la terapia dell’ipertensione arteriosa polmonare - aristea · carlo d’agostino cardiologia...

Carlo D’Agostino

Cardiologia Ospedaliera

Policlinico Bari

Guida alla terapia dell’Ipertensione

Arteriosa Polmonare

Ca

DISCLOSURE INFORMATION

• Carlo D’Agostino

negli ultimi due anni non ho avuto rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario

1. Pulmonary arterial hypertension 1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2

1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3

1.2.3 Unknown

1.3 Drug- and toxin-induced

1.4 Associated with

1.4.1 Connective tissue diseases

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart disease

1.4.5 Schistosomiasis

1’ Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis

1’’ Persistent PH of the newborn (PPHN)

2. PH due to LHD 2.1 LV systolic dysfunction

2.2 LV diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart inflow/outflow obstruction

3. PH due to lung diseases and/or hypoxia 3.1 COPD

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4. CTEPH

5. PH with unclear multifactorial mechanisms 5.1 Haematological disorders: chronic haemolytic

anaemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.

5th World Symposium on PH: Modified classification of PH

78%

5%

10%

1,5%

5%

Ipertensione Arteriosa Polmonare - Gruppo 1 OMS

1. Idiopatica

2. Ereditaria

1. BMPR2

2. ALK1

3. SCONOSCIUTA

3. Da farmaci e tossine

4. Associata con (APAH)

1. Connettivopatia

2. HIV

3. Ipertensione portale

4. Cardiopatia congenita

5. Schistosomiasi

1.1 IAP veno occlusiva e capillari

1.2 IAP persistente del neonato

Circa il 5% delle PH

Prevalenza = 5,9-15 casi/milione

Incidenza = 2,4 casi/milione/anno

• 39,2% IPAH

• 3,9% FPAH

• 15,3% Connettivopatia

(prevalentemente

sclerodermia)

• 11,3% Cardiopatia congenita

• 10,4% Ipertensione Portale

• 9,5% Anoressizzanti

• 6,2% HIV

Prognosi dei pazienti con Ipertensione Arteriosa Polmonare

Humbert M, et al . Circulation 2010;122:158-63

Classe NYHA alla presentazione Distanza percorsa al 6MWT alla presentazione

Il ricorso motivato e ragionato a mezzi idonei al raggiungimento di uno scopo.

Devoto-Oli Vocabolario della lingua italiana

La descrizione di un piano d'azione di lungo termine usato per impostare e successivamente coordinare le azioni tese a raggiungere uno scopo predeterminato.

Wikipedia

Strategia

#1 Counselling

#2 Terapia di supporto

#3 Vasoreattività? > Ca antagonisti

#4 Inizio terapia specifica

#5 Rivalutazione periodica frequente

#6 Implementazione/modifica della terapia (rivalutazione e cateterismo cardiaco)

#7 Terapia interventistica (settostomia/Trapianto….)

Exercise training improves peak oxygen consumption and haemodynamics in patients with severe

pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a

prospective, randomized, controlled trial

Ehlken E et al. Eur Heart J. 2016 Jan 1;37(1):35-44.

#1 Counselling







Risposta positiva = Riduzione PAPm ≥10 mmHg per raggiungere un valora assoluto di PAPm ≤40 mmHg con CO incrementata o immodificata.

TEST DI VASOREATTIVITA’

#1 Counselling







Hum

bert

M, S

itbon O

, Sim

onneau

G: N

EJM

2004;3

51:1

425

Meccanismi coinvolti

Farmaci approvati per il trattamento della IAP

21; 29 March 2015

Approval of PAH therapies

Bosentan

2001 – US

2002 – Europe

Epoprostenol i.v.

1995 – US

2001 – Europe

Room-temperature stable epoprostenol i.v.

2012 – US, Switzerland & Canada

2013 – Japan & Europe*

2013

Macitentan†

Treprostinil oral†

US

Riociguat†

2013 – US

2014 – Europe

Iloprost inhaled

2004 – US

2003 – Europe

Iloprost i.v.

Only approved in

New Zealand

2010 2015 2005 1995 2000

2009

Treprostinil inhaled†

Tadalafil

2008 – Europe

2009 – US

Sildenafil

2005 Beraprost‡†

2007

*End of decentralised procedure in EU; local approvals ongoing †Approval of these therapies varies by country, and thus they

might not be approved in the indications mentioned in your

country. Please refer to your local full SmPC before prescribing. ‡Prolonged release derivative

Ambrisentan

2007 – US

2008 – Europe

Beraprost†

1999

Treprostinil i.v. or s.c.

2002 – US

2005 – Europe

Sebbene ci sia stato un miglioramento dell’outcome negli ultimi 15 anni, la prognosi a lungo termine rimane insiddisfacente

Benza RL et al Chest 2012; 142:448-56

Nickel N, et al . Eur Respir J 2012;39:589-596

WHO I I

WHO III-IV I-II

WHO I-II III-IV

WHO III-IV III-IV

CI ≥2,5 L/min/m2 =

CI <2,5 L/min/m2 ≥2,5

CI ≥2,5 L/min/m2 <2,5

CI <2,5 L/min/m2 =

SvO2 ≥ 65% =

SvO2 <65% ≥ 65%

SvO2 ≥ 65% <65%

SvO2 <65% =

NT-proBNP <1800 =

NT-proBNP ≥1800<1800

NT-proBNP <1800 >1800

NT-proBNP ≥1800≥1800

Significato prognostico della variazione al follow up

Scelta della strategia terapeutica

• Monoterapia iniziale

– Con quale farmaco?

– Come proseguire?

• Terapia di combinazione iniziale

– Con quali farmaci

– Come proseguire?

Possibili terapie di associazione

Antagonisti Recettoriali

della ET-1

Prostanoidi

(e.v., s.c., os, inal)

Inibitori della

Fosfodiesterasi 5

o GCS

Time to 1st

morbidity or

mortality event

A decrease in 6MWD of at least 15%,

confirmed by 2 tests on different days

Worsening of PAH symptoms, which must

include either:

• An increase in FC, or

• Appearance or worsening of symptoms of

right heart failure

Need for new PAH treatment(s):

• Oral or inhaled prostanoids

• Oral PDE-5 inhibitors

• ERA after discontinuation of study drug

• Intravenous diuretics

AND

AND

All-cause death

Atrial septostomy

Lung

transplantation

Initiation of i.v. or

s.c. prostanoids

OR

OR

OR

OR Other worsening

of PAH

Other worsening

of PAH

OR

32; 29 March 2015

SERAPHIN primary endpoint: Morbidity/mortality

(composite endpoint) up to end of treatment

242 208 187 171 155 91 41 Macitentan 10 mg

250 188 160 135 122 64 23 Placebo

Pulido T, et al. N Engl J Med 2013; 369:809-18.

Time from treatment start (months)

Macitentan 10 mg

Placebo

Patients at risk

0 0

20

40

80

100

60

12 18 24 30 36 6

Pati

en

ts w

ith

ou

t an

even

t (%

)

Macitentan reduced the risk of a morbidity/mortality event

(composite endpoint) by 45% (hazard ratio 0.55; p < 0.001)

Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015

Raccomandazioni per la monoterapia nella IAP 33

2015; 379(9):834–44.

AMBITION

Combination vs pooled monotherapy

Galie N et al, et al. New Engl J Med 2015; 379(9):834–844.

BONSAI: Six-month results: % change comparison

Mono

(11)

Upfront

Combo (19) p

RAP (%) +11 ± 67 -17 ± 50 0.205

mPAP (%) -19 ± 16 -33 ± 13 0.017

CI (%) +23 ± 19 +56 ± 31 0.003

PVR (%) -40 ± 10 -61 ± 12 < 0.001

PA-SO2 (%) +6 ± 9 +17 ± 11 0.007

6MWD (%) +10 ± 21 +25 ± 16 0.038

Bachetti C. et al. J Respir Crit Care Med 2015.

4/6-month results: % change comparison

AMBITION - BONSAI

Ambrisentan + Tadalafil

(19)

Joint - INTENTION

Bosentan + Sildenafil

(23)

RAP (%) -17 - 36

mPAP (%) -33 - 21

CI (%) +56 +63

PVR (%) -61 -60

PA-SO2 (%) +17 +25

6MWD (%) +25 + 42

M. Palazzini et al, ATS 2016.

38


Raccomandazioni per la terapia di combinazione

iniziale nella IAP

#1 Counselling







43


Raccomandazioni per la terapia sequenziale nella

IAP

#1 Counselling







5th World Symposium on PH: Evidence-based treatment algorithm

Combination therapy and interventional procedures

Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.

Inadequate clinical response

Sequential combination

therapy (I-A)

ERAs

Prostanoids PDE-5i

or sGCS

+

+

Initial therapy with PAH approved drugs

+

Referral for LUNG TRANSPLANTATION

(I-C)

Consider eligibility for

lung transplantation

BAS (IIa-C)

Inadequate clinical

response on

maximal therapy

Recommendations for evaluation of severity of pulmonary arterial hypertension and clinical response to therapy

46


Definizione della prognosi nella IAP 2015 ESC/ERS Guidelines

REAL IP REGISTRO ITALIANO IPERTENSIONE POLMONARE

la terapia dell’ipertensione arteriosa polmonare - aristea · carlo d’agostino cardiologia...

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