3/10/2017 Disclosures Damien Bonnet has received fees for - - PowerPoint PPT Presentation

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Aggressive vs. Progressive Therapeutic Approach

Damien Bonnet

M3C-Necker Enfants malades, Université Paris Descartes Centre de référence des Malformations Cardiaques Congénitales Complexes Centre de référence des Maladies Cardiaques Héréditaires ICarP, Institut Hospitalo-Universitaire IMAGINE, Paris, France

Disclosures

Damien Bonnet has received fees for consulting, steering committee membership, board advisor from Actelion Pharmaceuticals, Bayer HealthCare, Pfizer, Novartis

Time (months) Survival (%) 12 24 36 72 84 20 40 60 80 100 48 60

Children <1 year1,2 Adults 2.8 years

• 1. Houde C, et al. Br Heart J 1993;70:461-8.
• 2. Barst, RJ, et al. Circulation 1999; 99:1197-208.

Median survival: 2.8 years (n=194) Pediatric median survival: 0.8 years (n=16)

Natural History of IPAH: NIH Registry

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Fraisse et al. ACVD 2010

Improved survival in pediatric PH with off label use of drugs approved in adults

Barst R, et al. Circulation 1999; 99:1197-208. Van Loon, et al, Am J Cardiol, 2010.

Initial treatment in the TOPP1 registry This improvement occurred with mono therapy

Humpl T et al. CiTY 2016

iPAH/fPAH and CCB treatment

Douwes M et al. JACC 2016

First, treat your patient with drugs adapted to their hemodynamic profile

Haworth SG, et al. Heart 2009; 95:312-7.

n (brackets) and predicted survival over 5 years are shown.

Differences in survival of PAH in children according to cause

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Survival of adults with Eisenmenger syndrome according to type of lesion

Standardised mortality ratio 3.8; 95% CI 2.0 – 7.0; p<0.0001

Diller et al EHJ 2006

Immortality bias in Eisenmenger syndrome

ASD-PAH > 40y ASD-PAH < 40y

Survival of patients with Eisenmenger syndrome according to type of lesion and age at diagnosis of PH

Hascoet S et al. ACVD 2017

Individual susceptibility for the time course of PVR increase

Prevalent cases Incident cases

Van Loon, et al. Am J Cardiol, 2010.

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RCTs with monotherapy in PAH

Improvement in exercise capacity (3-4 months)

Control* Active treatment

Epoprostenol

• 40
• 20

20 40 60 80 Treatment effect p

(IPAH)

+ 47 m < 0.003

(PAH-SSc)

+ 108 m* < 0.001 Treprostinil + 18 m 0.005 Iloprost

(AIR)

+ 36 m 0.004

(BREATHE-1)

Bosentan + 44 m 0.0002 Sildenafil

(SUPER-1)

+ 42 m < 0.001 * Control = placebo except for epoprostenol trials (‘Conventional therapy’) #: monotherapy only Change in 6MWD (m)

(AERIES)

Ambrisentan + 44 m < 0.001 Tadalafil

(PHIRST)

+ 44 m# < 0.001 Barst, NEJM 1996. Badesch, Ann Int Med 2000. Galiè, NEJM 2005. Galiè, Circulation 2009. Simonneau, AJRCCM 2002. Olschewski, NEJM 2002. Rubin, NEJM 2002. Galiè, Circulation 2008.

+ 26 m p=0.051 Placebo-corrected effect on 6MWD (m)

N=64

Pbo-adjusted effect of sequential combo therapy on primary EP (6MWD)

+ 28.8 m p<0.001

N=277

+ 20 m p=0.01

N=235

+ 11 m p=0.072

N=350

Sequential combination therapies in RCTs

• 1. McLaughlin VV, et al. AJRCCM 2006. 2. Simonneau G, et al. Ann Intern Med 2008.
• 3. McLaughlin VV, et al. J Am Coll Cardiol 2010. 4. Tapson V, et al. Chest 2012. 5. Tapson V, et al. Chest 2013.

+ 10 m p=0.089

N=310 Drug tested Background STEP ILO BOS PACES SIL EPO TRIUMPH Inh TREP ERA or PDE5i FREEDOM Oral TREP ERA &/or PDE5i

Meta-analyses have provided conflicting evidence on combination therapy

A meta-analysis of 6 short-term RCTs could not show a beneficial effect of sequential combination therapy on a combined clinical worsening endpoint

Fox BD, et al. Am J Cardiol 2011; 108:1177-82.

0.1 0.5 1 2 10 Favours combination therapy Favours monotherapy ComboRx MonoRx Study Events Total Events Total PHIRST-1b 2 42 1 45 TRIUMPH-1 4 115 6 120 PACES 10 134 36 133 STEP 34 5 33 Random effects model 16 325 48 331

Heterogeneity: I-squared = 38.2%, p = 0.1829

RR 95%-CI W (random) 2.14 [0.20; 22.77] 12.1% 0.70 [0.20; 2.40] 29.8% 0.28 [0.14; 0.53] 49.4% 0.09 [0.01; 1.53] 8.8% 0.42 [0.17; 1.04] 100%

SERAPHIN primary end-point according to pretreated status

Naive patients

Macitentan 10 mg 20 40 80 100 60 12 18 24 30 36 6 Freedom from event (%) Placebo

Pretreated patients

Macitentan 10 mg Freedom from event (%) 12 18 24 30 36 20 40 80 100 60 6 Placebo Risk reduction 55% Risk reduction 38%

Difference between arms 10 mg Hazard ratio (HR) 0,45 p (test Log-rank) < 0,001 Difference between arms 10 mg Hazard ratio (HR) 0,62 p (test Log-rank) 0,009 Months since initiation of treatment Months since initiation of treatment 96. 66 54 45 42 24 13 Patients at risk 154 122 106 90 80 40 10 Patients at risk 154 134 119 107 97 53 24 88 74 68 64 58 38 17 Pulido T, et al. N Engl J Med 2013; 369:809-18.

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Case 1

Enzo 3.5 years old male referred for syncope at school while running No personal or family history of PH No overt heart failure CT no argument for PVOD RHC PAP 129/86-103 mmHg PAo 85/50-65 mmHg PWp 7 mmHg Rap: 6 mmHg CI 4.3 L/min/m2 Non responder to NO° NT-proBNP : 350 ng/L What would you do ?

Risk assessment in pulmonary arterial hypertension

Galie N et al. Eur Respir J 2015; Galie N et al. Eur Heart J 2016.

Evidence-based treatment algorithm

Combination therapy and interventional procedures

Galiè N, et al. ESC/ERS Guidelines Eur Heart J. 2015. LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes No Progression of symptoms Yes No Syncope Yes Growth Failure to thrive I,II WHO functional class III,IV Minimally elevated BNP / NTproBNP Significantly elevated, rising syst CI > 3.0 L/min/m2 mPAP/mSAP < 0.75 Acute Vasoreactivity Hemodynamics syst CI < 2.5 L/min/m2 mPAP/mSAP > 0.75, rising RAP > 10mmHg PVRI > 20 WU*m2 Echocardiography Severe RV dysfunction, PE > 450 m, stable (> z-2 ; % predicted) 6MWD (if ≥ 8 yr and developmentally able) ≤ 350m decreasing

Pediatric PAH Treatment Goals

Level of evidence C

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How to treat this patient ?

Treated with PDE5i + ERA WHO-FC I NT-proBNP 32 ng/L TAPSE 22 mm RVEF 45% RHC after 6 months PAP 70/30-45 mmHg mPWp 7 mmHg PAo 116/60-83 mmHg PVRi decreased from 23 to 6.2 WU.m2 6 weeks after treatment initiation

Case 1-Follow-up

First line therapy Continue first line therapy Escalation therapy Continue escalated therapy

Escalate therapy at time of clinical worsening

• r disease progression

Baseline Good ! Clinical worsening Good ! Clinical worsening

Clinical worsening as composite study endpoint in pediatric PAH

Component 1 = death Component 2 = lung-transplantation Component 3 = non-elective PAH-related hospitalization Component 4 = initiation of intravenous prostanoid Component 5A = functional deterioration (defined as worsening of WHO-FC only) Component 5AB = functional deterioration (defined as worsening of WHO FC and/or ≥ 15 % decrease in 6-MWD) CW-endpoint = Full composite clinical worsening endpoint consisting of death, lung- transplantation, non-elective PAH related hospitalization, initiation of intravenous prostanoids and functional deterioration.

6 months

Event-free survival of 6 endpoint combinations Only the first occurrence of endpoint components are incorporated as events

Ploegstra MJ et al. Eur Respir J 2015.

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Disease progression composite outcomes

Disease progression 1 (n = 255) Disease progression 2 (n = 255) Disease progression 3 (n = 255) Number of events

121 173 175

Person–years

524.7 396.5 377.6

Rate (95 % CI)

23.1 (19.3, 27.6) 43.6 (37.6, 50.6) 46.3 (40.0, 53.7)

Death (all-cause) Death (all-cause) Death (all-cause) PAH related hospitalisation* PAH related hospitalisation* PAH related hospitalisation* Lung transplantation Lung transplantation Lung transplantation Atrial septostomy Atrial septostomy Atrial septostomy WHO FC deterioration† WHO FC deterioration† Initiation of i.v. / s.c. prostanoids (only first event) Initiation of i.v. / s.c. prostanoids (only first event) Syncope Syncope PAH worsening (symptoms) *Increased right heart failure, haemoptysis; †Increase ≥1 WHO FC CI, confidence interval; i.v., intravenous; PAH, pulmonary arterial hypertension; s.c., subcutaneous; WHO FC, World Health Organization Functional Class

Beghetti M et al. submitted

Association for Pediatric Pulmonary Hypertension (PePH)

First events predictive of long-term outcomes death and lung transplantation (multivariate)

27

HRs and 95% CIs from multivariate analysis including variables from univariate analysis with p<0.15. *p<0.01; †p<0.05 CI, confidence interval; HR, hazard ratio; PAH, pulmonary arterial hypertension; WHO FC, World Health Organization Functional Class

WHO FC deterioration PAH-related hospitalisation PAH worsening

* *

†

Increased risk of death or transplantation Independent risk factors for long-term outcomes: WHO FC deterioration PAH-related hospitalisation and PAH worsening Independent risk factors for long-term outcomes: WHO FC deterioration PAH-related hospitalisation and PAH worsening

Case 2

Ilona 10.5 years old female referred for fatigue and episodes of chest pain. No personal or family history of PH No overt heart failure CT no argument for PVOD 6MWT 512 m, Borg 2 RHC mean PAP 38 mmHg PAo 112/63-82 mmHg PWp 7 mmHg Rap: 6 mmHg PVRi 11 WU.m2 Non responder to NO° NT-proBNP : 88 ng/L What would you do ?

Case 2 -Follow-up

Ilona 10.5 years old female Monotherapy with ERA 6 months later WHO-FC II No improvement of symptoms Echo unchanged 6MWT 482 m Borg 2 NT-proBNP 169 ng/L RHC mean PAP 47 mmHg PAo 102/56-72 mmHg PWp 8 mmHg Rap: 8 mmHg PVRi 13.8 WU.m2 Non responder to NO° What would you do ?

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Case 2 -Follow-up 2

Ilona 10.5 years old female Combined therapy ERA+PDE5i 6 months later WHO-FC II No improvement of symptoms Echo TAPSE 17 mm NT-proBNP 278 ng/L RHC mean PAP 49 mmHg PAo 99/48-71 mmHg PWp 9 mmHg Rap: 10 mmHg PVRi 15.9 WU.m2 What would you do ? Ilona 10.5 years old female Combined therapy ERA+PDE5i + SC treprostinil Disease progression after 4 months WHO-FC III Echo TAPSE 17 mm Finally had a Potts’shunt after 2 years Baseline First line therapy Escalation therapy Good ! Continue escalated therapy Escalation therapy

« Common strategy » in pediatric PH treatment

Inadequate clinical response Inadequate clinical response

Zijlstra WM, Douwes JM, et al. J Am Coll Cardiol. 2014;63:2159-69

Is combination therapy a valid option in pediatric iPAH? Quality of life & complications of parenteral prostanoids

Marr et al. Pulm Circ. 2015 Jun;5(2):322-6.

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Progressive therapeutic approach

• No clear demonstration of reduced mortality with PAH targeted therapies in children

receiving combined therapy up-front

• No demonstration of superiority of upfront vs sequential combo
• Treatment complications (inhaled, subcutaneous, IV prostanoids)
• Absent data on safety for new drugs in pediatric PAH
• Absent data on PK/PD for combo
• No study proving efficacy in children
• Treatment cost
• Local health system organization

I am sorry. I lied during all my talk. UK health system will not be able to pay for aggressive treatment after the Brexit. I am sorry. I lied during all my talk. UK health system will not be able to pay for aggressive treatment after the Brexit.

What can we learn from other chronic diseases ?

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Up-front combination therapy with epoprostenol and bosentan

Up-front combination therapy with epoprostenol, bosentan and sildenafil Up-front combination therapy with epoprostenol, bosentan and sildenafil

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Ambition Ambrisentan + Tadalafil Hemodynamic effects after 3-6 months treatment

Humbert M, et al. Circulation. 2014.

Drugs 1+2+3

Sequential combination

2 or 3 drugs

(especially in patients who present with high risk features)

Drug 1 Drugs 1+2

Evolving Paradigm Upfront combination ? Impact on outcomes

Evolving paradigm: From sequential to initial combination therapy

Zijlstra WM, Douwes JM, et al. J Am Coll Cardiol. 2014;63:2159-69

Is combination therapy a valid option in paediatric iPAH?