Pulmonary Arterial Hypertension: Diagnosis and Novel ... · Pulmonary Hypertension, Nice 2013 GROUP 1 – Pulmonary Arterial Hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1

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Pulmonary Arterial Hypertension:Diagnosis and Novel Management

Strategies2016

Teresa De Marco, MD, FACCProfessor of Medicine & Surgery

Director, Advanced Heart Failure andPulmonary Hypertension Comprehensive Care Center

Medical Director, Heart Transplantation

Disclosures:• Grant/Research Support: Lung Biotechnology, Pfizer, Reata• Consultant: Actelion, Gilead, Bellerophon, Cardiokinetix, Respirix• I will not discuss off-label or investigational use of drugs/devices UC SF

Disclosure

• Grants/Research Support:– Lung Biotechnology, Pfizer, Reata

• Consultant– Actelion, Gilead, Bellerophon,

Cardiokinetix, Theranova/Respirex• Speaker’s Bureau: none• I will not discuss off label use and/or

investigational use of drugs or devices

ObjectivesReview:

• Definition and classification of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH)

• Epidemiology and natural history

• Diagnostic approach

• ManagementUC SF

Pulmonary Hypertension(PH)

•Sustained elevation of mean pulmonary artery pressure:

> 25 mmHg

UC SFSimonneau et al, J Am Coll Cardiol. 2013;62:D34-41

mPAP= 1/3 (PAs - PAd) + PAdNormal: 8 - 20 mmHg

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5th WSPH Updated Classification of Pulmonary Hypertension, Nice 2013

GROUP 1 – Pulmonary Arterial Hypertension 1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2

1.2.2 ALK-1, ENG, SMAD9, CAAV1, KCNK3

1.2.3 Unknown

1.3 Drug- and Toxin-Induced

1.4 Associated with:

1.4.1 Connective Tissue D isease

1.4.2 Hum an Im m unodeficiency Virus (H IV) Infection

1.4.3 Portal Hypertension

1.4.4 Congenital Heart D isease

1.4.5 Schistosom iasis

1’ Pulm onary Veno-occlusive D isease and/or Pulm onary Capillary Hem angiom atosis

1” Persistent Pulm onary Hypertension of the Newborn (PPHN)

GROUP 2 – PH Due to Left Heart Disease2.1 Left Ventricular Systolic Dysfunction

2.2 Left Ventricular D iastolic Dysfunction

2.3 Valvular D isease

2.4 Congenital/Acquired Left Heart Inflow/Outflow Tract Obstruction and Congenital Cardiom yopathies

GROUP 3 –PH Due to Lung Disease and/or Hypoxia3.1 Chronic Obstructive Pulm onary D isease

3.2 Interstitial Lung D isease

3.3 Other Pulm onary D iseases W ith M ixed Restrictive and Obstructive Pattern

3.4 S leep-disordered Breathing

3.5 A lveolar Hypoventilation D isorders

3.6 Chronic Exposure to H igh A ltitude

3.7 Developm ental Lung D iseases

GROUP 4 – Chronic Thromboembolic PH (CTEPH)

GROUP 5 – PH With Unclear Multifactorial Mechanisms5.1 Hem atologic D isorders: Chronic Hem olytic Anem ia,

Myeloproliferative D isorders, Splenectom y

5.2 System ic D isorders: Sarcoidosis, Pulm onary H istiocytosis, Lym phangioleiom yom atosis

5.3 Metabolic D isorders: G lycogen Storage D isease, Gaucher D isease, Thyroid D isorders

5.4 Others: Tum oral Obstruction, Fibrosing Mediastinitis, Chronic Renal Failure, Segm ental PH

Simmoneau G, et al. JACC. 2013; 62:D34-41.

BMPR2 = bone morphogenetic protein receptor type 2; CAV1 =caveolin 1; ENG = endoglin; KCNK3 = gene encoding K2P3.1 (K+ channel) Strange G et al. Heart 2012;98:1806-1811.

• Single center study from Australia • 6,994 screened à 936 pts (9.1%) with PH on ECHO

(defined as ePASP >40 mmHg)

Etiology of PH on Echocardiogram

5th WSPH Clinical Classification of PAH (WHO Group 1)

Group 1―Pulmonary Arterial Hypertension (PAH)Idiopathic PAHHeritable

BMPR2ALK-1, endoglin, SMAD9,CAAV1,KCNK3Unknown

Drug and toxin-inducedPAH associated with:

Connective tissue diseaseHIV infectionPortal hypertensionCongenital heart diseaseSchistosomiasis

1’ – Pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis1’’ – Persistent PH of the newborn

Simonneau et al, J Am Coll Cardiol. 2013;62:D34-41.

Group 1: Pulmonary Arterial Hypertension (PAH)

• Characterized by progressive and sustained elevation ofpulmonary artery pressure and vascular resistance: – PA mean > 25 mmHg (nl 8-20 mmHg)– PAWP/LVEDP < 15 mmHg (nl 4-12 mmHg)– PVR > 3 W units (240 dyn/sec/cm-5)

• Subset of PH (15 cases/ million)• US prevalence 50-100,000

• 15 – 25,000 dx & rx• Vasoconstriction, remodeling, thrombosis in situ• Progressive cardiopulmonary deterioration• Leads to RH failure and death (67% 5-yr survival)

Hoeper MM, et al. J Am Coll Cardiol. 2013;62:D42-50.

Humbert M et al. Am J Respir Crit Care Med 2006;173:1023-30Thenappan T, et al. Eur Respir J. 2010;35:1079-1087.

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NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE

Pathogenesis of Pulmonary ArterialHypertension

Gaine S, J Am Med Assoc 2000;284:3160-68

Survival of PAH Patients in Current Era: Comparison with Historical Controls

Thenappan T, et al. Eur Respir J. 2010;35:1079-1087.

6765

32

10091

76

43

0102030405060708090

100

Baseline 1 year 3 year 5 year

Perc

enta

ge (%

) Sur

viva

l

Observed

Predicted (NIH)

N = 276, IPAH and HPAH patients diagnosed from 1982-2006; matched for disease variables at baseline with historical controls

Low Risk Determinants of Risk High Risk

No Clinical evidence of RV failure Yes

Gradual Disease progression Rapid

II, III WHO functional class IV

Longer (> 400 meters) 6-MWD Shorter (< 300 meters)

Peak VO2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO2 < 10.4 mL/kg/min

Minimally elevated and stable BNP/NT-proBNP Significantly elevated

PaCO2 > 34 mm Hg Blood gasses PaCO2 < 32 mm Hg

Minimal RV dysfunction ECHO findings Pericardial effusion, RV dysfunction, RA enlargement

RAP < 10 mm Hg;CI > 2.5 L/min/m2

HemodynamicsRAP > 20 mm Hg;

CI < 2 L/min/m2

McLaughlin, et al. J Am Coll Cardiol 2009;53:1573D’Alonzo, et al. Ann Int Med 1991;115:343Raymond, et al. J Am Coll Cardiol 2002;39:1214

PAH Determinants of Patient Risk and Prognosis

ACC/AHA Expert Consensus

Provencher, et al. E Heart J 2006: 27:589Nagaya, et al. Circ 2000;102:865Blyth, et al. Eur Respir J. 2007;29:737

Hemodynamic Changes Correlate with Disease Progression

CO=cardiac output; PAP=pulmonary arterial pressure; PVR=pulmonary vascular resistance;RAP=right atrial pressure.

Time

PAPPVR

CO

Presymptomatic/ Compensated

Symptomatic/ Decompensating

Symptom ThresholdRight Heart

Declining/ Decompensated

RAP

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Evaluation

UC SF

REVEAL Database: Most Frequent Symptoms at Diagnosis

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

Dyspnea at rest

Cough

Dizzy/lightheaded

Presyncope/syncope

Edema

Chest pain/discomfort

Other

Fatigue

Dyspnea on exertion 84.0%

26.0%

24.0%

23%

21.0%

23.0%

16.0%

13.0%

11%

83%

29%

27%

20%

20%

20%

14%

13%

11%

0 25 50 75 100 Incidence (%)

IPAHAPAH

N=1479.

PAH Diagnostic Guidelines:Decision Analysis

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

Unexplained Symptoms of Dyspnea onExertion, Syncope/Near Syncope, Fatigue

Clinical History, Examination,ECG, Chest X-Ray

Signs on Physical Examination

• Loud pulmonic valve closure (P2) (93%)• TR murmur (40%)• PR murmur (13%) • Right-sided fourth heart sound• Right ventricular lift• Jugular venous distention• RV third heart sound (23%)• Peripheral edema (32%)• Ascites• Low BP, low PP, cool extremities (low CO,

peripheral vasoconstriction, hypoperfusion)• Stigmata of associated causes of PAH

Sign

s of

RH

F

McLaughlin VV et al. J ACC. 2009;53:1573-1619McGoon M, et al. Chest. 2004;126:14S−34S. Rich S, et al. Ann Intern Med. 1987;107:216-223. UC SF

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Electrocardiogram

Image courtesy of Vallerie McLaughlin, MD

• Insufficiently sensitive as screening tool for PH•Prognosis:p-wave in II, qR V1, RVHèrisk of death • RAD, RAE, RBBB,RVH

Bossone E, et al. Chest 2002;121:513McGoonM,etal.Chest 2004;126:14S-34SMcLaughlinVVetal.JACC2009;53:1573-1619.

ProminentCentralPulmonary Artery

PeripheralHypovascularity

RightDescendingPulmonaryArtery

RVEnlargement

§• Cardiac enlargement§• Prominent proximal PA s§• “Pruning” of distal PA s

§ • No evidence of pulmonary edema§ • Lungs appear normal

Chest Radiograph in PAH

PAH Diagnostic Guidelines:Decision Analysis


Clinical History, Examination,Chest X-Ray, ECG

Is There a Reason to Suspect PH?

Yes No

Echocardiography Work-Upfor Other

ConditionsLV

RV

Apical Four Chamber

Normal PAH

LVRV

RA LA

Parasternal Short Axis

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Signs of PAH with Echo/Doppler• Increased sPAP or TR jet• Right atrial and ventricular

hypertrophy/enlargement• Flattening of intraventricular

septum• Tricuspid regurgitation• Small LV dimension

LVRV

LARA

IVS

ePAsP = 4V2 + eRAP

Traditional ECHO does not accurately measure:

•Mean PA pressure•PAWP•Cardiac output (blood flow)

• Cannot calculate PVR• Other limitations-15% no TR jet,not all congenital lesions obvious, smallerrors in TRV tracing can alter results

McGoon M, et al. Chest. 2004;126:14S−34S

• Contraction of RV is mainly longitudinal; tricuspid annulus displaced toward apex during systole

• Imaging through lateral wall with M-mode to measure this motion known as tricuspid annular plane systolic excursion (TAPSE)

• Less displacement as RV becomes more dysfunctional• Baseline TAPSE <1.8 cm has negative prognostic implications

Forfia PR et al. Am J Respir Crit Care Med. 2006;174:1034-1041.

RV function: Tricuspid Annular Plane Systolic ExcursionNormal RVF: 2.3 – 2.7 cm

Mild RVD: 1.9 – 2.2 cm Moderate RVD: 1.5 - 1.8 cm Severe RVD: <1.5 cm

PAH Diagnostic Guidelines


Echocardiography Indicates PH

Evaluate for Associated Causes V/Q scan PFTs

Arterial Saturation

HIV Infection, Scleroderma, SLE, Other CTD, Liver Disease, CHD, Drug-

Associated

Parenchymal Lung Disease, Hypoxemia,

or Sleep Disorder

SuspectedChronic PE





Arterial Saturation


Associated


or Sleep Disorder

SuspectedChronic PE

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Ventilation Perfusion Lung Scan

Idiopathic PAH Chronic PE

VentilationPerfusion PerfusionVentilation

Ø 3 – 4% of acute PE do not entirely resolveØ 50% of those with CTEPH do not have hx of acute PEØ V/Q scan is sensitive, should be performed to exclude

CTEPH even when another explanation for PH is presentØ CTEPH: >1 segmental-sized or larger mismatched

perfusion defectsØ Normal or very low probability V/Q scan excludes CTEPH

Bands

Absent branches

Pouch

CTEPH: A “Curable” Form of PHNot to Be Missed





Arterial Saturation


Associated


or Sleep Disorder

SuspectedChronic PE

Pulmonary Function Tests, Arterial Blood Gases, and Oxygen Saturation

• Findings suggestive of PAH– ê DLCO 40% - 80% of

expected– Mild to moderate ê of

lung volumes– Peripheral airway

obstruction– Arterial O2 tension normal

or slightly ê at rest– Arterial CO2 is ê– SpO2 preserved at rest,

may be ê with exercise/ambulation

• Findings suggestive of alternate PH diagnoses– Hypoxic PH due to COPD

• Irreversible airway obstruction + increased residual volumes

• reduced DLCO + normal or increased CO2 tension

– Interstitial lung disease• Decrease in lung volume +• Decreased DLCO

Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.

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PAH Diagnostic Guidelines:Confirmation of PAH

Adapted from McGoon M, et al. Chest. 2004;126:14S-34S.


Right Heart Catheterization• Establish diagnosis• Ascertain etiology• Establish severity & prognosis• Verify presence and severity of shunts• Evaluate vasoreactivity• Guide treatment

VC RA RV PA PVPC

LA LV Ao

Isolated post-capillary (Passive PH )

PH Hemodynamic Profiles:Where is the lesion?

(mean PAP > 25 mmHg)

Combined post-pre-capillary

PH(Mixed PH)

Pre-capillaryPH

High flow PHnl range or éPVR

(CHD, AV fistula, thyrotoxicosis,

chronic anemia)

PAWP: Normal 4-12 mmHgTPG= mPAP - PAWP

Normal < 10 mmHgDPG= dPAP – PAWP

Normal < 5 mmHgPVR= mPAP - PAWP/CO

Normal < 1 Wu

Vachiery JL et al, J Am Coll Cardiol 2013;62: D100-8Fang J et al, J Heart Lung Transplant 2012;31:913–33Galie N et al, Eur Respir J 2009;34(6):1219-63

Algorithm for Assessment of Vasoreactivity in Patients with PAH

Right Heart Catheterization With Acute Vasoreactivity Testing(iNO, epoprostenol, adenosine)

Non - responder

Consider:Oral ERAs/PDEI-5/sGCS/IPAInhaled IloprostSQ/IV/inhaled/PO TreprostinilIV Epoprostenol

Responder (<15%)

Consider: Hemodynamically-Monitored Trial of

Calcium Channel Blocker

mPA ¯10 mmHg¯mPA < 40 mmHgNo D CO

(<10% respond long-term)

PAH Diagnostic Workup


Right Heart Catheterization Confirms PAH

6-minute walk,Borg score

NYHA/WHOfunctional class

Establish Baseline, Prognosis, and DocumentProgression/Response to Treatment With Serial Re-assessment

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Management

UC SF

Goals of Management of PAHPrevent right heart failure

• Alleviate symptoms• Improve exercise capacity• Improve functional class• Improve hemodynamics• Prevent clinical worsening• Reduce morbidity, mortality

Overview: 2013 WSPH Treatment Algorithm

Adapted from Galié N et al JACC. 2013;62 (25, Suppl. D):D60-D72.

General Measures and Supportive

Therapy

Expert Referral (PH Center)

Acute Vasoreactivity Testing

Oral AnticoagulantsIPAH, heritable PAHanorexigen-induced PAHAPAH

DiureticsOxygenDigoxin (controversial)

Non-VasoreactiveWHO-FC I-IIICCB

Sustained Response(WHO FC I-II)

Continue CCB YES

Initial Therapy With PAH Approved DrugsDepending on WHO-FC Status and risk profile

Vasoreactive

NO

Supervised Exercise TrainingPsychosocial SupportAvoidance of Strenuous ActivityPregnancy AvoidanceImmunizations (influenza)

Therapeutic Targets for PAH

Modified from Humbert M, Sitbon O, Simonneau G. N Engl J Med 2004;351:1425-36

Phosphodiesterase type 5 inhibitor

Exogenous nitric oxidesGC stimul.

Endothelin receptor antagonists

Prostacyclin derivatives IP rec. agonist

Endothelin receptor A

Endothelin 1Nitric oxide

Prostacyclin (prostaglandin I2)

Endothelin receptor B

Vasodilation and antiproliferation

Vasodilation and antiproliferationVasoconstriction

and proliferation

cGMP

cAMP

Pre-proendothelin à Proendothelin

L-arginine à L-citrulline

Arachidonic acid à Prostaglandin I2

++

Phosphodiesterase type 5

Sm ooth m uscle cells

Endothelin cells

Vessel lum enNitric oxide pathway

Endothelin pathway Prostacyclin pathway

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FDA -Approved Specific Therapies for PAH

Class of Agent Name Route of Administration

Oral Inhaled IV/SC

Endothelin Receptor Antagonist

Ambrisentan ✔

Bosentan ✔

Macitentan ✔

Phosphodiesterase Type 5 Inhibitor

Sildenafil ✔

Tadalafil ✔

Soluble Guanylate Cyclase Stimulator

Riociguat ✔

Prostacyclin Receptor Agonist

Selexipag ✔

Prostacyclin analogEpoprostenol IVIloprost ✔

Treprostinil ✔ ✔ IV and SC

US Food and Drug Administration. Approved product list as of December 22, 2015. Intravenous epoprostenolSubcutaneous treprostinil

Inhalational Iloprost Inhalational

Treprostinil

2015 ESC/ERS Guidelines: Treatment Algorithm for PAH-specific Therapy

Galie N, et al. Eur Respir J. 2015;46:903-975.

Low or intermediate risk(WHO FC II-III)

High risk(WHO FC IV)

Inadequate clinical response

Consider referral for lung transplantation

Inadequate clinical response

Patient already

on treatment

Initial monotherapy*

Initial oral combination

Initial combination including IV prostacyclin

Double or triple sequential combination

Consider listing for lung transplantation

*Initial combination with ambrisentan plus tadalafil has proven to be superior to monotherapy in delaying clinical failure.

5th WSPH: Prognostic Variables Used in Clinical Practice To Set Treatment Goals

Variable Recommended Goal NYHA Functional class I or II

Echocardiography/CMR Normal/near normal RV size and function

Hemodynamics Normalization of RV function•RAP < 8 mm Hg and•CI > 2.5 to 3.0 L/min/m2

6 Minute walk distance

Cardiopulmonary exercise testing

>380-440 m (or more in younger pts)

Peak VO2 >15 mL/min/kg andEqCO2 <45 L/min/min

B-type natriuretic peptide Normal range

McLaughlin VV, et al. J Am Coll Cardiol. 2013;62:D73-81.

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Inadequate Clinical Response to Initial PAH Therapy

Failure to show improvement or deterioration with monotherapy

Consider eligibility for

lung transplant

Inadequate Clinical Response on

Maximal Therapy?Lung transplant

(I-C)BAS (Iia- C)

Adapted from Galié N et al JACC. 2013;62 (25):D60-D72.

GRIPHON: Selexipag for PAHPrimary Endpoint: Time to First Event

Placebo 582 433 347 220 149 88 28Selexipag 574 455 361 246 171 101 40

No. at Risk: Months

Patie

nts

with

out a

n ev

ent (

KM)%

Selexipag vs placebo: RR 40%HR = 0.60; 99% CI, 0.46-0.78

P<0.0001

Selexipag

Placebo

Sitbon O, et al. N Engl J Med. 2015:373:2522-2533.

At baseline: 20% PAH therapy naive 47% on monotherapy (ERA or PDE-5i) 33% on combination therapy (ERA & PDE-5i)

New Paradigm- AMBITION: Ambrisentan-Tadalafil Up-front Combination Therapy

Primary Endpoint: Time to First Clinical Failure EventPrimary Analysis Set

Eve

nt-F

ree

(%)

Time (weeks)

HR: 0.50295% CI(0.348, 0.724)

p=0.0002

0 24 48 72 96 120 144 168 192

1 year 88.9%

1 year 75.5%

Combination therapy Pooled monotherapy

2 year 79.7%

2 year 63.2% 3 year

56.1%

3 year 67.6%

Combination: 253 229 186 145 106 71 36 4

Pooledmonotherapy:

247 209 155 108 77 49 25 5

Number at risk:

Galie N, et al. N Engl J Med. 2015;373:834-844.

PAH: Therapy

Transplantation - lung / heart-lung• Indicated for patients who continue to deteriorate

with poor QOL despite aggressive therapy• 1 year survival – 70-90% • 5 year survival – 50-60%• Mortality on waiting list remains high

(20% per yr despite LAS)• Aggressive pre-transplant management can ê mortality

UC SFChen H … De Marco et al. Am J Resp Crit Care Med 2009;180:468

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PAH: Summary

• PAH is a progressive disease associated withsignificant morbidity and mortality

• Echocardiography and right heart catheterizationare the primary diagnostic modalities

• Strides made thus far in pathogenesis andpathobiology have lead to more effective therapies

• Current therapies have significant limitations andare costly

• New therapeutic agents and strategies areavailable and emerging

Documents

Pulmonary Arterial Hypertension: Diagnosis and Novel ... · Pulmonary Hypertension, Nice 2013 GROUP 1 – Pulmonary Arterial Hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1