Pulmonary Hypertension for the Primary Care Provider Kenneth … Hypertension for … · Pulmonary...

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Pulmonary Hypertension for the Primary Care ProviderKenneth W. Presberg, MD

Professor of Medicine

Director, PHA Pulmonary Hypertension Comprehensive Care Center,

Division of Pulmonary and Critical Care Medicine

Froedtert & Medical College of Wisconsin Milwaukee, Wisconsin

Disclosures: (no direct honorariums; research meetings support) Research PI: Actelion, United Therapeutics.

Review the DEFINITION of pulmonary hypertension (PH)

Discuss the different GROUPS of PH Patients

Examine the PROGNOSIS of PH patients in the different GROUPS

Differentiate the BENEFITS and SIDE EFFECTS of different treatments for PH patients.

Review new guidelines for assessment of ADEQUATE TREATMENT RESPONSE in PAH.

Objectives:

PH with Left HeartDisease

PH with LungDisease and/or

Low Oxygen Levels

“PAH”

MiscellaneousMiscellaneousChronic Thrombosis

(clot) PHChronic Thrombosis

(clot) PH

Pulmonary HypertensionComes in Several Varieties

Right Heart Catheterization: The Definitive Diagnosis:

• Normal Pulmonary Artery (PA) Pressure: 30/15, mean 20 mmHg.

• Pulmonary Hypertension (PH) when mean > 25 mmHg (40/20 mmHg )and Elevated Pulmonary Vascular Resistance (PVR)

Introductory Questions:

Is Pulmonary HTN common?

If so, Which Group?

Is Pulmonary HTN rare, an “orphan” disease

If yes, which Group?

Can Pulmonary HTN be cured?

Are there effective treatments?

Yes, Many patients with left sided heart failure have Group II Pulmonary HTN.

Yes, Group I PAH Pulmonary HTN remains an uncommon disease.

Chronic PE patients who have a successful surgery return to near normal: OSA patients on CPAP.

Yes, particularly for Group I PAH patients now.

PH with Left HeartDisease

PH with LungDisease and/or

Low Oxygen Levels

“PAH”

MiscellaneousMiscellaneousChronic Thrombosis

(clot) PHChronic Thrombosis

(clot) PH

Pulmonary HypertensionComes in Several Varieties

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Epidemiology of PH by Echo Single echo lab / Australian community of 165,450

Etiology of PH noted on echocardiogram

N=936 of 10,314 patients with echo PASP >40 mm Hg.Strange G et al. Heart. 2012;98:1805‐1811.

Miscellaneous, 2.7%

Lung disease,Sleep‐related

hypoventilation,9.3%

CTEPH, 2.0%

PAH, 2.7% Unknown,15.4%

Left heartdisease, 67.9%

Right Heart Catheterization: The Definitive Diagnosis:

• Normal Pulmonary Artery (PA) Pressure: 30/15, mean 20 mmHg.

• Pulmonary Hypertension (PH) when mean > 25 mmHg (40/20 mmHg )and Elevated Pulmonary Vascular Resistance (PVR)

Pulmonary Hemodynamics:Pre‐capillary and Post‐capillary Patterns

Pulmonary ArterialPre-Capillary

Pulmonary VenousPost-CapillaryLeft Heart Disease

5th World Symposium on PH:Classification /GROUPS1. Pulmonary arterial hypertension

1.1 Idiopathic PAH1.2 Heritable PAH

1.2.1 BMPR21.2.2 ALK1, ENG, Smad 9, CAV1, KCNK31.2.3 Unknown

1.3 Drug- and toxin-induced1.4 Associated with

1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases (update)1.4.5 Schistosomiasis

1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis

1’’. Persistent PH of the newborn

2. PH due to left heart disease

2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract

obstruction and congenital cardiomyopathies

3. PH due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive

and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases (update)

4. Chronic thromboembolic PH. CTEPH

5. PH with unclear multifactorial mechanisms

5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis,

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

5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.

Physical Examination Findings

Presence of PH

• Loud second heart sound

• RV heave

• Heart murmur

• RV gallop

Presence of RV Failure

• Distended neck veins

• Enlarged liver

• Swollen feet and ankles

• Swollen abdomen

Pulmonary Hypertension Diagnosis

REVEAL. Brown LM et al. Chest. 2011;140:19-26. Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Is There a Reason to Suspect PH? Clinical Presentation

HistoryNonspecific Complaints Diagnostic Tests

• Dyspnea (86%)

• Fatigue (27%)

• Chest pain (22%)

• Edema (22%)

• Syncope (17%)

• Dizziness (15%)

• Cough (14%)

• Palpitations(13%)

• H & P, CXR, ECG: Suspicion, Risk Factors

• PFT, ABG, Overnight/ Sleep study.

• VQ scan best screening test for Chronic PE. CT Angiocomplementary tests.

• Echo: Structure, function, ESTIMATE hemodynamics

• Exercise Testing: CPET, 6MW

• Heart CatheterizationREVEAL. Brown LM et al. Chest. 2011;140:19-26. Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

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Pulmonary Hypertension Risk Factor List:

Cardiovascular Disease

Lung Disease

Sleep History

Thyroid Disease: autoimmune

Liver disease

Collagen vascular disease

Blood, clotting disorders, splenectomy

Viral Exposure Risk: HIV, Hepatitis.

Recreational Drug Use: Cocaine, Meth, other amphetamines.

Diet Pill, Weight loss prescription:

Is There a Reason to Suspect PAH? Echo• RV enlargement

• RA enlargement

• Septal straightening

• Loss of IVC inspiratory collapse

• Tricuspid regurgitation

• Pericardial effusion

• Decreased RV systolic dysfunction

– TAPSE (tricuspid annular plane systolic excursion)

TAPSE 1.5 cmTAPSE 2.3 cm

Relatively preservedRV function

RV dysfunction

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

IVC Collapse PH.avi

Estimation of RV Systolic Pressure (RVSP)

RVSP = 4(velocity of TR)2 + RA pressure= 4(4)2 + 20= ~84 mm Hg Echocardiogram prediction of PH: ERS 2015

PA 30

PA 35‐45

PA > 45

Diagnostic algorithm.

Nazzareno Galiè et al. Eur Respir J 2015;46:903-975©2015 by European Respiratory Society

Case: TN

60 yo female

Alcohol Abuse, Osteopenia

Fall and Pelvic fracture with severe left femur fracture.

Pre‐op evaluation done.

Referred 2013 for evaluation of abnormal echo with RV enlargement and PH suggested by echo.

Normal VQ scan, US no cirrhosis.

Mild elevation in ANA.

Echo: Mild RV enlargement, Mild RV systolic Dysfunction, Mild elevation in PASP.

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Mild PAH20.avi

Mild PAH20.avi

Mild PAH56.avi

Mild PAH

Diastole in short-axis view

Systole in short-axis view

TR jet

Apical 4-chamber view

IVS

RV

LV

Case TN (2)

Right Heart Catheterization done. RA pressure 4, PA pressure mean 26, PAWP 9 (all mmHg). CI 2.8 L/min m2.

Mild PAH , Idiopathic with preserved RV function.

Recommended to complete surgery and then return promptly for treatment. LOW RISK Status to start.

Surgery Successful with no complications.

Lost to fu for period of time.

PH Case -DS

60 year old manager

DOE for months: Stairs at work and Lawn work now more difficult. WHO functional class?

PMH: Viral CM; ? HTN on ARB

FH: Estranged sister with lung condition; on pump medication, oxygen and now pills

SH: Manager, Layoffs coming, Insurance?

Exam: JVP 4 cm, Loud P2, TR Murmur, RV impulse,noedema.

Walk test: 440 m

VQ scan: Normal

ECG: NSR, R axis, RVH

Case DS

What Diagnoses need to be considered?

What additional tests do you want?

Outside Echo suggests pulmonary hypertension with RV dysfunction.

Case DS

PH Echocardiogram on 03/06/07: Left ventricular EF 40-45%. Mild diastolic dysfunction

was identified. Left atrium appears visually normal (adjusted for BSA 17ml/M2).

Right ventricle is severely enlarged and has severe systolic dysfunction.

Estimated PASP: at least 65 mm Hg. IVC compatible with RAP of 10 mm HG. Agitated saline contrast at rest with Valsalva reveals no shunt.

No pericardial effusion is seen.

Case DS Right heart catheterization on 04/16/07 at FMLH:

RA Press 7; RV Press 93/13; PA Press 94/40/mean 62; PWP Wedge Pressure 12, LV EDP: 10 Cardiac Output CO/ Index Cl: 3.9 lpm/1.95 lpm/m2;

HR:65/min ; PVR: 12.2 WU; Mixed Venous Sat% 62%.

*Vasodilator trial with Nitric Oxide (10 ppm) revealed: No significant change.

Severe Precapillary Pulmonary HTN. Normal LV filling pressures.

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Case DS

What Diagnoses to be considered?

Group I PAH. Heritable PAH?, IdiopathicPAH

Are there any barriers to treatment? Insurance.

Lesson 2

WHO Group I PAH Is Rarebut Deadly—

Make the Diagnosis Early

Group I PAH Distributions in the US: REVEAL Registry

Based on Venice Clinical Classification (2003); 2967 patients.Adapted from Badesch DB et al. Chest. 2010;137:376‐387.

Overall Associated

Associated(50.7%)

Idiopathic(46.2%) Connective tissue/

collagen vascular(49.9%)

Heritable (2.7%)

Pulmonaryveno‐occlusive

(0.4%)

Congenitalheart disease(19.5%)

HIV (4.0%)

Other (5.5%)

Drugs/toxins (10.5%)

Portopulmonary (10.6%)

Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40:780‐788. D’Alonzo GE et al. Ann Intern Med.1991;115:343‐349. McLaughlin VV et al. Chest. 2004;126:78S‐91S. Benza RL et al, Chest 2012; 142: 448‐456.

Idiopathic PAH: Survival

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 50

20

40

60

80

100

Years of follow‐up

Percentage surviving

NIH registrySitbon historical controlACCP estimate

• Incidence: 2‐6 cases per million in US

• Poor prognosis in an era lacking therapy 50% ‐ 3 year survival.

• Therapeutic options and research efforts now offer more HOPE !

REVEAL Registry 2012, PAH treatment era: 50% ‐ 7 year survival.

Group I PAH: Pulmonary Arterial Hypertension:

Symptoms often nonspecific; average 14‐month delay from initial presentation to diagnosis

Poor prognosis without therapy and close follow‐up

Evaluation must be methodical and include right heart catheterization (RHC)

Prognosis improves with therapy, but PAH remains a progressive fatal disease

Therapies and management strategies continue to evolve

5th World Symposium on PH:Classification1. Pulmonary arterial hypertension


1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown











4. Chronic thromboembolic PH







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Most Common Cause of Elevated PAPs by Echo: Left Heart DiseaseSymptoms

– paroxysmal nocturnal dyspnea

– orthopnea

History

– diabetes

– hypertension

– obesity

– coronary artery disease

– metabolic syndrome

ECG

– atrial fibrillation

– absence of right axis deviation

Echo

– left atrial enlargement

– left ventricular hypertrophy

– normal RA, RV

– abnormal diastolic filling

– mitral or aortic disease

Pulmonary Venous Hypertension/ Left Heart Disease:A Simplified View• Normal, or mildly elevated transpulmonary gradient with

readily apparent cause

– treat underlying cause

• Substantially elevated transpulmonary gradient (PH out of proportion to LHD)

– treat cardiovascular risk factors (including aggressive volume control) as best you can

– improvement in PH may be slow (months)

– No FDA-approved therapies for diastolic dysfunction yet





















Sleep-disordered Breathing and PH

• Nocturnal hypoxemia results in pulmonary arterial constriction and remodeling

• PH can occur with either obstructive sleep apnea (OSA) or central sleep apnea

• PH can occur with obstructive sleep apnea in the absence of intrinsic heart or lung disease

• Little correlation in severity of OSA and degree of PH;

• PH is usually Mild; Mean <35 mmHg

Sajkov D et al. Am J Respir Crit Care Med. 1994;149:416-422.

Pulmonary Hypertension in Lung/Respiratory Disease

• May explain worsening symptoms in patient with stable PFTs

• May contribute to exercise limitation: ventilatory vs cardiovascular limitation

• Disproportionately low DLCO may suggest pulmonary vascular disease

• Correlates better with low oxygen levels vs PFTs

• NO approved PH therapies. Positive Small studies or case series. (BUT negative trials)

0

Lettieri CJ et al. Chest. 2006;129:746-752.

PH

No PH (mPAP <25 mm Hg)

p<0.001

N=79No difference in lung volumesLower 6MWD

PH as a Predictor of Survival in Patients With IPF

1000500 1500 2000 2500

Days to event

Cum

ulat

ive

prob

abili

ty o

f sur

viva

l

0.0

0.2

0.4

0.6

0.8

1.0

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3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive









Incidence of CTEPH

• Approximately 3% to 4% 1-2 yr after acute PE (large, Recurrent higher risk)

• USA: 600,000 cases of acute PE each year

• Only 40% to 50% of CTEPH patients have a history of previous episodes of acute PE

• VQ scan identifies old PE better than CTA

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.Pengo V et al. N Engl J Med. 2004;350:2257-2264.Tapson VF, Humbert M. Proc Am Thorac Soc. 2006;3:564-567.

Years

Cu

mul

ativ

e in

cide

nce

of C

TE

PH

0 1 2 3 4 7 8 9 10 115 60.00

0.01

0.02

0.03

0.04

Pulmonary Thromboendarterectomy*

*This surgery now offered at Froedtert and MCW

PH Treatment Goals

Fewer/less severe symptomsImproved exercise capacityImproved “hemodynamics” Prevention of clinical worsening (heart failure, admissions, increased SOB)

Improved quality of life (benefits versus side effects)

Improved survival ? Achieve “Low Risk” Status

Chronic Adjuvant Therapies in PAH

Oxygen

• Use to prevent hypoxic vasoconstriction

• Consider exercise, sleep, altitude

• Aim for target saturation >90%

• May not correct hypoxia with shunt

Adapted from: Badesch DB et al. Chest. 2004;126:35S-62S. Badesch DB et al. Chest. 2007;131:1917-1928.McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Chronic Adjuvant Therapies in PAH

Diuretics

• Needed by most patients; hypotension not a contraindication in RV failure ( may need BP support)

Anticoagulation

• Recommended in IPAH

• Observational studies only (2 retrospective, 2 prospective); need to balance unproven benefits with known risks

• INR 1.5 – 2.5

Adapted from: Olsson KM et al. Circulation. 2014; 29:57–65. Fuster V et al. Circulation. 1984;70:580-587. Badesch DB et al. Chest. 2004;126:35S-62S. Badesch DB et al. Chest. 2007;131:1917-1928. McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

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Selection of Appropriate Therapy:

Group I PAH Patients:Chronology1980s: Calcium Channel Blockers, Diuretics, Oxygen. 1996: IV Epoprostenol (Flolan) ‐ “PPH” only; then 1998 All Group I PAH. 2001: Bosentan (Endothelin Receptor Antag.), first oral drug. Group I PAH2005: Sildenafil (PDE5 Inhibitors), Group I PAH. 2013: Riociguat (sGuanylate Cyclase, GMP) Group I PAH, Group IV

2019: 12 Drugs: Group I PAH, ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐Group IV CTEPH. 1 Drug. Riociguat.

(No Approved Drugs: Group II PH ‐ Heart Disease; Group III PH ‐ Lung Disease)

Evolution From Exercise Capacity to Morbidity and Mortality Randomized Controlled Trials

*Estimated mean study drug exposure. †Estimated median study drug exposure. ‡Estimated target enrollment.PAH=pulmonary arterial hypertension; RCT=randomized controlled trial. Channick RN et al. Lancet. 2001;358:1119-1123. Rubin LJ et al. N Engl J Med. 2002;346:896-903. Galiè N et al. Lancet. 2008;371:2093-2100. Galiè N et al. Circulation. 2008;117:3010-3019. Galiè N et al. N Engl J Med. 2005;353:2148-2157. Simonneau G et al. Am J Respir Crit Care Med. 2002;165:800-804. McLaughlin VV et al. Am J Respir Crit Care Med. 2006;174:1257-1263. Galiè N et al. Circulation. 2009;119:2894-2903. Simonneau G et al. Ann Intern Med. 2008;149:521-530. Olschewski H et al.N Engl J Med. 2002;347:322-329. Pulido T et al. N Engl J Med. 2013;369:809-818. Sitbon O et al. N Engl J Med. 2015;373:2522-33. Galiè N et al. N Engl J Med. 2015;373:834-44.McLaughlin VV et al. Eur Respir J. 2015;46:405–413

Weeks0 20 40 60 80 100 120 140 160

N=32N=213

N=185N=202N=192N=277N=470N=67

N=405N=267

N=203AIRPACES

PHIRSTSTEP

Simonneau et al (2002)SUPER-1ARIES-2ARIES-1

EARLYBREATHE-1

Study 351

6MWD Trials

n=235TRIUMPHCHEST n=443

FREEDOM-EV n=858

N=742*N=1150*N=545‡†AMBITION

GRIPHONSERAPHIN

COMPASS-2

Morbidity and Mortality Trials

n=344

Mechanisms of Action of Approved Therapies for GROUP I PAH (not other groups)

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

cGMP

cAMP

Vasoconstriction and proliferation

Endothelinreceptor A

Endothelin-receptor

antagonists

Endothelinreceptor B

Phosphodiesterase type 5 inhibitor

Vasodilationand antiproliferation

Phosphodiesterase type 5


Prostacyclin derivatives

Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells

Prostacyclin (prostaglandin I2)

Smooth muscle cells

Exogenous nitric oxide sGC stimulator

PAH Determinants of Risk

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619. RAP = Right Atrial Press. CI = Cardiac Index

LOWER RISK DETERMINANTS OF RISK HIGHER RISK

NoClinical evidence of

RV failureYes

Gradual Progression of symptoms Rapid

II, III WHO class III, IV

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

Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min

Minimal RV dysfunction Echocardiography

Pericardial effusion,significant RV

enlargement/dysfunction; RA enlargement

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

RAP >20 mm Hg;CI <2.0 L/min/m2

Minimally elevated BNP Significantly elevated

5th World Symposium on PH:Treatment Algorithm

Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.AMBITION study, N Engl J Med, 2015*

Sequential, Initial* CombinationTherapy (I-A)

Referral for Lung Transplantation (I-C)

Consider Eligibility for Lung Transplantation

Inadequate Clinical Response

on Maximal Therapy

INITIAL THERAPY WITH PAH-APPROVED DRUGS

PDE-5 I orsGCs

ERAs

Prostanoids

++

+

Balloon Atrial Septostomy (IIa-C)

Inadequate Clinical Response

ERS Risk Assessment 2015

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Case DS

What Diagnoses to be considered?

Group I PAH. Heritable PAH?, IdiopathicPAH

Is this patient HIGH risk or LOW risk at present?

“ A tweener ”

High because: Low normal Cardiac Ouput. High BNP

Low because: normal RA pressure, Functional class II symptoms, no heart failure.

“INTERMEDIATE RISK” Are there any barriers to treatment? Insurance.

PH Case DS Treated with Sildenafil alone with improvement;

Escalated dose to 80 mg TID

Walk Test 660 m, no desat

WHO functional Class I most days. II on some chore days.

BNP 12

Echo: Severe RV enlargement; Low normal TAPSE. Right Heart Cath 11/08 on Revatio 80 TID. RA 7, PA 91/33 mean 55, PWP 8, CO5.4 CI 2.7 PVR

8.6, MVO2 sat 71, AVO2 diff 5.0 New Medication to discuss?

cGMP

cAMP



Endothelin-receptor

antagonists







Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells


Smooth muscle cells

Approved Therapeutic Targets

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

Exogenousnitric oxide

sGC stimulator

Evolution From Exercise Capacity to Morbidity and Mortality Randomized Controlled Trials

*Estimated mean study drug exposure. †Estimated median study drug exposure. ‡Estimated target enrollment.PAH=pulmonary arterial hypertension; RCT=randomized controlled trial. Channick RN et al. Lancet. 2001;358:1119-1123. Rubin LJ et al. N Engl J Med. 2002;346:896-903. Galiè N et al. Lancet. 2008;371:2093-2100. Galiè N et al. Circulation. 2008;117:3010-3019. Galiè N et al. N Engl J Med. 2005;353:2148-2157. Simonneau G et al. Am J Respir Crit Care Med. 2002;165:800-804. McLaughlin VV et al. Am J Respir Crit Care Med. 2006;174:1257-1263. Galiè N et al. Circulation. 2009;119:2894-2903. Simonneau G et al. Ann Intern Med. 2008;149:521-530. Olschewski H et al.N Engl J Med. 2002;347:322-329. Pulido T et al. N Engl J Med. 2013;369:809-818. Sitbon O et al. N Engl J Med. 2015;373:2522-33. Galiè N et al. N Engl J Med. 2015;373:834-44.McLaughlin VV et al. Eur Respir J. 2015;46:405–413

Weeks0 20 40 60 80 100 120 140 160

N=32N=213

N=185N=202N=192N=277N=470N=67

N=405N=267

N=203AIRPACES

PHIRSTSTEP

Simonneau et al (2002)SUPER-1ARIES-2ARIES-1

EARLYBREATHE-1

Study 351

6MWD Trials

n=235TRIUMPHCHEST n=443

FREEDOM-EV n=858

N=742*N=1150*N=545‡†AMBITION

GRIPHONSERAPHIN

COMPASS-2

Morbidity and Mortality Trials

n=344

PDE-5 Inhibitor: Sildenafil, TadalafilSide Effects

• Nose bleed

• Headache

• Dyspepsia

• Flushing

• Diarrhea

• Visual changes

• Contraindicated with use of nitrates

sGC Stimulator : RiociguatSide Effects

• Headache

• Dizziness

• Dyspepsia/gastritis

• Nausea

• Diarrhea

• Hypotension

• Vomiting

• Anemia

• Gastroesophageal reflux

• Constipation

• Contraindicated in pregnancy, with use of nitrates or NO donors in any form, or with use of PDE inhibitors

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Mechanisms of Action of Approved Therapies for GROUP I PAH (not other groups)

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

cGMP

cAMP



Endothelin-receptor

antagonists







Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells


Smooth muscle cells


*PHA Scientific Leadership Council recommends LFT testing at onset of all treatments for PAH and periodically thereafter, at prescriber’s discretion.

Endothelin Receptor Antagonists: (Bosentan, Ambrisentan, Macitentan) Side Effects:

• Nasal congestion

• Abnormal hepatic function*

– monthly LFTs required for bosentan

• Anemia

– monitor CBC quarterly

• Edema

– lower extremity edema may require diuretic adjustment

• Teratogenic

– Avoid pregnancy.

Weeks0 1921444824 72 96 168120

Hazard ratio, 0.50 (95% Cl, 0.35-0.72)p<0.001

0

60

100

80

40

20

Combination therapy

Pooled monotherapy

AMBITION: Effect of Ambrisentan Plus Tadalafil Versus Monotherapy on Clinical Worsening*

* Death, hospitalization for worsening PAH, disease progression, unsatisfactory long-term clinical response. Galiè N et al. N Engl J Med. 2015;373:834-44.

Pa

rtic

ipa

nts

wit

h N

o E

ven

t (

%)

No. at risk:Combination therapyPooled monotherapy

229

209

186

155

145

108

106

77

71

49

36

25

4

5

253

247

SERAPHIN: Effect of Macitentan on Disease Progression

* Worsening of PAH, initiation of treatment with IV or SC prostanoids, lung transplantation or atrial septostomyPulido T et al. N Engl J Med. 2013;369:809-818.

0

40

80

100

60

20

Months

Pa

tien

ts w

itho

ut

an

eve

nt

rela

ted

to P

AH

or

de

ath

fro

m

fro

m a

ny

cau

se*

(%)

0 6 12 363018 24

No. at risk:PlaceboMacitentan 3 mgMacitentan 10 mg

250250242

188213208

160188187

233241

648091

135166171

122147155

Macitentan 10 mg qdMacitentan 3 mg qdPlacebo

64% on background therapy:- 62% PDE5I- 5% Prostanoid

Approved Therapeutic Targets

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

cGMP

cAMP



Endothelin-receptor

antagonists







Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells


Smooth muscle cells


Iloprost (Ventavis®)Treprostinil (Tyvaso®)

Prostacyclin Analogues: Intravenous, Subcutaneous, Inhaled, or Oral

WG

Treprostinil (Remodulin®)

Treprostinil (Orenitram®)Selexipag (Uptravi®)

Epoprostenol (Flolan®

or Veletri®)Treprostinil (Remodulin®)

Epoprostenol IV: FC III‐IV, 2 ng/kg/min titrated to desired clinical response in 1‐2 ng/kg/min increments.Treprostinil IV / SC: FC II‐IV, 1.25‐2.5 ng/kg/min/wk. IV=diluted. Inhaled: FC III, to 54 mcg, 4 inh/d. Oral: FC II‐III, starting at 0.25 mg bid and titrated in 0.25 mg increments as tolerated.Iloprost Inhaled: FC III‐IV, 2.5‐5 mcg, 6‐9 inh/d.

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11

Oral Prostacylin Therapy: Time to First Morbidity or Mortality Event—GRIPHON

Sitbon O et al. N Engl J Med. 2015;373:2522‐33.

Selexipag vs placebo: RR 40%; HR=0.60; p<0.0001

No. at Risk

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

Patients without an event (%

)

00

20

40

80

60

12 18 24 30 366Months

Placebo

Selexipag

80% on background therapy:

‐ SIDE EFFECTS STILL

Prostanoid Side Effects

Flushing

Headache

Diarrhea, nausea, vomiting

Jaw pain

Leg pain

Hypotension

Dizziness

Syncope

Rebound PH if interruption of infusion delivery

Delivery site complications (pain, infection, cough, thrombosis,)

Vary according to drug and route of delivery (Po, Inhaled, SQ, IV)

PH Case DS Treated with Sildenafil alone with improvement; Escalated dose

to 80 mg TID

Walk Test 660 m, no desat

WHO functional Class I most days.

BNP 12

Echo:Severe RV enlargement; Low normal TAPSE. Right Heart Cath 11/08 on Revatio 80 TID. RA 7, PA 91/33 mean 55, PWP 8, CO5.4 CI 2.7 PVR

8.6, MVO2 sat 71, AVO2 diff 5.0 New Medication to discuss? Macitentan added to Sildenafil in 2016. Doing Great 12 years later - 2019.

Case TN (3) Returned : Primary Care MD

Sildenafil TID monotherapy for PAH in 2014.

Erratic FU but compensated initially on therapy and better exercise tolerance. ETOH use.

Returned one year later 2015: Increased edema, DOE, consistent with early RV failure.

Unable to get in for repeat Right Heart Catheterization.

Diuretics added to Sildenafil.

Echo shows worsening RV size and Worsening function. Estimated PASPIs > 60 mmHg. Estimated RA pressure is higher

Candidate for additional combinationTherapy? Compliance, Cost? ‐Oral Selexipag added 2016

‐NOT candidate for infusion therapy: Social Barriers

‐ Palliative care: 2018.

Summary PH should be in the differential diagnoses for the dyspneic patient.

Usual diagnostic studies can determine who has a higher likelihood of PH and help to determine the possible cause and Group.

Therapy follows according to the Group.

Group I PAH‐specific therapies promote vasodilation and remodeling, leading to improved RV function and exercise.

Selection of initial therapy largely depends upon severity of disease at diagnosis low‐risk patients can be treated with oral agents Initial or early combination therapy of benefit high‐risk patients require parenteral prostacyclins

Summary—Cont’dLongitudinal assessment of PAH patients includes monitoring of:clinical parameters functional parametershemodynamic parameters laboratory parameters imaging parameters

Current strategy is to achieve “Low Risk” Status in all patients. Directed combination therapy and potent therapies should be used in a timely fashion to achieve this status.

1/14/2019

12

Mary Furbee: Spiral. (Used with permission)

Pulmonary Hypertension

Correct Diagnosis, Best Plan, Partner before you jump in……

PH Patient Chronic Care Needs: Heart Failure Overlap (Group II), Chronic Lung Disease Overlap (Group III),

Specialty PH Care (Groups I, IV, V)

MCW‐FMLH: Among first 26 PHA CC Centers in USA

Froedtert –MCW PHA CCC

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