IPERTENSIONE POLMONARE PRIMITIVA

Transcription

Ipertensione polmonare
Carmine Dario Vizza
Centro Ipertensione Polmonare
Primitiva e Forme Associate
Dip. Malattie Cardiovascolari e Respiratorie
Universita’ di Roma “La Sapienza”
Direttore Prof Francesco Fedele
e-mail : dario.vizza@uniroma1.it
Ipertensione polmonare: definizione
emodinamica
ARTERIE CAPILLARI
VENE
ART POLM
Normale
ATRIO SIN
16 mmHg
8 mmHg
PVR 2-3 WU
PAPm>25 mmHg a riposo
e/o
>30 mmHg durante sforzo (?)
Pulmonary Hypertension Unit
La Sapienza University oi Rome
Classificazione emodinamica
IP Post-capillare
ARTERIE CAPILLARI
ART POLM
ATRIO SIN
IP postcapillare26 mmHg
18 mmHg
PVR 2-3 WU
VENE
Classificazione emodinamica
IP Pre-capillare
ARTERIE CAPILLARI
ART POLM
ATRIO SIN
IP precapillare 35 mmHg
8 mmHg
PVR > 3 WU
VENE
Pulmonary hypertension: Classification 2013
1. Pulmonary Arterial Hypertension
• Idiopatic
• Hereditary (BMPR-II ; ALK-1)
• Drug and Toxin induced
• Associated with :
– Connective Tissue Disease
– HIV infection
– Portal hypertension
– Congenital heart diseaswe
– Schistosomiasis
•Persitent PH in the new born
1A Veno-occlusive disease
2. PH due to left heart disease
• Systolic/Diastolic dysfunction
• Valvulopaties
3. PH due to lung disease or hypoxia
• COPD
• Interstiial lung disease
• Breathing sleep disorders
• Chronic exposure to high altitude
• Developtmental lung disorders
4. Chronic Thrmoboembolic PH
5. PH with multifactorial mechanisms
Hematologic disorders, Vasculitis,
Sarcoidosis, Metabolic disorders
(glicogenosisi)
Ipertensione Polmonare: PAPm> 25 mmHg
Progressiva obliterazione
Delle arteriole polmonari
Disfunzione
Ventricolare destra
Grave insufficienza
cardiaca
Approccio diagnostico e
diagnostica differenziale ….
Iter Diagnostico: diagnosi differenziale
Sospetto clinico
Anamnesi,Rx Torace, ECG
Eco 2D- Doppler
Ipertensione Polmonare
Esclusione di patologie VS
Invio al centro di riferimento
Diagnosi Differenziale
Ipertensione
Polmonare Cronica
Tromboembolica
Ipertensione
Arteriosa
Polmonare
Ipertensione
Polmonare sec.
Pneumpatie
Rilievo ECO Doppler di
Ipertensione Polmonare
Ventr Sx
IP Post-Capillare
Anormale
Normale
Studio ECO contrasto
Funzione respiratoria
DIA, DIV
Deficit
Normale
Mod-severo
TC Alta Ris.
Scintigrafia Perfusionale
Lieve
Polisonno
grafia
Normale o
difetti sfumati
Difetti segmentali
TC Spirale o Angio
IP Pneumo
Botallo
OSAS
Ipert Art Pol
Ricerca:
Auto-anticorpi
Capillaroscopia
HIV
ECO
V Porta
La Sapienza
University oi Rome
IPCTE-CTEPH
Studio emodinamico
Test Vasoreattività
Strategie terapeutiche ..
Pulmonary hypertension: Classification 2013
1. Pulmonary Arterial Hypertension
• Idiopatic
• Hereditary (BMPR-II ; ALK-1)
• Drug and Toxin induced
• Associated with :
– Connective Tissue Disease
– HIV infection
– Portal hypertension
– Congenital heart diseaswe
– Schistosomiasis
•Persitent PH in the new born
1A Veno-occlusive disease
2. PH due to left heart disease
• Systolic/Diastolic dysfunction
• Valvulopaties
3. PH due to lung disease or hypoxia
• COPD
• Interstiial lung disease
• Breathing sleep disorders
• Chronic exposure to high altitude
• Developtmental lung disorders
4. Chronic Thrmoboembolic PH
5. PH with multifactorial mechanisms
Hematologic disorders, Vasculitis,
Sarcoidosis, Metabolic disorders
(glicogenosisi)
Approccio Terapeutico nell’ Iperetensione
Arteriosa Polmonare (IAP)
Fino al 1995
Trattamento
Medico
•Anticoagulanti
• Diuretici
• Vasodilatori
Risultati soddisfacenti
In circa 10% dei casi
• Settostomia atriale
con pallone
• Trapianto polmonare
1995-2007
• Prostanoidi
• Antagonisti recettoriali ET1
• Inibitori della PDE5
Trattamento
chirurgico
Rationale of specific PAH treatments
PDE5-I
Prostanoids
Decreased production
NO,PGI2
ET-1 Antagonists
Increased production
ET1
 Vasodilators anti-proliferative factors
 Vasoconstrictor proliferative factors
PAH specific Drugs
Half-life
Route
Prostanoids
Epopoprostenol
Iloprost
Treprostinil
Beraprost
2-4 min
20-40 min
4-6 ore
40-120 min
i.v.
i.v./inhal
s.c.
os
ET-1 Antagonists
Bosentan
Ambrisentan
360-480 min
9-15 ore
os
os
PDE-5 Inhibitors
Sildenafil
Tadalafil
180-240 min
36-40 ore
os
os
Prostanoidi
Epoprostenolo
(emivita 2-4 min)
Effetti sistemici
- Dolori muscolari
- Diarrea
- Flush cutaneo
Treprostinil
Iloprost
(emivita 4-6 ore) (emivita 20-40 min)
Infezioni
Frequenti
Inalazioni
Broncospasmo
PAH specific Drugs
Half-life
Route
Prostanoids
Epopoprostenol
Iloprost
Treprostinil
Beraprost
2-4 min
20-40 min
4-6 ore
40-120 min
i.v.
i.v./inhal
s.c.
os
ET-1 Antagonists
Bosentan
Ambrisentan
360-480 min
9-15 ore
os
os
PDE-5 Inhibitors
Sildenafil
Tadalafil
180-240 min
36-40 ore
os
os
PAH specific Drugs
Half-life
Route
Prostanoids
Epopoprostenol
Iloprost
Treprostinil
Beraprost
2-4 min
20-40 min
4-6 ore
40-120 min
i.v.
i.v./inhal
s.c.
os
ET-1 Antagonists
Bosentan
Ambrisentan
360-480 min
9-15 ore
os
os
PDE-5 Inhibitors
Sildenafil
Tadalafil
180-240 min
36-40 ore
os
os
Short-term Efficacy on 6-min walk distance
Epoprostenol
Mean change in the 6 ’WD (m)
80
PPH
81 pts
SSc
111 pts
60
Active Tx
40
20
0
-20
Control
-40
Tx effect + 47 m + 108 m
+ 25 m + 18 m
+ 36 m + 44 m + 37 m + 47 m + 46 m + 33 m
P value < 0.003 < 0.001
0.036
0.004
Open trials
0.005
0.0002 0.001
Double-blind trials
0.001
0.001
0.001
Short-term Efficacy on Pulmonary Vascular Resistance
Epoprostenol
Mean change in PVR (mmHg/L)
(PPH)
(Scl)
8
6
Control
4
2
#
0
-2
-4
Active Tx
Tx effect- 4.9
- 5.5
P value <0.001 < 0.001
-1.6
-4.7
ns
0.001
PulmonaryOpen
Hypertension
trials Unit
-4/-1.1
- 5.1
- 3.3
0.01 / ns <0.001 <0.001
Double-blind trials
-2.6
-1.5 -2 -3.2 -2.6
<0.01 0.01 0.001
0.05
Mean change in Cardiac Index (L/min/m2)
Short-term Efficacy on Cardiac Index
Epoprostenol
(PPH)
(Scl)
0,8
0,6
Active Tx
(CO)
0,4
0,2
0
#
-0,2
-0,4
Control
Tx effect +0.5
+ 0.6
+ 0.2
+0.18
0.01
0.01
ns
0.003
P value
Pulmonary Hypertension
Unit
Open trials
+0.75/0.25 + 1.0
0.001
0.001
+ 0.4
+ 0.3 + 0.23/0.26/0.4+ 0.36
0.001
0.01 ns/0.03/0.001 0.05
Double-blind trials
Reduction in short-term mortality
Mortality Reduction 43% (p=0.023)
after 12-16 wks of active treatment
I nuovi farmaci…
Macitentan…..
In vitro data
Log D (Distribution
coefficient)
Lipid:Aqueous
Macitentan
Bosentan
Ambrisentan
800:1
20:1
1:2.5
Blood
Membrane
Tissue
•
The distribution coefficient (Log D) defines the distribution of a compound
between an aqueous and a lipid phase
•
A greater affinity for the lipid phase may favour tissue penetration
•
Macitentan may have a greater affinity for the lipid phase compared with
other ERAs*
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.
Seraphin Study
Multicentre, double-blind, randomised, placebo-controlled,
parallel-group, event-driven, phase III clinical trial
Macitentan 10 mg
Macitentan 3 mg
Screening
28 days
Placebo
Variable double-blind treatment duration
(event-driven)
Randomisation
May 2008 - December 2009
End of study
(EOS; 285 events)
March 2012
Patients were censored at end of double-blind treatment
Pulido T, et al. N Engl J Med 2013; 369: 809-18.
Primary endpoint: Morbidity and mortality
Patients without the event (%)
100
Risk reduction of primary
endpoint event vs placebo
80
Macitentan 10 mg: 45%
60
Macitentan 3 mg: 30%
40
Treatment difference
Macitentan 10 mg
20
Macitentan 3 mg
Placebo
3 mg
10 mg
Hazard ratio (HR)
0.70
0.55
Log-rank p-value
0.01
< 0.001
0
0
6
12
18
24
30
36
Patients at risk Time from treatment start (months)
242
208
187
171
155
91
250
213
188
166
147
80
250
188
160
135
122
64
41
32
23
Macitentan 10 mg
Macitentan 3 mg
Placebo
Morbidity and mortality in patients on
background PAH therapy
100
80
Risk reduction of primary
endpoint event vs placebo
60
Macitentan 10 mg:
38%
Macitentan 3 mg:
17%
Treatment difference
3 mg
10 mg
Hazard ratio (HR)
0.83
0.62
Log-rank p-value
0.27
0.009
40
Macitentan 10 mg
20
Macitentan 3 mg
Placebo
0
0
6
12
18
24
30
36
154
134
119
107
97
53
164
139
125
107
91
51
154
122
106
90
80
40
24
19
10
Macitentan 10 mg
Macitentan 3 mg
Placebo
Riociguat…..
sGC
GTP
sGC
cGMP
GTP
GTP
GTP
cGMP
cGMP
GTP
cGMP
GTP
•cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; sGC, soluble guanylate cyclase.
•Stasch J-P & Hobbs AJ. Handb Exp Pharmacol 2009;191:277–308. Stasch J-P et al. Circulation 2011;123:2263–73.
La Sapienza University oi Rome Ghofrani HA et al. Future Cardiol 2010;6:155–66. Schermuly R et al. Expert Opin Invest Drugs 2011;20:567–76.
Riociguat: PATENT study
Placebo-corrected treatment effect = 36 m (95% CI: 20–52 m; p<0.0001)
40
Mean change from baseline
in 6MWD (m)
n=241
n=233
n=235
n=243
30
* n=254
n=247
20
n=111
10
n=116
n=117
n=112
n=121
0
Riociguat
Placebo
-10
0
2
*
4
* n=126
Observed
Imputed
6
Week
8
10
12
•Last visit = last observed value (not including follow-up) for patients who completed the study or withdrew, except imputed worst value (zero) in case of death or
clinical worsening without a termination visit or a measurement at that termination visit. 6MWD, 6-minute walking distance.
29
•Ghofrani HA et al. N Engl J Med 2013. In Press.
Riociguat
Primary endpoint: entire population
(n=254/126)
Naïve population (n=123/66)
+38 m
(95% CI: 15–62 m)
+36 m
p<0.0001
(95% CI: 20–52 m)
Pretreated population (n=131/60)
+34 m
(95% CI: 15–56 m)
•6MWD, 6-minute walking distance.
Unit
•GhofraniPulmonary
HA et al. N EnglHypertension
J Med 2013. In Press.
30
Riociguat: secondary endpoints
Parameter
Riociguat vs placebo; p value
PVR
<0.0001
NT-proBNP
<0.0001
WHO FC
0.0033
Time to clinical worsening
0.0046
Borg dyspnea score
0.0022
EQ-5Da
0.0660
LPHa
0.0019
•aHierarchical testing.
•EQ-5D, EuroQol Group 5-Dimension Self-Report Questionnaire; LPH, Living with Pulmonary Hypertension questionnaire;
•NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PVR, pulmonary vascular resistance; WHO FC, World Health Organization functional class.
31
•Ghofrani HA et al. N Engl J Med 2013. In Press.
Treatment algorithm 2013:
General measures and Hemodynamic
Specific PAH treatment
Cosa ci dobbiamo aspettare
quando cominciamo una
monoterapia orale ?
Clinical Worsening in Bosentan-Treated Patients
with iPAH
Breath-1 NEJM 2002
Mc Laughlin ERJ 2005
Provencher Thorax 2005
Vizza CD, et al. Int.J:Cardiol 2012. 26;589-595.
Clinical worsening in PDE5-I treated patients
100
80
40%
60
Placebo (PDE5-I)
40
Macitentan 10 mg
20
Placebo
0
0
6
12
18
24
30
154
134
119
107
97
53
164
139
125
107
91
51
154
122
106
90
80
40
36
24
19
10
Macitentan 10 mg
Macitentan 3 mg
Placebo
When to combine
Scheduling the examinations….
Baseline
1° month
4-6 month
NYHA
X
X
X
EKG
X
X
X
Walk Test
X
X
X
SpO2 Rest/Ex
X
X
X
DLCO
X
ECHO
X
MRI
X
CPX
X
Cath study
X
(X)
Biomarkers
X
(X)
1 year
Clinical
judgement
(X)
X
X
X
(X)
X
X
X
X
X
X
Dovremmo trattare i pazienti in
maniera più aggressiva ?
Impact of RV EF and PVR changes after
therapy on survival
van de Veerdonk M. J Am Coll Cardiol 2011;58:2511–9
Up-front combination therapy ?
Upfront triple combination therapy :
Effect on haemodynamics
Prospective, observational analysis of idiopathic or heritable PAH patients (n = 10)
treated with upfront combination therapy (epoprostenol, bosentan and sildenafil)
Baseline
4-month
Last visit
(12-28 months)
10
7
5
13 ± 6
6 ±7
6 ±5
mPAP (mmHg)
68 ± 17
45 ± 13*
48 ± 10*
PCWP (mmHg)
8 ±3
7 ±3
7 ±4
1.6 ± 0.4
3.7 ± 0.4 ‡
3.2 ± 0.4 ‡
1798 ± 713
461 ± 134 ‡
563 ± 188 ‡
Heart rate (bpm)
92 ± 13
85 ± 13
84 ± 10
BP (mmHg)
90 ± 14
79 ± 10
97 ± 27
SvO2 (% )
48 ± 10
70 ± 3 ‡
74 ± 4 ‡
n
RAP (mmHg)
CI (l/min/m2 )
PVR (d.s.cm-5 )
Sitbon O, et al. Am J Respir Crit Care Med 2011; 183:A5910.
Upfront triple combination therapy in IPAH
100%
p = 0.047
80%
Survival
60%
40%
20%
Triple combination therapy group
Matched control group
0%
0
Patients, 18
at risk (n)
35
12
24
36
Time, months
48
60
17
11
8
2
Triple Rx
31
26
18
7
Control
Data from University Paris-Sud, France. Slide courtesy of Olivier Sitbon.
In summary …
Epoprostenol
monotherapy
(n=46)
Epoprostenol + bosentan
combination therapy
(n=23)
Epo + bosentan + sildenafil
combination therapy
(n=17)
2000
2000
2000
1600
PVR (d.s.cm-5)
PVR (d.s.cm-5)
PVR (d.s.cm-5)
1500
1500
1000
1000
1200
800
500
500
400
0
0
Baseline
4-mo.
-29 ± 17%
Baseline 4-mo.
-48 ± 17%
0
Base
Baseline
44-mo.
mois
- 69 ± 8%
Courtesy Olivier Sitbon
AMBITION – Study design
Combo AMB+TAD
PAH
Rand
WHO FC II-III
2:1:1
N=500
Mono AMB+PBO
Mono TAD+PBO
Drug titration
Combination
arm
Monotherapy
arm
W0 to W4
W4 to W8
> W8
AMB 5 mg
TAD 20 mg
AMB 5 mg
TAD 40 mg
AMB 10 mg
TAD 40 mg
AMB 5 mg
PBO
PBO
TAD 20 mg
AMB 10 mg
PBO
PBO
TAD 40 mg
105 events
1° EP
AMBITION – Primary end-point
Time to clinical failure
Death (all cause)
Hospitalisation
for worsening PAH
non-elective hospitalisation (CW)
lung transplantation
atrial septostomy
initiation of prostanoid therapy
Disease progression
Decrease in 6MWD > 15% vs base
With FC III-IV (2 visits >14 days)
Unsatisfactory
long-term response
ALL
> 6 months on therapy
Disease progression
Sustained FC III-IV > 6 months
AMBITION: results
Mean randomised treatment duration was 78.6, 66.6
and 71.6 weeks, respectively
Ambrisentan + Tadalafil
Reduction 50% (HR 0.502 95% CI: 0.348, 0.724;
p=0.0002) of clinical events
Combo was superior to each individual Mono
(p<0.01),
ERS 2014
AMBITION: results
ERS 2014
Treatment algorithm 2015 ????
Up-front Ambrisentan-tadalafil
Up-front Triple
Considerazioni conclusive
• L’utilizzo di trattamenti specifici per l’ipertensione arteriosa
polmonare ha condotto ad un miglioramento della
sopravvivenza (+ 10-15% annuo)
• Attualmente l’approccio consigliato è una terapia di
combinazione sequenziale in caso di mancato
raggiungimento dei target terapeutici
• Sta emergendo l’efficacia di terapia di combinazione
upfront
• E’ fondamentale adottare una strategia terapeutica
aggressiva che contempli l’uso dei prostanoidi parenterali
• Necessaria collaborazioni tra diversi centri per uniformare
gli approcci diagnostici-terapeutici
Classificazione Ipertensione Polmonare
3° Revisione 2008 – Dana Point
1. Ipertensione Arteriosa Polmonare
• Idiopatica
• Ereditaria (BMPR-II ; ALK-1)
• associata a :
– Malattie del connettivo
– Infezione HIV
– Ipertensione portale
– Anoressizzanti
– Cardiopatie congenite
– Schistosomiasi
- Anemia emolitica cronica
• Ipertensione persistente neonato
1A. IAP + venule/capillari
2. IP secondaria a cardiopatie sin
• Sistolica/Diastolica
• Valvulopatie
3. IP secondaria a
pneumopatie/ipossiemia
• BPCO
• Interstiziopatie
• Apnee notturne
• Esposizione cronica altitudine
• Alterazioni dello sviluppo
4. IP cronica tromboembolica
• Ostruzione prossimale
• Ostruzione distale
• Embolia non trombotica
5. Miscellanea
• Malattie Ematologiche, Vasculiti,
Sarcoidosi, Tesaurismosi (Gaucher)
CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: SURGICAL TREATMENT
TYPE OF OPERATION
• Median sternotomy
• Cardio Pulmonary Bypass
• Deep hypotermia (16-18ºC)
• Circulatory arrest (25 min)
• Reperfusion period (10 min)
• Bilateral
J Thorac Cardiovasc Surg 1993;106:116-27
A. D’Armini – Policlinico S. Matteo Pavia
Ipertensione Polmonare Cronica Tromboembolica – Trattamento Chirurgico
P.A. – 66 yrs M – Jun 2001 – PEA #60
Base
PAPm
CI
PVR
50
1.4
1385
3 mesi EAP
15
2.2
293
A. D’Armini – Policlinico S. Matteo Pavia
Riociguat in CTEPH: studio CHEST
Adverse event
1 (0.2%)
Death
4 (0.9%)
Not eligible
165 (37%)
Withdrawal of consent 15
(3.4%)
Screened n=446
Randomized
and treated
n=261
Riociguat
individual titration
n=173
Adverse event
4 (2.3%)
Death
2 (1.2%)
Lack of efficacy
2 (1.2%)
Non-compliance
1 (0.6%)
Protocol violation
2 (1.2%)
Withdrawal of consent 2
(1.2%)
Not
completed
n=13 (8%)
Completed
treatment
n=160 (92%)
Unit
•GhofraniPulmonary
HA et al. N EnglHypertension
J Med 2013. In Press.
Placebo
n=88
Adverse event
Death
Lack of efficacy
2 (2.3%)
2 (2.3%)
1 (1.1%)
1 death during
follow-upa
Not
completed
n=5 (6%)
Completed
treatment
n=83 (94%)
End-point primario: test della marcia
Primary endpoint: entire population
(n=173/88)
Population with persistent/
recurrent PH after PEA (n=52/20)
+27 m (95% CI: -10–63 m)
+46 m
p<0.0001
(95% CI: 25–67 m)
Inoperable population (n=121/68)
+54 m
(95% CI: 29–79 m)
•6MWD, 6-minute walking distance; PEA, pulmonary endarterectomy.
•Ghofrani HA, D'Armini A, Grimminger F et al. N Engl J Med 2013.
End points secondari
Secondary endpoints
- Pulmonary vascular resistance (PVR) (p<0.0001),
- N-terminal prohormone brain natriuretic peptide (NT-pro BNP)
(p<0.0001),
- WHO functional class (FC) (p=0.0026),
- Borg dyspnea score (p=0.0035)
- A trend in Time to clinical worsening (TTCW) (p=0.17)
PH Unit
La Sapienza, University of Rome
Coordinator Carmine Dario Vizza
PH clinicians (Cardiology ward, CCU, consultation & outpatients management):
Senior Cardiologists
Dr Vizza, Dr Badagliacca Dr. Poscia
Fellows:
Dr Gambardella, Dr. Pezzuto, Dr Papa,
In Training:
Dr Mezzapesa, Dr Nocioni
Echo Lab
Dr. Sciomer
Dr. Badagliacca
PFTs-CPX Lab
Prof. Palange
Dott.Valli
Reumathologists
Prof Valesini
Prof.Riccieri
Pulmonologists
Prof. Parola
CT & RNM Lab
Dott. Carbone
Dott. Francone
Liver Transplant Unit
Prof. Rossi
Prof. Corradini
Right Cath Lab
Dott. Mancone
Dott. Stio
HIV clinic
Prof.Vullo
Lung Transplant Program
Prof.Venuta

IPERTENSIONE POLMONARE PRIMITIVA

Transcription

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