Pulm onary Hyper t ension in Lef tHear t Disease (PH-LHD): Is There a

Role f or Pulm onary Ar t er ialHyper t ension (PAH) Specif ic

Therapy? and Who May Benef i t ?

Antoine Hage, M.D

Director, Solid Organ Transplant CardiologyCo-Director, Pulmonary Hypertension ProgramCedarsSinai Heart InstituteClinical Professor of Medicine/ Cardiology

Disclosures

• Research grants:

• Actelion Pharmaceuticals

• Bayer

• United TherapeuticsCorporation/ Lung RXLLC

• REATA

• Arena

HemodynamicDefinitionsof Pulmonary Hypertension (PH)

Definition Characteristics Clinical group(s)

Pulmonary hypertension (PH) Mean PAP> 25 mm Hg All

Pre-capillary PH Mean PAPш25 mm Hg

PWPч15 mm Hg

COnormal or reduced

1. Pulmonary arterial hypertension (PAH)

3. PH due to lung disease

4. CTEPH

5. PH with unclear or multifactorialmechanisms

Post-capillary PH

Isolated post-capillary PH(Ipc-PH)

Combined post-capillary andpre-capillary PH (Cpc-PH)

Mean PAPш25 mm Hg

PWP>15 mm Hg

COnormal or reduced

TPGч12 mm HgDPAP-PCWP< 7 mm HgPVR< 3 WU

TPG>12 mm HgDPAP-PCWP> 7 mm HgPVR> 3 WU

2. PH due to left heart disease (PH-LHD)5. PH with unclear and/ or

multifactorial mechanisms

Modified from 2015 ESC/ ERSGuidelineson PH

TARGETFORRx:Patients with severe aspect ofthis abnormality/ RV dysfunction

IsThere a Role for PAH Specific Therapiesin PH-LHD?

Exploratory Studies

• MELODY-1: The primary endpoint/ (safety) outcome was the proportion ofpatientsexperiencingsignificant fluid retention or a worsening of WHOfunctional class from baseline. In thisexploratory study, macitentan was welltolerated in the Group 2 pulmonary hypertension patient population with heartfailure. In addition, encouraging hemodynamic effectswere observed.

• LEPHT: Riociguat in Patients with Pulmonary Hypertension due to Systolic LeftVentricular Dysfunction: A Phase IIb Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging Hemodynamic Study: the primary endpoint of thestudy, change in mPAPwas not met (PAP-3 mm Hg; p=0.1), because of increasein CI and SVI, but riociguat waswell tolerated in patients with PH-sLVD andimproved cardiac index, decrease in pulmonary (-16%) and systemicvascularresistance ( -15%) and improved Minnesota living with heart failure score.

• DILATE-1: Effect of Single dose riociguat on PAPin HFpEF

No requirement for high PAPor PVRRELAXshould be considered a trial of sildenafil in HFpEF, not PH-LHD

2015 ESC/ERSGuidelines for the diagnosisAnd treatment of pulmonaryhypertensionGalie, N et al: Eur Heart J .37: 67-119;Galie N, et al. Eur Respir J2015; 46:903-975

Why is Cpc-PHa target for Rx?

Cardiopulmonary In te rac tion and Pathobio logy of Pu lmonary Hypertens ion(PH) in Left Ven tricu la r Heart Fa ilure : S imila ritie s with PAH.

Stephan Ros enkranz e t a l. Eur Heart J2015;eurhea rtj.ehv512

100 cases of MVRfor severe MSin India

PA pressure correlated with degree of medial thickness

*Tandon HD and Kasturi J . British Heart Journal 1975 Delgado J F et al. Eur J Heart Fail 2005;7:1011-1016

Linear correlation between medial thickness and:- Transpulmonary gradient (TPG)

- Pulmonary vascular resistance (PVR)

2015 ESC/ERSGuidelines for the diagnosisand treatment of pulmonary hypertensionGalie, N et al: Eur Heart J. 37: 67-119; Galie N, et al. Eur Respir J2015; 46:903-975

Ad ap ted fro m:D’Alo nzo GE et a l. Ann In t Me d . 1991;115:343-349.Benza , R e t a l. Ches t 2012, 142:448-456

1 yr: 85%

68%

5 yr: 57%REVEAL7 yr:49%

7.0/ /

Of 2967 adult patientsenrolled, 239 (8%)had an elevated PAWP(16-18 mm Hg)

Gregory D. Lewis e t a l. Circula tion. 2007;116:1555-1562

r = 0.62, p = 0.01

-4

-2

0

2

4

0 10 20 30 40 50 60

Bas eline RVEF at Res t

Ch

an

ge

inV

O2

(m

r = 0.62, p = 0.01

-4

-2

0

2

4

0 10 20 30 40 50 60

Bas eline RVEF at Res t

Ch

an

ge

inV

O2

(m

VO2 , Car d iac Out put propor t ionat et o de g ree of reduc t ion in RVEF ande levat ion in PVR.

Sildenafil improves exercise capacity(6MWT) and QOL in HFrEF+PH

-69%

HFpEF, n=4412 monthsof sildenafil 50mgTID vsplaceboRAP=23, PCWP=22, PVR=3.3, TAPSE=11.2.DPG9 mmHg(Ptswith CpcPH)

Guazzi M et a l. Circula tion. 12 J uly 2011,124 (2), p 164–174

PDE5i improved hemodynamics (PVR, RA and PCWP) , RV function (TAPSE),gaz exchange, QOL and multiple other cardio-pulmonary parameter s.

Improvement also in:• Pulmonary vascular resistance• Right ventricular (RV) end-diastolic pressure–

stroke volume relationship• pulmonary arterial elastance• Tricuspid annular plane systolic excursion

(TAPSE)• Right ventricular (RV) mean systolic ejection

rate (MSEJR)• Mean RA and PCWP• Benefitial changes in alveolar-capillary

membrane conductance• QOL.

Tedford,Ret al: Circulation: Heart Failure. 2008;1:213-219

138 consecutive LVAD patients.58 ptshad persistent PHpost LVAD ( PVR=5.4 WU)Sildenafil group (n=26) improved (2-4 weekspost sildenafil)Persisted through 12-15 weekspost24/26 of sildenafil group reduced PVR<3–19 became Tx eligible–10 transplanted–1 had post-tx RV dysfunctionControl group (n=32)– 18 transplanted without complication– 5 post op RV dysfunction

PAH

‡

A Comparison of Characteristicsand Outcomes of Patients with Atypicaland Classical Pulmonary ArterialHypertension from the AMBITION Trial

J Harris, J Langley, LJ Rubin

American Thoracic Society International ConferenceMay 17, 2015Denver, COOral Abstract #A2196

PAH

‡

15PAH

Time to First Clinical Failure Event (Ex-PAS)

AMBITION Study – PAS vs. Ex-PAS Subgroup Analysis (ATS 2015)

ABS+TAD Combo: 49 41 31 25 20 14 9 5

Pooled Monotherapy: 56 42 33 28 24 14 7 1

Number at risk:Time (weeks )

Ev

en

t-F

ree

(%)

McLaughlin et al. Am J Respir Crit Care Med 2015;191: Abstract A2196.

ed :is ks fac to rs :- BMI > 30- HTN- DM- CAD

COMPERA Registry:Pre-Capilla ry, Combined, and Pos t-Capilla ry Pulmonary Hypertens ion:

A Pathophys iologica l Continuum

COMPERA cohortN= 5935

PH-HFpEF(N=226)

mPAP> 25PCWP> 15

Atypical IPAH ( N=139)

> 3 risk factors

Typical IPAH ( N=421)

< 3 risk factors

IPAH ( N=560)mPAP> 25 PCWP< 15

Excluded (N 5149)• Non IPAH-PAH• Non HFpEFPH• Children• Prevalent cases• Inconsistent hemodynamics,• etc

Opitz, C e t a l. J Am Coll Cardiol. 2016;68(4):368-378.

PH-HF-pEFHemodynamics:mPAP46 mm HgCI 2.2TPG26

TotalN=786

Comparison of typical IPAH, AtypicalIPAH(>3 Risk Factors) and HF-pEF

Opitz, C e t a l. J Am Coll Cardiol. 2016;68(4):368-378.

Date of download: 10/31/2016 Copyright © The American College of Cardiology. All rights reserved.

From: Pre -Capillary, Combined , and Pos t-Capilla ry Pulmonary Hypertens ion : A Pathophys io logica l Continuum

J Am Coll Cardiol. 2016;68(4):368-378. doi:10.1016/j.jacc.2016.05.047

5-Year Overa ll Surviva l

There was no s ignificant difference in survival among patients with PH who were s tudied. p1 = p va lue for typica l IPAH versus a typica l IPAH;p2 = p va lue for typica l IPAH versus PH-HFpEF; p3 = p va lue for a typica l IPAH versus PH-HFpEF; othe r abbrevia tions as in Figure 1.

All groups s howed improvement in exerc is ecapac ity, functional c las s , and natriure ticpeptides from bas eline to 12 months

Date of download: 10/31/2016 Copyright © The American College of Cardiology. All rights reserved.

From: Pre-Capillary, Combined , and Pos t-Cap illa ry Pulmonary Hypertens ion : A Pathophys iologica l Continuum

J Am Coll Cardiol. 2016;68(4):368-378. doi:10.1016/j.jacc.2016.05.047

Figure Legend :

Pulm onary Hypertens ion in Typical PAH, Atypica l PAH, and HFpEF

Various fac tors and com orbid ities appear m ore or les s frequently in patien ts with typical id iopa th ic pulm onary arte ria l hyper tens ion (IPAH), defined as <3 ris kfac tors for le ft hea rt d is eas e; in patien ts with a typica l IPAH (≥3 ris k factors ); and in patien ts with PH–heart fa ilure with pres e rved e jection fraction (HFpEF). Giventhe patte rns and tendencies s een , is there a dis eas e continuum ranging from typica l IPAH through atypical IPAH to PH-HFpEF? AF = atria l fibrilla tion ; CAD =coronary artery dis eas e; DPG = dias to lic pres s ure gradient; PAH = pulm onary arte ria l hypertens ion; PVR = pulm onary vas cula r res is tance; TPG = trans pulm onary

pres s ure gradient.

Cologne Consensus Conference 2010:SpecificRecommendationsof The WorkingGroup Regardingtreatment of PHAssociated with Left Heart Disease (Cpc-PH)

• Potential Use of Targeted PAH Therapies in PH-LHD (PCWP> 15 mm Hg):

– Requirement: Complete diagnostics including RHCand LHC

– Pronounced precapillary component foregrounded to the disease

– Persistent High PVR/ TPG/ DPGdespite optimization of LHD (remodeling ofPA/ RV dysfunction)

• Patientsmust fulfill the following criteria:

– No treatable cause of heart failure (CAD, valvular disease)

– Guideline-based, evidence-based treatment for heart failure for a reasonabletime (>3-6 months), and at the anticipated target doses

– Exclusion of other causesof PHand CTEPH

• Primary Goal: Inclusion in clinical trials/ careful Phenotyping ( e.g, VICTORIA,SOPRANO, SERENADE, MELODY, SOCRATES, DILATE-1, LEPHT)

Modified from Rosenkranz et al, DMW 2010, 135 (suppl 3: S102-S114)