Pulmonary Hypertension for the Internist

Lana Melendres-Groves MD Director Pulmonary Hypertension Program

University of New Mexico Health Science Center 11/04/16

Disclosures

• Consultant and member of the Speaker Bureaus for Actelion Pharmaceuticals, Gilead Pharmaceuticals, and Bayer Pharmaceuticals.

Objectives

• Define pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH)

• Describe the pathophysiology/pathobiology of PAH

• Discuss the classification system of PH • Discuss detection and diagnosis of PH and PAH • Review general and acute care management of

PH • Discuss PAH specific medical therapies briefly

Case #1

• 38yo woman with progressive shortness of breath over the past year. Now, unable to perform her daily activities without assistance. Currently requiring 4 liters of oxygen.

• PMHx significant for chronic renal insufficiency

• Presenting to her PCP for further work-up.

Definition of PH

• PH refers to the presence of abnormally high pulmonary vascular pressure

Normal mPAP: 8-20mmHg at rest

PH Defined: mPAP> 25mmHg at rest

WHO Classification System for PH

• Group 1: Pulmonary Arterial Hypertension (PAH)

• Group 2: PH due to left heart disease • Group 3: PH due to lung disease and/or

hypoxia • Group 4: Chronic thromboembolic pulmonary

hypertension • Group 5: PH with unclear multifactorial

mechanisms

Clinical Classification of Pulmonary Hypertension (NICE, 2013)

1. Pulmonary arterial hypertension (PAH) 1.1 Idiopathic PAH (IPAH) 1.2 Heritable PAH 1.3 Drug- and toxin-induced PAH 1.4 Associated PAH 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1’. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemagiomatosis (PGH) 1”. Persistent pulmonary hypertension of the newborn (PPHN) 2. PH due to left heart disease 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

3. PH due to lung disease and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary disease with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 4. Chronic thromboembolic hypertension (CTEPH) 5. PH with unclear multifactorial mechanisms 5.1 Hematologic disorders 5.2 Systemic disorders 5.3 Metabolic disorders 5.4 Others

Simonneau G, et al. J AmColl Cardiol. 2013;62(25, suppl D);D34-D41

Mixed PH

Pre-capillary PH High-flow PH (O2 sat run)

Hemodynamic Classification of PH (mean PAP >25 mm Hg)

VC RA RV PA PV PC

LA LV Ao

Post-capillary PH

Diagram courtesy of Teresa De Marco, MD, UCSF

Hemodynamic Classification of PH (mean PAP >25 mm Hg)

VC RA RV PA PV

↑PVP PC

LA

↑LAP

LV Ao

↑LVEDP

Post-capillary PH PCWP>15 mm Hg; PVR normal

Diagram courtesy of Teresa De Marco, MD

Hemodynamic Classification of PH (mean PAP >25 mm Hg)

VC RA RV PA PV

↑PVP PC

LA

↑LAP

LV Ao

↑LVEDP

Post-capillary PH PCWP>15 mm Hg; PVR normal

Diagram courtesy of Teresa De Marco, MD

Systemic HTN AoV disease Myocardial Disease

Dilated CMP-ischemic/non-ischemic Hypertrophic CMP Restrictive/infiltrative CMP Obesity related CMP Pericardial disease

MR

Hemodynamic Classification of PH (mean PAP >25 mm Hg)

VC RA RV PA PV PC

LA LV Ao

Pre-capillary PH PCWP <15 mm Hg;

PVR >3 woods units

{

{

PAH Lung diseases +/- hypoxemia

CTEPH

Diagram courtesy of Teresa De Marco, MD

Presence of PH Worsens Outcomes Across All Groups

WHO Group 1 PAH

WHO Group 2 Left-heart related

WHO Group 3 Lung/hypoxia related

WHO Group 4 CTEPH

Based on a sample of 194 patients

followed between 1981 and 1986, median survival

was estimated at 2.8 years (IPAH)

In a study of 379 patients referred to a single center between 1992

and 1998, patients with Group 2 PH

had 7x higher mortality than left-sided heart failure

alone

5-year survival rate in a study of 84

COPD patients was 62% in patients

without PH and only 36% in those with PH

In a study of 79 IPF patients, the 6.5-year survival rate was 40% among those with PH vs

70% in patients with IPF alone

Mean survival 6.8 years without surgical

intervention in a study of 48

Japanese patients versus 75% survival at >6 years post-

PTE

Case #2

• 28yo woman from rural New Mexico presenting to the ER for chest pain. Experiencing progressive fatigue and shortness of breath after the birth of her child 10 months ago.

• PMHx: none • Work-up in unremarkable presenting to her

PCP for follow-up.

Pulmonary Arterial Hypertension

A further look into WHO Group 1

How is PAH Defined

• PAH is a syndrome resulting from restricted blood flow in the pulmonary arterial circulation resulting in increased pulmonary vascular resistance which causes right ventricular strain and ultimately failure.

Hemodynamic - mPAP >25mmHg definition of PAH: - PCWP <15mmHg - PVR > 3 wood units

Pathogenesis of PAH: Aberrant Pathways

Loss of Biological “Balance” in PAH

Vasodilation Apoptosis

Vasoconstriction Proliferation

Vasodilation Apoptosis

Vasoconstriction Proliferation

SMC

Endothelium elastic lamina injury

Injury serum leak

SMC PROLIFERATION & MIGRATION

Pathobiology of PAH

Pulmonary Arterial Hypertension

1.1 Idiopathic PAH (IPAH) 1.2 Heritable PAH 1.3 Drug- and toxin-induced PAH 1.4 Associated PAH 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis

Prevalence of PAH in Connective Tissue Diseases

Systemic lupus erythematosis (SLE): 0.5% to 17% Mixed Connective tissue disease (MCTD): up to 25%

Systemic Sclerosis: 8% to 27%

SLE

MCTD

Systemic Sclerosis

Drugs and Toxins Associated with PAH

Definite - Aminorex - Fenfluramine - Dexfenfluramine - Toxic rapeseed oil - Benfluorex - Dasatinib

Likely - Amphetamines - L-tryptophan - Methamphetamines

Possible - Cocaine - Phenylpropanolamine - St. John’s Wort - Chemotherapeutic

agents - SSRI* - Pergolide

Unlikely - Oral contraceptives - Estrogen - Cigarette smoking

* Related to persistent pulmonary hypertension of the newborn

Drugs and Toxins Associated with PAH

Definite - Aminorex - Fenfluramine - Dexfenfluramine - Toxic rapeseed oil - Benfluorex - Dasatinib

Likely - Amphetamines - L-tryptophan - Methamphetamines

Possible - Cocaine - Phenylpropanolamine - St. John’s Wort - Chemotherapeutic

agents - SSRI* - Pergolide

Unlikely - Oral contraceptives - Estrogen - Cigarette smoking

* Related to persistent pulmonary hypertension of the newborn

PAH associated with Portal Hypertension

• Prevalence of PAH in portal htn ranges from 2% to 6%

• Risk of developing PAH increases with duration of portal hypertension

• Liver disease is the most common cause of portal hypertension, but it can be secondary to nonhepatic causes

• Portal pulmonary hypertension plays a significant part in transplant candidacy

Time

PAP PVR

CO

Pre-symptomatic Compensated

Symptomatic Decompensating

RV Failure

Declining Decompensated

CO α PAP

PVR

Schematic Progression of PAH

Case #3

• 62yo man h/o htn referred to pulmonary for progressive dyspnea. Now, unable to work.

• Prior smoking history, quit 5 years ago • PFT’s reported as normal but no records

available • Exam significant for a holosystolic ejection

murmur at the LLSB • Bilateral lower extremity edema present

What does a PH patient look like

Symptoms

• Breathlessness • Chest pain • Dizziness • Syncope • Loss of energy • Edema • Dry cough

Physical Exam • Increased jugular venous

pressure • Accentuated split S2 • Presence S3 • TR murmur- heard best LL

sternal border • Edema and/or ascites • Hepatojugular reflux • Skin- telangiectasias,

Raynaud’s, Sclerodactyly

McGoon et al. Chest 2004;126:14S-34S

No further evaluation

for PAH

Is PAH likely? Echo

Is there a reason to suspect PAH Clinical history (symptoms, risk factors, family Hs.),

Exam, CXR, ECG

Is PAH due to LH disease? Echo

Is PAH due to CHD? Echo with contrast

Is PAH due to CTD, HIV? Serologies

Dx Scleroderma, SLE, other CTD, HIV: Medical treatment of PAH and further evaluation for

other contributing causes, including RHC

Dx abnormal morphology; shunt: Surgery. Medical treatment of PAH or evaluation for

further definition or other contributing causes, including R&LHC if necessary

Dx LV systolic, diastolic dysfunction; valvular disease: Appropriate treatment and further evaluation

if necessary, including R&LHC

TRV to measure RVSP; RVE; RAE; RV Dysfunction:

yes

yes

yes

Rationale

no

no

no

yes

yes no

no

PAH: Detection and Diagnosis

Is chronic PE suspected? VQ scan

McGoon et al. Chest 2004;126:14S-34S

Dx parenchymal lung disease, hypoxemia, or sleep disorder: Medical treatment, oxygen, positive pressure breathing

as appropriate, and further evaluation for other contributing causes, including RHC if necessary

yes

Document exercise capacity regardless of cause of PH: Establish baseline, prognosis and document progression/

response to treatment with serial reassessments

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

What limitations are caused by the PAH?

Functional class; 6-minute walk test

What are the precise pulmonary hemodynamics?

RHC

Is chronic PE suspected? VQ scan

Is PAH due to lung disease or hypoxemia?

PFTs, arterial saturation

Is chronic PE confirmed and operable? Pulmonary angiogram

Anatomic definition (CT, MRI may provide additional useful but not definitive information):

Thromboendarterectomy if appropriate or medical treatment; clotting evaluation; a/c

yes yes

no

no

no VQ normal

PAH: Detection and Diagnosis

Right Heart Catheterization: Diagnostic Gold Standard

• Hemodynamics: – RAP, mPAP, PCWP, CO/CI, PVR

• Saturations: – Rule out shunts

• Angiography: – Vessel properties – CTEPH

• Vasodilator response

Case #4

• 52yo woman with obesity, depression and worsening fatigue. Recently started on anti-depressant. Continues to work as a hairdresser.

• Work-up thus far shows normal basic lab work.

• Patient returning for follow-up, now concerned about intermittent dizziness with minimal exertion and some chest discomfort.

We have a diagnosis, now what?

Survival After Diagnosis

2.8 Years

3.9 Years

5.5 Years

7 Years

0

2

4

6

8

1980s 1990s 2000s 2010s

Estim

ated

Med

ian

Surv

ival

(Y

ears

)

D'Alonzo GE, et al. Ann Intern Med. 1991:115:343-349; Thenappan T, et al. Eur Respir J. 2010;35:1079-1087; Humbert M, et al. Eur Respir J. 2010;36:549-555; Benza RL, et al. Chest. 2012;142:448-456

Importance of Accurate Diagnosis

• RePHerral study: – Multicenter, descriptive, cross-sectional study – Consisting of 140 patients – Performed to determine:

• accuracy of PH diagnoses in patients referred to PH centers • frequency of PAH-specific medication use despite an uncertain or

incorrect diagnosis.

• Results indicated that 33% of patients diagnosed with PAH upon referral had an incorrect diagnosis.

• 42% did not have a confirmatory heart catheterization at the time of referral

Deano RC, et al. JAMA Intern Med 2013; 173: 887-893

WHO Functional Class is a Symptom-Based Indicator of Disease Severity

Class Functional Classification of Patients with PAH

I No limitation of usual physical activity, ordinary physical activity does not cause increased dyspnea, fatigue, chest pain, or pre-syncope

II Slight limitation of physical activity. No discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or pre-syncope

III Marked limitation of physical activity. No discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or pre-syncope

IV Unable to perform any physical activity and possible signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any physical activity.

Functional Assessment

• Functional assessment is key to appropriate therapeutic approach – WHO functional class (WHO I-IV)

• The RePHerral study indicated that at the time of referral, more than half of all 140 patients had functional class III and IV disease (62%) – REVEAL registry showed a mortality of 50%

at 2 years for class IV patients

Deano RC, et al. JAMA Intern Med 2013; 173: 887-893

Case #5

• 41yo woman with admitted early in the year for hypoxia and treated for pna.

• Presenting for hospital follow-up to her PCP to see if she can get off the oxygen s/p discharge.

• Hasn’t been able to get back to her prior baseline energy level or activity level with ongoing SOB.

• PFTs normal, CXR normal, lab work normal.

Bringing it All Together:

General and Acute Care of the Pulmonary Hypertension

Patient

General and Acute Care in PH

• Approximately 658,000 ED encounters annually in the US are primarily due to heart failure.

• 3-9% of those are due to acute right ventricular failure (RVF) – 20-60 thousand encounters

• Recent study estimates more than 64,400 ED visits in the US, over 5 years, were due to PAH patients – Few studies to guide the management of PH or RVF in

the acute setting

Stein et al. Scope of the problem of PAH. Am J Med. 2015

Assessing a PH Patient

• Identifying the signs and symptoms of decompensated right heart failure. – Edema, ascites, sob, chest pain, arrhythmias – EKG, CXR, bedside echo

• Understanding the cause of PH to appropriately treat – Group 1 versus groups 2-5

PH/PAH General Care • Fluid/volume control

• Oxygen

• Anticoagulation

• Underlying Diseases

• Diuretics • Low sodium diet • Daily weights/I&Os • Hypoxia is a potent

vasoconstrictor and can elevate PA pressure

• CTEPH patients life-long anticoagulation

• Optimization of their other diseases

• Drug screening

Right Ventricular Failure Management Considerations

• RV failure in PAH (Group 1): – Continue/resume pulmonary vasodilator regimen – Early consultation with PH specialist – Consider risks of volume overload (no large

volume boluses) – Provide hemodynamic support with inotropes,

vasopressors, pulmonary vasodilators as indicated – Consider early referral for more specialized

treatments

RV Failure Management Considerations

• RV failure in other types of PH (Group 2-5) – Aggressively treat underlying condition, such as

diuresis for PH from left-sided heart failure or bronchodilators for PH from COPD

– Correct hypoxemia and respiratory acidosis – Consider ionotropic support as indicated, with

norepinephrine as a first-line agent – Early consultation with cardiology, pulmonary, or

PH specialist – For CTEPH, emergency referral to expert center

Pharmacologic Therapies for the Maintenance of PAH

Therapeutic Pathways

Introduction of PAH Therapies

Mid-80’s

•Conventional therapy

1995

•Prostanoids introduced

2001

•ERAs introduced

2005

•PDE-5is introduced

2013

•sGC introduced

2016

•Oral prostanoid analog

Current

•Continued exploration of new treatment strategies

FDA Approved PAH Therapies

• Prostanoid/Prostanoid Analogs – Epoprostenol (flolan/veletri) – Treprostinil (IV/SQ/Inhaled) – Inhaled Iloprost (Ventavis) – Oral treprostinil (Orenitram) – Selexipag (Uptravi)

• PDE-5 Inhibitors – Sildenafil (Revatio) – Tadalafil (Adcirca)

• ERA’s – Bosentan (Trecleer) – Ambrisentan (Letairs) – Macitentan (Opsumit)

• Soluable Guanylate Cyclase Stimulator – Riociguat (Adempas) (Only medication currently approved for the use in CTEPH)

Therapies

• The only groups that have been approved for the specialized medications for pulmonary hypertension are WHO Group 1 (PAH) and Group 4 (CTEPH)

• The WHO Group 2, 3, and 5 require treatment of the underlying condition or optimization of that condition

Treatment Recommendations

• Despite ongoing updated therapeutic guidelines (most recently from 2015 in ESC/ERS), there is still a substantial problem with inappropriate prescribing of PAH therapies.

• 57% of the RePHerral study patients who had been prescribed PAH-specific medications prior to referral, showed treatment guidelines had not been adhered to Galiè N, et al. Eur Heart J. 2016; 37:67-119; Galiè N, er al. Eur Respir J., 2015; 46:903-975

Treatment Recommendations

• Even when there is a Grade 1A recommendation: Epoprostenol IV/SQ for functional class IV PAH patients

• REVEAL registry showed that at time of death for these WHO class IV patients, 42% had still not received appropriate therapy

• Increasing evidence for sequential and dual upfront combination therapy

Ongoing Management

• The standard of care for PAH patients is establishment with a PH Care Center – Multidisciplinary approach to care – PHA initiative to standardized care through CCC and

RCC (currently 37 in the US) • Patients on advance therapies to be seen every 3

months if not more frequently • Ongoing escalation of care, more evidence

coming out showing the importance of up-front combination therapies.

Back to the Cases

• Case #1: 38yo woman CRF and NYHA class 4 symptoms on 4 liters oxygen with SOB.

• Case #2: 28yo woman with 10months old who has chest pain and sob.

• Case #3: 62yo man with DOE, former smoker now with increasing LEE.

• Case #4: 52yo woman with obesity, depression and profound fatigue now with episodes of dizziness.

• Case #5: 41yo woman with pna discharged on oxygen with ongoing fatigue and now CP.

What do you think?

• Do any of the patients have PH? • Do any of the patients have PAH? • They all have PH and 4 of them have PAH:

– Patient #1: found to have CTEPH, underwent PTE – Patient #2: PAH associated with CHD from ASD – Patient #3: PAH associated with CTD – Patient #4: PAH associated with drugs and toxins – Patient #5: IPAH

Discussion

• PH is an umbrella term that encompasses a multitude of disease processes. – Simply a hemodynamic definition

• Classification of PH includes 5 WHO groups • The pathobiology for PAH is the same no matter

the underlying etiology: 3 pathways • PH is screened with an echo and diagnosed with

RHC • Management is multifactorial and requires a

multidisciplinary approach to care.

Questions?