Aristotle University of Thessaloniki

Cardiology Clinic, AHEPA Hospital

Σταδιοποίηση κινδύνου και

φαρμακευτική αγωγή στην

πνευμονική αρτηριακή υπέρταση

Χρήστος Ν Φελουκίδης

Καρδιολόγος

ΠΓΝ ΑΧΕΠΑ

Conflicts of interest: none

0

20

40

60

80

100

0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5

Sur

viva

l (%

)

Years of Followup

PAH Survival

68%

48%

34%

Humbert M et al Circulation 2010, 122:156-164

PAH Prognosis

The prognosis for patients with PAH has improved in the last 20 years

from a median survival of 2.8 years from diagnosis to…

ZINC: GR/ABT/0010/18

Risk assessment in pulmonary arterial hypertension2015 ESC/ERS Guidelines

Risk stratification for IPAHRisk assessment drives treatment plan

SYMPTOMS

EXERCISE CAPACITY

RV FUNCTION

WHO Functional Class

WHO-FC is a significant

predictor of prognosis .

Despite this, many

patients in WHO FC II

continue to experience

disease progression and

early death

Humbert M, et al. Circulation 2010; 122: 156–163.

FCIII

FCII

FCIV20% of mortality at 3 years for

patients in FC II

Data from French registry

n=172

n=421

n=81

– Data from AMBITION

REVEAL risk score was a more accurate predictor of worsening events than WHO functional class alone

Frost A et al. J Heart Lung Transplant. 2018

Patients with PAH presenting in WHO FC II

may not be at low risk

Characteristic Functional Class II(n=192)

Functional Class III(n=413)

Total(n=605)

REVEAL Risk Score – 3 categories

High risk (>8) 20 (10.4) 209 (50.6) 229 (37.9)

Intermediate risk (6-8) 101 (52.6) 177 (42.9) 278 (46.0)

Low risk (<6) 71 (37.0) 27 (6.5) 98 (16.2)

Kylhammar D et al., Eur Heart J. 2017

Swedish PAH Registry (SPAHR)

Stability is not an acceptable condition

for intermediate or high-risk patients

Treatment algorithm for treatment-naïve PAH6th World Symposium Proceedings

Galie N et al. Eur Resp J 2019

kjk

European Respiratory Review 2017 26: 170095

Galiè et al. Eur Heart J 2016; 37: 67-119

Drugs

AMBITION trial - A strategy of initial double oral combination vs monotherapy

Event-driven study: n=500 patients with PAH (31% FC II)

95% CIs (using log-log transform method) are presented for each treatment group at weeks 4, 8, 16, 24, and then every 12 weeks up to week 96.

Upfront combination therapy with ambrisentan/tadalafilreduced the risk of clinical failure in newly diagnosed patientsPrimary Endpoint: Time to First Clinical Failure Event (Primary Analysis Set)

50% Risk

Reduction

N. Galiè, et al. N Engl J Med 2015;373:834-44

CONFIDENTIAL

Forest Plot of First Adjudicated Clinical Failure bySubgroups: Pooled MonotherapyPrimary Analysis Set

Initial combination

therapy is associated with

larger improvements in

hemodynamics and

exercise capacity in

comparison with

monotherapy

Single centre blinded evaluation

with 30 pts

Initial combination therapy in

naïve PAH patients might be

associated with a survival

advantage compared with

patients in initial monotherapy

Upfront combination - What do we mean?• A short delay between initiation of therapies may allow patients to adapt to the vasodilator effects of one

drug before another is added, and would make determination of which agent is responsible for the side

effect in question more likely.

• In the AMBITION trial, ambrisentan and tadalafil were started together at low doses (5 and 20 mg,

respectively) and up-titrated to 10 and 40 mg over an 8-week period.

• French PH Network, patients were initiated on an ERA and a PDE-5i on the same day and then up-titrated to

the maximal dose within 4 weeks.

• in OPTIMA study, patients receive macitentan 10 mg once daily and tadalafil 20 mg once daily on day 1,

followed by a step up to tadalafil 40 mg once daily at day 8.

SPAHR COMPERA French

Number of patients at baseline/follow-up

530/383 1588/1094 1017/1017

Mean age 65 64 57

Associated-PAH cases Yes Yes No

Definition of low-risk Average risk<1.5 Average risk<1.5 3-4 of 4 low-risk criteria

% low-risk at baseline 22.6% 12.3% 17%

% low-risk at follow-up 29% 23.9% 41.5%

Initial combo 12% 17% 48%

Kylhammar D et al., Eur Heart J. 2017, Hoeper MM, et al. Eur Respir J 2017, Boucly A., et al. Eur. Respir J 2017

Initial monotherapy

• Stable PAH and low risk profile on long term monotherapy

• >75 years old with multiple risk factors for LHD

• High probability for PVOD

• PAH associated with HIV, portal hypertension, uncorrected CHD

(they were not included in RCTs of initial combination therapy)

• Mild PAH (mPAP<30mmHg, PVR 3-4 WU) normal RV at echo

Eur Respir J 2019;53:1801889

Risk assessment in pulmonary arterial hypertension2015 ESC/ERS Guidelines

Selexipag: Time to first morbidity or mortality event* up to EOT

Pati

en

ts w

ith

ou

t an

even

t (%

)

00

20

40

80

100

60

12 18 24 30 366

Months

Selexipag

Risk reduction 40%

selexipag vs placebo

HR = 0.60; 99% CI 0.46–0.78; p < 0.001

Placebo

No. at risk

Placebo 582 433 347 220 149 88 28Selexipag 574 455 361 246 171 101 40

ITT population; *As measured by a composite primary endpoint.

ITT = Intention to treat; HR = Hazard ratio; CI = Confidence interval.

Study drug exposure, median: 63.7 weeks for placebo and 70.7 weeks for selexipag

Sitbon O, et al. New Engl J Med 2015.

What will be the future?

Upfront triple combination

Data from 19 newly diagnosed

NYHA FC III-IV PAH patients

initiated on upfront triple

combination therapy with

I.V.epoprostenol, bosentan and

sildenafil

Fdd15d + selexipagUptitrated 12w

TRITON

TRITONTriple combination – 41% reduction in disease progression

Disease progression - all caused death

- hospitalization

- initiation of prostacyclin

- clinical worsening (>15% 6MWD, WHO FC III->IV)

Take home messages

• Aggressive disease – aggressive treatment

• Upfront combination therapy should be the initial choice for the

majority of patients with PAH

• Close follow up of PAH pts (monitor side effects – risk stratification)

• Achievement of low-risk status is recommended-Keep pts in green

2018 Nice Symposium - Need for a simplified risk stratification in PAH

Prognostic

CriteriaLow-risk variables

Intermediate-risk

variablesHigh-risk variables

A WHO FC I, II III IV

B 6MWD > 440 m 165 - 440 m < 165 m

C

NT-

proBNP/BN

P

plasma

levels

OR

RAP

BNP < 50 ng/l

NT-proBNP < 300 ng/l

OR

RAP < 8 mmHg

BNP 50–300 ng/l

NT-proBNP 300–1400

ng/l

OR

RAP 8–14 mmHg

BNP > 300 ng/l

NT-proBNP > 1400

ng/l

OR

RAP > 14 mmHg

DCI

OR

SvO2

CI ≥ 2.5 l/min/m2

OR

SvO2 > 65%

CI 2.0–2.4 l/min/m2

OR

SvO2 60–65%

CI < 2.0 l/min/m2

OR

SvO2 < 60%

Acknowledgements AHEPA University HospitalPulmonary Hypertension Unit

Thank you

Low risk Intermediate risk High risk

At least 3 low risk

criteria and no

high risk criteria

Definitions of low

or high risk not

fulfilled

At least 2 high risk

criteria including

CI or SvO2

2018 Nice Symposium - Need for a simplified risk stratification in PAH

2004

33 pts with PAH

started on epoprostenol

+bosentan or placebo

Combination therapy

showed greater

improvement in

haemodynamics and

functional class

(but not statistical

significant)

Backup slides

_ Ομάδα ασθενών με διπλή θεραπεία• Προβλεπόμενη επιβίωση με French

equation

97 patients( 86% in WHO-FC ІІІ-ІV) received upfront combination therapy

Bosentan+sildenafil(n=61)Bosentan+tadalafil(n=17)

Ambrisentan+Tadalafil(n=11)Ambrisentan+sildenafil(n=8)

Actual survival 96% VS 84% in 1 year

Retrospective study – 80 pts – AmsterdamERA+PD5i VS monotherapy. 1year F up with MRI – RHC

RV volume and RV wall stress improved only in combination group

0

20

40

60

80

100

0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5

Sur

viva

l (%

)

Years of Followup

PAH Survival

68%

48%

34%

Humbert M et al Circulation 2010, 122:156-164

PAH Prognosis

The prognosis for patients with PAH has improved in the last 20 years

from a median survival of 2.8 years from diagnosis to…

ZINC: GR/ABT/0010/18

Reveal score

PAH therapy in real world

• Most patients belong to both at baseline diagnostic assessment and at follow-up after treatment initiation

• Changes in risk group provide prognostic information. Prognostic significance of response to therapy is irrespective of baseline values.

• Patients who reached a low-risk profile at follow-up had similar survival as those who remained low risk from baseline to the follow-up

Kylhammar et al. Eur Heart J 2017

2018 Nice Symposium - Need for a simplified risk stratification in PAH

Prognostic

CriteriaLow-risk variables

Intermediate-risk

variablesHigh-risk variables

A WHO FC I, II III IV

B 6MWD > 440 m 165 - 440 m < 165 m

C

NT-

proBNP/BN

P

plasma

levels

OR

RAP

BNP < 50 ng/l

NT-proBNP < 300 ng/l

OR

RAP < 8 mmHg

BNP 50–300 ng/l

NT-proBNP 300–1400

ng/l

OR

RAP 8–14 mmHg

BNP > 300 ng/l

NT-proBNP > 1400

ng/l

OR

RAP > 14 mmHg

DCI

OR

SvO2

CI ≥ 2.5 l/min/m2

OR

SvO2 > 65%

CI 2.0–2.4 l/min/m2

OR

SvO2 60–65%

CI < 2.0 l/min/m2

OR

SvO2 < 60%

Larger number of low-risk criteria at follow-up*: Significantly better survival rates

4 criteria 175 153 128 102 63 483 criteria 247 204 175 140 102 722 criteria 275 219 171 122 78 491criterion 225 183 128 91 62 45

0 criteria 95 61 44 22 18 14

4 criteria

3 criteria

2 criteria

1

criterion

0 criteria

Boucly A, et al. Eur Respir J 2017; 50:1700889.

Low-risk criteria:

• FC I or II

• CI ≥ 2.5

L/min/m²

• RAP < 8 mmHg

• 6MWD > 440 m

Number at risk, n = 1017

80

6

0

4

0

20

10

0

00 1 2 3 4 5

p < 0.001

Su

rviv

al (%

)

Time (years)

*Median (interquartile range) interval between diagnosis and first re-evaluation was 4.4 (3.6–6.4) months

Risk stratification and medical therapy of pulmonary arterial hypertension

N Galiè, Et AL European Respiratory Journal 2018; DOI: 10.1183/13993003.01889-2018

• The tolerability of sequential combination therapy is supported by data

from the SERAPHIN trial, in which macitentan was generally well-

tolerated, despite the majority (64%) of patients receiving a PAH

therapy at baseline.

• Similar results were obtained with riociguat in the PATENT trial, in

which 50% of patients were receiving PAH therapies at baseline

• PAH therapies are also associated with side effects that are not related to vasodilation. For

example, ERAs, PDE-5is and sGC stimulators have been associated with anemia, PDE-5is

and sGC stimulators can cause muscle pain, and bosentan has been associated with liver

enzyme elevations. However, drug or drug-class–specific side effects are not expected to be

additive during combination therapy

• The use of vasodilators may lead to a greater degree of hypoxia in patients with systemic

sclerosis complicated by interstitial lung disease

Pulmonary Arterial Hypertension: Combination Therapy in Practice

M. Burks et al. Am J Cardiovasc Drugs. 2018; 18(4): 249–257.

• A short delay between initiation of therapies may allow patients to adapt

to the vasodilator effects of one drug before another is added, and would

make determination of which agent is responsible for the side effect in

question more likely.

• double initial combination therapy with an ERA and a PDE-5i involves

starting the two therapies a few weeks apart, with the aim of establishing

patients on the full dose of both treatments within 1 month.

• In the AMBITION trial, ambrisentan and tadalafil were started

together at low doses (5 and 20 mg, respectively) and up-titrated to

10 and 40 mg over an 8-week period.

• While the number of AEs was increased in the combination therapy

arm, no differences were observed in the rates of discontinuations

due to AEs

• French PH Network, patients were initiated on an ERA and a PDE-5i on the

same day and then up-titrated according to clinical need and tolerability.

However, this study utilized a faster up-titration schedule than AMBITION,

with patients achieving their maximal dose within 4 weeks. This treatment

regimen was well-tolerated: over a median follow-up of 30 months, only

one patient out of 97 discontinued double combination therapy

Sitbon O,et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J. 2016;47:1727–1736

• Further changes to the up-titration schedule have been made in the

ongoing OPTIMA study, where patients receive macitentan 10 mg

once daily and tadalafil 20 mg once daily on day 1, followed by a step

up to tadalafil 40 mg once daily at day 8 (± 3 days)

• Disease etiology may also influence the selection of drugs used in each patient’s treatment regimen. For example, caution must be applied for human immunodeficiency virus patients treated with anti-retroviral drugs that are strong CYP3A4 inhibitors, such as ritonavir and saquinavir, as these can interfere with the metabolism of ERAs and PDE-5is [2, 3, 31]. Care is needed when managing PAH patients with associated connective tissue disease, who may be receiving immunosuppressive therapies to treat their underlying condition. For example, co-administration of bosentan with the immunosuppressant cyclosporine is contraindicated [32]. It is also important to be mindful that PAH therapies can exacerbate symptoms in certain etiologies. For instance, the use of vasodilators may lead to a greater degree of hypoxia in patients with systemic sclerosis complicated by interstitial lung disease

Achievements with combination therapy

35% reduction of

clinical worsening with

combination therapy vs.

monotherapy

Lajoieal., Pulmonary Circulation 2017

▪ Meta-analysis (1990-2015)

▪ 4095 patients from 15 studies

Initial triple therapy

ClinicalTrials.gov. NCT02558231

TRITON TRIAL

Safety findings in the AMBITION trialAmbrisentan and tadalafil combination therapy (n = 253)

Ambrisentan monotherapy (n = 126)Tadalafil monotherapy (n = 121)

Most common AEs (≥ 10% in any group), n (%)Peripheral edema 115 (45) 41 (33) 34 (28)Headache 107 (42) 41 (33) 42 (35)Nasal congestion 54 (21) 19 (15) 15 (12)Diarrhea 50 (20) 29 (23) 23 (19)Dizziness 50 (20) 24 (19) 14 (12)Dyspnea 44 (17) 22 (17) 20 (17)Nausea 43 (17) 18 (14) 20 (17)Cough 40 (16) 14 (11) 21 (17)Flushing 38 (15) 18 (14) 11 (9)Anemia 37 (15) 8 (6) 14 (12)Nasopharyngitis 37 (15) 26 (21) 18 (15)Pain in extremity 37 (15) 14 (11) 18 (15)

URTI 34 (13) 20 (16) 20 (17)Arthralgia 32 (13) 17 (13) 19 (16)Back pain 31 (12) 13 (10) 18 (15)Fatigue 30 (12) 17 (13) 15 (12)Dyspepsia 29 (11) 5 (4) 14 (12)Palpitations 28 (11) 20 (16) 17 (14)Vomiting 28 (11) 11 (9) 12 (10)Bronchitis 27 (11) 5 (4) 10 (8)Non-cardiac chest pain 27 (11) 10 (8) 8 (7)Myalgia 23 (9) 12 (10) 15 (12)UTI 18 (7) 9 (7) 15 (12)

AEs leading discontinuation, n (%)31 (12) 14 (11) 14 (12)

Survival has been improved but still was not optimal

THE Outcome of the disease remains poor

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

Naples

21 high risk IPAH pts

Upfront triple combimation

Ambrisentan + tadalafil

sc treprostinil

2 years f up

Considerable clinic and

haemodynamic improvement

RH reverse remodeling

Larger number of low-risk criteria at baseline: Significantly better survival rates

Number at risk, n = 1017

0 1 2 3 4 5

0

2

0

4

0

6

0

8

0

100

p < 0.001

4 criteria

3 criteria

2 criteria

0 criteria

Time (years)

Su

rviv

al (%

)

Boucly A, et al. Eur Respir J 2017; 50:1700889.

Low-risk criteria:

• FC I or II

• CI ≥ 2.5

L/min/m²

• RAP < 8 mmHg

• 6MWD > 440 m

1 criterion

Risk-stratified outcomes with initial combination therapy in pulmonary arterial hypertension: Application of the REVEAL risk score

J Heart Lung Transplant. 2018 Dec;37(12)

Mouratoglou SA, et al. J Am Soc Echocardiogr 2018