progress in pulmonary hypertension

1

Wael Berjaoui MDPulmonary,Critical care and Sleep medicine SHMG.

4th Annual: Topics in pulmonary and critical care medicine.

Progress in Pulmonary

Hypertension.

No present conflict of interest.

Talk Highlights:

•Brief review of PAH including classification, pathophysiology and Dg.

•Updates from the 5th World Symposium on PAH (Nice, France 2013) .

•New approved drugs and therapeutic strategies for G1 PAH.

•PH and LHD

•.PH and lung disease

•Case review of PH in a rare disease.

ESC/ERS Guidelines for the diagnosis and treatment of pulmonary

hypertension. Eur Heart J 2016; 37 (1): 67-119

7

ESC/ERS Guidelines for the diagnosis and treatment of

pulmonary hypertension. Eur Heart J 2016; 37 (1).

RV in PAH:

Adaptive remodeling: Concentric, High mass-volume ratio, preserved

systolic and diastolic function (usually seen in Eisenmenger;s syndrome)

Maladaptive remodeling: eccentric, reduced function, mostly seen in

CTD-PAH or IPAH.RV disynchrony ( RV free wall contracting while LV in

early diastole leading to late systolic septal movement), more R-L shunt

via PFO)

Less RV fibrosis with pressure overload thus better recovery after lung

transplant

Updates in PAH management

- New FDA approved medications include Riocigualt ( sGC) , oral

Treprostinil ( PCA), Selexipeg (selective IP agonist) and Macitentan (

ERA).

- Intital Combintaion therapy ( Ambition trial)

- Sequential combination therapy

- Goal targeted therapy

Therapy-General Tx

Avoid hypoxemia, high altitude

Low salt diet

Immunizations

Avoid pregnancy

Diuretics

OXYGEN

Exercise/ Rehab: Class 1 recommendation

Approved PAH Drugs

Prostacyclin analogues

■ Epoprostenol, IV

■ Treprostinil, IV, sq, inhaled, PO

■ Iloprost, inhaled

■ Beraprost, PO (Japan)

■ Selexipeg, PO

Endothelin Receptor Antagonists

■ Bosentan

■ Ambrisentan

■ Macitentan

PDE V Inhibitors

■ Sildenafil

■ Tadalafil

sGC Stimulators

■ Riociguat

Riociguat: Mode of action

Riociguat directly stimulates the

native sGC independently of NO

Riociguat increases the sensitivity of

native soluble guanylate cyclase

(sGC) to NO

Both actions lead to vasodilatation

(and anti-proliferation)

Effect of riociguat is not limited by low

NO levels (unlike PDE-5-I)

Constricted

Pressure

Flow rate

Relaxed

Pressure

Flow rate

sGC*Riociguat cGMP

* native (intact)

NO

PDE-5-I = phosphodiesterase-5-inhibitor

NO = mitroc oxide

Endothelin Receptor Antagonists

Macitentan (Opsumit):

Nonselective dual action Endothelin receptor antagonist.

Sustained receptor binding and enhanced tissue penetration.

Functional Class II, III, IV

Improves mortality, morbidity and 6 MWT

Prostacycline Pathway:

Oral treprostinil

FREEDOM M trial: improved 6-minute walk distance (6MWD) by 23

meters at 12 weeks in 349 treatment-naive PAH patients (95%

confidence interval 4 to 41 m, p = 0.0125). However, there was no

improvement in functional class or time to clinical worsening.

Kanwar, Manreet K. et al.Update in treatment options in pulmonary hypertension

The Journal of Heart and Lung Transplantation , Volume 35 , Issue 6 , 695 - 703

Selexipag:

Orally available, non-prostanoid, highly selective agonist of inositol

triphosphate (IP) receptor.

This selectivity allows for minimal side effects (nausea, vomiting,

diarrhea and jaw pain), better tolerability and successful dose escalation.

GRIPHON trial, which was a multicenter, double-blind, placebo-

controlled trial of 1,156 patients who were randomized in a 1:1 fashion to

selexipag or placebo.

The primary end-point was a composite of death, lung transplantation,

atrial septostomy, hospitalization for worsening PAH or worsening PAH.

It reduced the risk of primary end-point by 40% compared with placebo

(hazard ratio [HR] = 0.60; 99% confidence interval [CI] 0.46 to 0.78; p <

0.0001).

Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension

Nazzareno Galiè, M.D., Joan A. Barberà, M.D., Adaani E. Frost, M.D., Hossein-Ardeschir Ghofrani, M.D., Marius M. Hoeper, M.D., Vallerie V. McLaughlin, M.D., Andrew J. Peacock, M.D., Gérald Simonneau, M.D., Jean-Luc Vachiery, M.D.,

Ekkehard Grünig, M.D., Ronald J. Oudiz, M.D., Anton Vonk-Noordegraaf, M.D., R. James White, M.D., Ph.D., Christiana Blair, M.S., Hunter Gillies, M.D., Karen L.

Miller, Ph.D., Julia H.N. Harris, M.A., Jonathan Langley, B.Sc., Lewis J. Rubin, M.D., for the AMBITION Investigators

N Engl J MedVolume 373(9):834-844

August 27, 2015

Components and Definitions of the Primary End Point.

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

Primary and Secondary Efficacy End Points.


Kaplan–Meier Curves for the Probability of a First Adjudicated Primary End-Point Event.


Study Overview

• Patients with previously untreated pulmonary arterial hypertension who were randomly assigned to combination therapy with ambrisentan and tadalafil had a significantly lower risk of a composite clinical failure outcome at 20 months than did the pooled monotherapy group.

Conclusions

• Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy.

Lung transplant

PH Due to Left Heart Disease

Accounts for ~ 80%

LV systolic dysfunction

■ severity of PH is not related as much to the degree of systolic dysfunction, but is closer related to measures of diastolic dysfunction and MR, which in turn really determine LA pressure; it is LA pressure that drives PH

Diastolic (HFpEF): up to 70%

Left sided valvular heart disease

Left atrial disease: myxoma

How to Define Left Heart Disease

PAWP > 15 mmHg

History: age, DM, HTN, CAD, CHF, OSA

Symptoms: orthopnea, PND

Chest x-ray: congestion, history

Echo: EF usually normal; LVH, enlarged LA, diastolic dysfunction

Volume challenge or exercise RHC

■ 500 ml NS over 5 min: PAWP > 15 *

■ Supine cycle: PAWP > 20 – 25 mmHg

Vachiery JL. JACC Supp 2013

PH in LHD

Confusing nomenclature: “out of proportion”, passive vs reactive PH

Out of proportion if TPG >12, PVR >3 ( only if PCWP <25)

PVR is a composite variable ( Mpap-pcwp /CO)

Diastolic pressure difference= DPAP- mean PCWP

DPAP less influenced by PCWP than SPAP or mPAP due to lower

sensitivity to vessel distensibility.

DPD appears a better reflection of Pulmonary vascular disease

PH in LHD

PH in LHDPH

Riociguat and LHD:

In a recent multicentre, placebo-controlled trial, 201 patients with PH

due to systolic heart failure were randomized in four arms comparing

three doses of riociguat (0.5, 1 and 2 mg t.i.d.) with placebo over 16

weeks.

No effect on the primary endpoint (a change in PAPm after 16 weeks)

was observed at any dose of riociguat compared with placebo.

Bonderman et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular

dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study.

Circulation 2013;128:502–511.

PH in LHD

Consensus from 5th World Symposium:

Not enough data to recommend use of PAH targeted therapy in G2

PH.

WHO Group 3: PH due to lung disease and/or

hypoxia

COPD: typically mild – moderate

ILD: IPF, scleroderma, sarcoid

Combined Fibrosis/Emphysema: often severe PH

Hypoventilation (> 50% in OHS)

Sleep Apnea (Overlap syndrome)

High Altitude

When to Suspect PH in Lung Dz

DLCO , PaO2, symptoms “out of proportion” to radiographic and PFT

changes

Physical, x-ray findings of PH

Echo often inaccurate

BNP may be useful

Adversely impacts functional status, survival particularly with RV dysfunction

Systemic PAH meds failed to show any improvement.

Risk of worsening mismatch and hypoxemia

Raghu, G., Behr, J., Brown, K.K. et al. Treatment of idiopathic pulmonary fibrosis with

ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013; 158: 641–649

King, T.E., Brown, K.K., Raghu, G. et al. BUILD-3: a randomized, controlled trial of

bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011; 184: 92–

99

Hoeper, M.M., Halank, M., Wilkens, H. et al. Riociguat for interstitial lung disease and

pulmonary hypertension: a pilot trial. Eur Respir J. 2013; 41: 853–860

Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil

in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010; 363: 620–628

Inhaled Therapies

Delivering vasodilator by inhalation appealing as directs the effect to

areas in the lung with best airflow

Minimizes systemic side effects

Favorable effects with acute dosing studies and small medium term trials

Inhaled Treprostinil Study (INCREASE

Trial)

Multi-center, randomized, double-blinded, placebo controlled

Idiopathic interstitial lung diseases

Significant pulmonary HTN confirmed by right heart catheterization

Evaluate change in 6 minute walk distance after 16 weeks

Open-label therapy after 16 wk

Case presentation:

63 y.o female

Few days of SOB and abd pain

CTA Chest: No PE., RLL consolidation, Dilated PA, large mass in the

right lobe of the liver measuring up to 8 cm in size.

History: Hereditary Hemorrhagic Telengectasia.

2d ECHO

The left ventricular ejection fraction is 62%.

The left atrium is severely dilated.

The right ventricle is moderately dilated. Right ventricle function is

moderately to severely decreased. The right ventricular fractional area

change is 8%.

The estimated right ventricular systolic pressure is 79 mmHg.

The estimated RA pressure is 15 mm Hg (10-20 mm Hg).

HEMODYNAMICS:

Under rest condition: Pulmonary pressure equals 62/35, with a mean pulmonary artery pressure of 44

mmHg. Pulmonary capillary wedge pressure 12 mm mean. Estimated Fick cardiac output equals 8.1

L/minute, with a cardiac index of 4.5 L

Nitric oxide inhalation vasodilator challenge: the pulmonary artery pressure did decline to 46/20, with a

mean of 30 mmHg. The pulmonary capillary wedge pressure was unchanged at 10 mmHg mean.

MRI Cardiac Morph/Func W + W/O contrast –

Impression:1. Mild left ventricular chamber dilation with normal left ventricular

systolic function. LVEF 62%. Systolic and diastolic septal flattening is present,

consistent with right ventricular pressure and/or volume

3. Severe right ventricular chamber dilation with moderate to severely reduced

right ventricular systolic function. RVEF 35%.4.

4. There is no evidence for significant intracardiac shunt by MRI criteria; the

calculated Qp/Qs is 0.9.5.

5. Mild tricuspid and mitral regurgitation as detailed above.6. Trivial-small

circumferential pericardial effusion.7. Dilated main pulmonary artery.

PH in HHT

1. High CO due to shunt via Liver AVMs.

2. Heritable PAH

2 months later after CCB started

Interpretation Summary

The left atrial volume is severely increased.

The right ventricular size, thickness, and function are normal. (Tricuspid

annular plane systolic excursion is 19 mm. Systolic excursion velocity is

18cm/s. The right ventricular fractional area change is 40%.).

The estimated right ventricular systolic pressure is 44 mmHg.

Progress in treating PH but we are not

there yet.

progress in pulmonary hypertension

Healthcare