concomitant treatment: pulmonary hypertension and (left)...

Concomitant Treatment:Pulmonary Hypertension and (Left) Heart Failure

Peter Leary, MD PhDDirector, UW Pulmonary Vascular Disease Program

University of Washington School of Medicine

6th Annual Full Spectrum of Heart Failure Therapy

DISCLOSUREPeter Leary, MD

Consulting, Speaking & Teaching: Bayer and United TherapeuticsGrant/Research Support: Lung LLC, AHA, CHEST Foundation, NHLBI

Disclosures and funding(within the last three years)

Supported by non-profit organizations: Pulmonary Hypertension Association, Cardiovascular Medical Research and Education Fund, CHEST Foundation & American Heart Association

Supported by the NIH: KL2TR000421, Loan Repayment Program, R61HL142539, R33HL142539, R01HL126536, R01HL152724 (pending)

Site PI for industry sponsored studies: Lung LLC, Bayer, and Actelion

Employed by the Cystic Fibrosis Therapeutic Development Network

Participation in a recurrent advisory board of Directors for CTEPH PTE centers for Bayer

Take home points

1. Refresher: Pulmonary hypertension is not one disease but manyAppropriate treatment requires appropriate diagnosis

2. Pulmonary hypertension in the setting of left heart failure either represents WHO Group II PH OR multi-physiology diseaseThe treatment approach for these two entities is quite disparate

The spectrum of diseases with high pulmonary pressures

The Physiology

New proposed definition of pulmonary hypertension is a mPA

of 20mmHg

mPA= PVR * CO + PCWP

mPA= mean pulmonary artery pressure; pcwp= pulmonary capillary wedge pressure;

PVR=pulmonary vascular resistanceCO= cardiac output

Simonneau G, et al. Eur Respir J. 2019;53(1):1801913

• Idiopathic, heritable, toxic, • Associated (HIV, CREST, etc)

Group 1Pulmonary Arterial Htn

• Systolic, diastolic, valvularGroup 2

Left Heart Disease

• Hypoxemia: Sleep Disorders• Capillary Bed Loss: ILD/COPD

Group 3 Alveolar Hypoxia/Lung

• CTEPH, Tumor embolismGroup 4

Thromboembolic

• Sarcoid, LAM, Vasculitis, • metabolic disease

Group 5 Miscellaneous

Pulmonary hypertension heterogeneity

Galie N, JACC (2013), McLaughlin V, JACC (2015)

WHO Group II Pulmonary Hypertension

Kulik TJ, Pulm Circ (2014); 125: 289-97 & Masri SC (2017); 63:139-45

WHO Group II PH

Wedge Pressure (mmHg)

10

20

30 4

0

Pre-LVAD 30 days

PVR (wood units)

0

2

4

6

8

Pre-LVAD 30 days

LVAD placement• Increased wall stress

• Activation of vascular stretch receptors

• Increased adrenergic tone of heart failure

PVR

PV C

ompl

ianc

e

Decreased pulmonary vascular compliance

A couple of treatment musingsThe bird in the hand is treating left heart failure and this is likely

to be the most effective treatment for WHO Group II PH

PAH-specific therapy doesn’t “lower pulmonary pressures”.• Instead pulmonary vasodilators lower pulmonary vascular

resistance in a suite of diseases defined by smooth muscle hypertrophy narrowing pulmonary vessels

• This observation underlies the many negative trials of pulmonary vasodilators and/or trials suggesting harm in non-PAH pulmonary hypertension populations.

Negative trials in heart failure: Endothlin-receptor antagonists: REACH-1, EARTH, ENABLE: no benefitProstacyclin analogues: FIRST: stopped early for excess heart failure

Packer et al, J Card Fail 2005; 11: 12-20; Anand et al, Lancet 2004; 364: 347-54.; Packer et al – Abstract at ACC 2002 in Atlanta; Calif et al, Am Heart J 1997;

134:44-54; Zile et al. JACC-HF 2014; 2: 123-30.

MELODY-1(AKA is macitentan benign?)

Vachiery, Eur Respir J 2018 51: 1701886.

Inclusion criteria:

Age >18, CpcPH (mPA >25mmHg + PAWP >15 mmHg + PVR >3 + DPG >7mmHg), EF >30%, NYHA Functional Class II or III, 6MWD >150m, no other PAH specific therapy

Intervention:

12 weeks of macitentan

MELODY-1

22.6%

12.5%

% WITH FLUID RETENTION OR WORSE NYHA FUNCTIONAL CLASS

Macitentan Placebo


WHO Group II PH:Observational evidence for sildenafil

Lewis et al, Circulation 2007; 116: 1555-62; Guazzi et al, Circ-HF 2011; 4: 8-17;

Left heart failure: sildenafil- EF

SIOVAC(AKA is sildenafil really benign?)

Bermejo, Eur Heart J. 2017;39(15):1255-1264.

Inclusion criteria:

Age >18, mPA >30 mmHg, valve repair or replacement at least one year before randomization, stable medications without a heart failure admission for at least one month

Intervention:

6 months of sildenafil

SIOVAC

Bermejo, Eur Heart J. 2017;39(15):1255-1264

INTERMACS(AKA is sildenafil really benign?)

Gulati, Circ: Heart Failure. 2019;12:e005537.

1,177 patients who received sildenafil after LVAD matched to patients with an otherwise similar propensity to receive

sildenafil… who didn’t.

Multi-physiology Pulmonary Hypertension

Multi-physiology pulmonary hypertension is uncommon

PVR (wood units)

0

2

4

6

8

Pre-LVAD 30 days

LVAD placement

Masri SC ASAIO (2017); 63:139-45

WHO Group 1 –Pulmonary Arterial HypertensionEndothelial thickening

Plexiform lesions & smooth muscle hypertrophy

In situ thrombosis

Mild/Moderate SevereNormalZwicke DL. Advances in Pulmonary Hypertension (2011)

PAH Drug Development Timeline

1995 2001 2002 2005 2007 2009 2010 20122004 2013 2014

Iloprost(inhaled)

AIR

Treprostinil (inhaled)

Epoprostenol(IV)

Treprostinil (SQ)

Treprostinil (IV) RTS Epoprostenol (IV)

Bosentan (PO)BREATHE

Sildenafil (PO)SUPER Tadalafil (PO)

PHIRST

Ambrisentan (PO)ARIES

Macitentan (PO)SERAPHIN

Riociguat (PO)PATENTCHEST

Treprostinil (PO)FREEDOM

Selexipag (PO)GRIPHON

WHO Group 4 –Chronic Thromboembolic Disease

Multi-Physiology PH in the setting of left heart failure

Multi-physiology PH

unlikely

• PVR 3-6 WU

• No risk factors for PAH or history of PE

Multi-physiology PH possible

• PVR 7-9 WU

• Presence of a strong risk factor for PAH• Methamphetamine• Systemic sclerosis• Cirrhosis• Congenital heart

disease

• History of PE or strong suspicion

Multi-physiology PH

likely• PVR >9 WU

• Regardless of the presence of a strong risk factor for PAH or PE

Take home points

1. Refresher: Pulmonary hypertension is not one disease but manyAppropriate treatment requires appropriate diagnosis

2. Pulmonary hypertension in the setting of left heart failure either represents WHO Group II PH OR multi-physiology diseaseThe treatment approach for these two entities is quite disparate

AcknowledgementsThank you to the patients, participants, and collaborators

who contributed to the work described in this presentation.Non-urgent questions: [email protected]

Clinic: 206-598-7356Clinic Fax: 206-598-3036

www.phassociation.org online university has good clinical resources and patient support for

Group I and IV disease

http://www.phassociation.org

Appendix

• MELODY-1 baseline characteristics• SIOVAC baseline characteristics• Ventricular interdependence

MELODY-1Baseline characteristics

Macitentann=31

Placebon=32

Age 70 72Women (%) 81% 50%BMI 33 31Blood pressure 129/77 133/72Right atrial (mmHg) 13 13mPA (mmHg) 44 49PAWP (mmHg) 20 20TPG (mmHg) 27 28Cardiac index 2.4 2.2


SIOVAC

Bermejo, Eur Heart J. 2017;39(15):1255-1264.

Baseline characteristicsSildenafil

n=104Placebo

n=96Age 70 73Gender (%) 73% 81%BMI 27 28Blood pressure 131/70 140/70Right atrial (mmHg) 12 12mPA (mmHg) 39 37PAWP (mmHg) 23 22TPG (mmHg) 16 15Cardiac index 2.8 2.8

Ventricular Interdependence“The Reverse Bernheim Effect”

Frost A, Chest (2013); & Wain Hobson, IJC Heart & Vessels (2014)

• Pressure is typically less than 25 mmHg and PVR >8wu in the rare case of ventricular interdependence

• “PAH” patients with high wedge on subsequent caths have less treatment response to pulmonary vasodilators and may not be PAH but unmasked HFpEF

Concomitant Treatment:�Pulmonary Hypertension and (Left) Heart FailureDISCLOSUREDisclosures and funding�(within the last three years)Take home pointsSlide Number 5Slide Number 6Pulmonary hypertension heterogeneitySlide Number 8WHO Group II PHA couple of treatment musingsMELODY-1�(AKA is macitentan benign?)MELODY-1WHO Group II PH:�Observational evidence for sildenafilSIOVAC�(AKA is sildenafil really benign?)SIOVACINTERMACS�(AKA is sildenafil really benign?)Slide Number 17Multi-physiology pulmonary hypertension is uncommonWHO Group 1 – �Pulmonary Arterial HypertensionPAH Drug Development TimelineSlide Number 21Multi-Physiology PH in the setting of left heart failureTake home pointsAcknowledgementsAppendixMELODY-1SIOVACSlide Number 28

concomitant treatment: pulmonary hypertension and (left)...

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