IPF: p < 0.0001CF vs. PPH: p < 0.0001CF vs. Sarcoidosis: p = 0.0007

J Heart Lung Transplant 2005;24: 945-982

QUESTIONS?