drugs for cteph - studi farmacologici

UNIVERSITY OF PAVIA SCHOOL OF MEDICINE - “SAN MATTEO” HOSPITAL - PAVIA - ITALY

SPECIFIC DRUGS FOR CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION

DRUGS FOR CTEPH

Dr. Marco Morsolini, MDResearch Doctorate in Experimental Surgery and Microsurgery

University of Pavia School of Medicine

Division of Cardiac SurgeryFoundation I.R.C.C.S. “San Matteo” Hospital – Pavia – Italy

PATHOPHYSIOLOGY

1. Hypertensive remodeling of the patent arteries

2. Chronic arteriopathy of the obstructed branches

3. Plexiform lesions

4. Development of pathological arterial shunts

5. In situ thrombosis

ACCORDING TO THE LENGTH OF THE DISEASE

PATHOPHYSIOLOGY

1. Hypertensive remodeling of the patent pulmonary vascular bed (Eisenmenger-like) due to volume and pressure overload

PATHOPHYSIOLOGY

“…the development of these hypertensive changes may explain the deterioration which these patients experience preoperatively over time…”

PATHOPHYSIOLOGY

2. Chronic arteriopathy of the obstructed branches with calcifications and possible retraction of the distal vessels

PATHOPHYSIOLOGY

“…thrombotic material can provide the basis elements for the pultaceous core of atherosclerotic plaques, whereas it has not been observed in the hypertensive non-thromboembolic arteries…”

PATHOPHYSIOLOGY

3. Plexiform lesions stemming from the capillary bed

PATHOPHYSIOLOGY

“…patients with plexiform lesions failed to show dramatic hemodynamic improvement despite successful PEA, suggesting that plexiform lesions were probably responsible for persistent pulmonary hypertension…”

PATHOPHYSIOLOGY

4. Development of pathological systemic-to-pulmonary arterial shunts to overcome the chronic segmental lung hypoperfusion, often causing hemoptysis

• bronchial arteries (orthotopic / heterotopic)

• intercostal arteries

• internal mammary arteries

• frenic arteries

• coronary arteries

PERCUTANEOUSEMBOLIZATION

PATHOPHYSIOLOGY

Right bronchial artery

Right mammary artery

Before After

Right thoracic artery

PATHOPHYSIOLOGY

Right intercostal artery

Right frenic artery

Before After

PATHOPHYSIOLOGY

5. The core of the pathologic process in CTEPH is the imbalance between prothrombotic factors and disturbed thrombus resolution

Moreover, pulmonary hypertension itself is associated with endothelial and platelet dysfunction

CTEPH patients are more likely to develop in situ thrombosis over their thromboembolic lesions

PATHOPHYSIOLOGY

Such pathophysiological modification of the pulmonary circulation are absolutely not predictable, since CTEPH may develop during indefinite months or years:

• following a single episode of acute PE with incomplete resolution despite medical treatment

• due to chronic relapses of asymptomatic PE

• due to an acute symptomatic PE over chronic relapsing PE

PATHOPHYSIOLOGY

EARLY DIAGNOSIS

EARLY TREATMENT

• Growing single surgeon’s experience due to learning curve

OPERABILITY ASSESSMENT

Which lesions have to be considered as inoperable?

• Different operability assessments from different Centers

JAMIESON CLASSIFICATION

L.M.E.L. - 65 yrs M - Oct 2004 - PEA #119mPAP 39 19 (-51%)CO 4.4 5.4 (+23%)PVR 665 222 (-66%)

G.A.C. - 52 yrs F - Jul 2003 - PEA #96mPAP 48 27 (-44%)CO 2.1 4.2 (+100%)PVR 1638 381 (-77%)

B.A. - 43 yrs F - May 2009 - PEA #233mPAP 49 19 (-61%)CO 3.3 5.0 (+52%)PVR 1067 224 (-79%)

Exclusively distal lesions

MEDICAL THERAPY !

OPERABILITY ASSESSMENT

SURVIVAL OF UNTREATED PATIENTS

Higher operability rate

PH RECURRENCY AFTER PEA

More Jamieson type III PEAs

MEDICAL THERAPY !

Higher PH recurrence after PEA

FOLLOW-UP TIMING AFTER PEA

• discharge

• 3th month

• yearly for 5 years

• 7th, 10th and 15th year

Pre-operative V/Q scan

Pre-operative right pulmonary angiogram

Pre-operative RHCmPAP 50CI 1.4PVR 1241RVEF 9

PRE-OPERATIVE LONG LASTING DISEASE

• A right monolateral PEA was performed

• Impossible to wean off the patient from cardio-pulmonary by-pass due to right ventricle failure

• On ECMO for two days; the sternum was left open for two more days

• Mechanical ventilation 9 days ICU stay 14 days Hospital stay

21 days

First PO RHC controlmPAP 26 (-48%)CI 2.0 (+43%)PVR 410 (-67%)RVEF 25 (+178%)

• No CT-scan evidence of new thromboembolic material

• Very long pre-operative NYHA III-IV class period (65 months): probably severe and non-reversible small vessels disease

2 years follow-up RHC

mean Pulmonary Artery Pressure

Before PEA Discharge 3 months 1 year 2 years

Cardiac Index

Pulmonary Vascular Resistances

Right Ventricle Ejection Fraction

TYPICAL PATIENT WITH

RECURRENT PH AFTER PEA

PH MEDICAL THERAPY

Pulmonary hypertension is a rare disease…

…but not an orphan disease at all!

PH MEDICAL THERAPY

- BOSENTAN

- AMBRISENTAN- SILDENAFIL

- TADALAFIL

- EPOPROSTENOL

- ILOPROST

- TREPROSTINIL

CTEPH MEDICAL THERAPY

No drugs are currently approved for CTEPH

Further clinical trials are needed

Author Drug Study Design Patients WHO Treatment Results

McLaughlin(1999)

Epoprostenol Observational 3 III-IV 8-16 monthsHemodynamic and exercise tolerance improvement

Higenbottam(1998)

EpoprostenolIloprost (i.v.)

Observational 39 II-IV 1-4 yearsSurvival improvement(if SVO2 < 60%)

Olschewski(2002)

Iloprost (inhaled) Controlled 33 III-IV 12 weeks No improvement

Nagaya(2002)

Beraprost (oral) Open 16 II-III 8-12 weeksExercise tolerance improvement

Vizza(2001)

Beraprost (oral) Open 3 II-IV 12 monthsExercise tolerance improvement

CTEPH MEDICAL THERAPYPHASE II STUDIES

BENEFiT TRIAL

– PHASE III –

STUDY DESIGN

• Phase III, randomized vs. placebo (1:1)

• International multicentre (26 sites in 13 Countries)

• 157 pts (18 – 80 yrs)

• CTEPH - inoperable (exclusively distal lesions)- persistent or recurrent PH after PEA

• WHO functional class II – IV

• 6mWT distance < 450 m

Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34

BENEFiT TRIAL

*Analysis excluded patients judged operable by the Operability Evaluation Committee (n=11)

†Analysis excluded patients with missing baseline or post-baseline assessment(s) (n=9 for pulmonary vascular resistance [PVR] analysis; n=6 for 6-min walk distance [6MWD] analysis)

mPAP = mean pulmonary artery pressure mRAP = mean right atrial pressure

NT-proBNP = N-terminal pro-brain natriuretic peptide; PEA = pulmonary endarterectomy; TPR = total pulmonary resistance; WHO = World Health Organization.

BENEFiT TRIAL

Modified Bruce Test

Pre-op 3 mesi 1 anno 3 anni 5 anni 7 anni 10 anni

Follow-up

pp < 0.01 < 0.01

Pre-op 3m 1y 3y 5y 7y 10y

RESULTS AFTER PEA

SOME COMMENTS:

• CTEPH patients are generally older than other-PH patients

• We are still far from early diagnosis of CTEPH(75% at diagnosis are in WHO functional class III or IV)

Significant muscolar and psychological deconditioning(19 months of WHO III or IV symptoms before diagnosis)

Short observation time(main phase study only 16 weeks)

• Hemodynamic endpoint satisfied• Functional endpoint not satistied

BENEFiT TRIAL

NEW PERSPECTIVES

RATIONALERIOCIGUAT Soluble guanylate-cyclase stimulator

Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial

riociguat

CHEST STUDY

• Phase III, double-blind, randomized vs. Placebo (2:1)• International, multicenter (28 Countries)• N = 270 pts (18 – 75 yrs)• Inoperable CTEPH (peripheral localization) or recurrent

PH after PEA• PH pts WHO II-IV• 6 MWD > 150 m and < 450 m• PVR > 300 dyne*sec*cm-5

• mPAP > 25 mmHg riociguat

CHEST STUDY

2 weeks

2.0 mg tid

1.5 mg tid

1 mg tid

∑: 16 weeks

0.5 mg tid

1.5 mg tid

1.0 mg tid

2.0 mg tid

2.5 mg tid2.5 mg tid

STUDY DESIGN

CHEST STUDY

drugs for cteph - studi farmacologici

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