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