Post on 09-Aug-2020
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
Vachiery, Eur Respir J 2018 51: 1701886.
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: learyp@uw.edu
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
Vachiery, Eur Respir J 2018 51: 1701886.
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