Acknowledgements ABcomm, Inc. is accredited by the Accreditation Council for Continuing Medical...

Acknowledgements

• ABcomm, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

• Support for this educational activity is provided by an independent educational grant from Gilead Sciences Medical Affairs.

Targeted Approach to Treatment of PAH

Learning Objectives

• Intensify the treatment plan when right ventricular impairment is evident.

• Adopt a goal-directed treatment approach to adjust the treatment plan when clinical decompensation occurs.

• Utilize a combination of agents with proven combined efficacy and an acceptable safety profile.

• Monitor relevant prognostic variables in patients with PAH.

• Incorporate progressive treatment strategies and protocols when appropriate.

Lecture Outline

• General measures and supportive therapy• Pathways and mechanisms of action• Evidence-based treatment algorithm• FDA-approved treatment options• Combination therapy• Prognostication and patient monitoring• Ongoing research

Treatment of PAH

• Complex strategy which includes:– Evaluation of disease severity

– Adoption of general measures and supportive therapy

– Assessment of vasoreactivity

– Estimation of drug efficacy– Combination of different drugs and interventions

(e.g. balloon atrial septostomy, lung transplantation)

Ghofrani, et al. Int J Cardiol. 2011;154(1):S20-33.

General Measures andSupportive Therapy

General measures

Supportive therapy

Referral to specialized PAH patient care center

Cardiac catheterization / Acute vasoreactivity testing

Chronic CCB therapy

Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.


Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

General Measures• Rehabilitation / Exercise

– Recommended after stabilized and on therapy– Requires close supervision by an experienced PAH care center – Optimal method, duration, and intensity of activity are unknown

• Psychosocial support• Family planning

– Pregnancy is associated with a considerable mortality rate in patients with PAH, and oral contraceptives are not contraindicated

• Vaccinations– Influenza and pneumococcal immunization



Supportive Therapy

• Anticoagulants

• Diuretics

• Oxygen

• Digoxin


Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Cardiac Catheterization / Acute Vasoreactivity Testing• Mandatory in patients with idiopathic PAH, may be

considered in patients with PAH associated conditions

• Identifies patients who will respond to chronic treatment with high-dose CCBs

• Inhaled nitric oxide (10 – 20 parts per million) is the preferred testing compound– Alternates: epoprostenol IV or adenosine IV


Agarwal, et al. Am Heart J. 2011;162:201-13. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Chronic CCB Therapy• Responders

– Patients with a positive response to acute vasoreactivity testing– Positive response = reduction of mean PAP ≥ 10 mm Hg to

reach a mean PAP ≤ 40 mm Hg with a normalized or increased cardiac output

– < 10% of patients with idiopathic PAH

• TherapeuticsAmlodipine 20 – 30 mg/day

Nifedipine 180 – 240 mg/day

Diltiazem 720 – 960 mg/day

Mechanisms of Pathology for PAH

Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436.

Nitric oxide

cGMP

Vasodilatation and antiproliferation

Endothelial cells

Nitric oxide pathway

Preproendothelin ProendothelinL-arginine

NOS

Arachidonic acid Prostaglandin I2

Prostaglandin I2

cAMPVasodilatation and

antiproliferationVasoconstriction and

proliferation

Endothelin-receptor A Endothelin-

receptor B

Endothelin pathway Prostacyclin pathway

Endothelin-1

Endothelin-receptor

antagonists

Exogenous nitric oxide

Prostacyclinderivates

Phosphodiesterase type 5 inhibitor

Phosphodiesterase type 5

GTPsGC stimulator

Prostacyclin Pathway

• Prostacyclin– Produced primarily by endothelial cells– Induces potent vasodilation of vascular beds– Inhibits platelet aggregation– Cytoprotective and antiproliferative properties

• Prostacyclin analogs


Epoprostenol Continuous IV infusion, inhalation

Iloprost Inhalation

Treprostinil Subcutaneous, IV, inhalation, oral

Endothelin Pathway

• Endothelin– Plasma levels are elevated in patients with PAH– Increases vasoconstriction– Mitogenic properties

• Endothelin receptor antagonists


Bosentan Oral

Ambrisentan Oral

Macitentan Oral

Nitric Oxide Pathway

• Nitric oxide – Impairment of nitric

oxide (NO) synthesis and signaling in patients with PAH

– Mediated through the NO-sGC-cGMP pathway

NOS NO

sGC cGMP


L-Arginine L-Citrulline

GMPVasodilation

PDE-5

Nitric Oxide Pathway

• Phosphodiesterase-5 inhibitors– Inhibit the cGMP degrading enzyme, PDE-5– Enhance the pathway, slowing cGMP

degradation– Vasodilation and antiproliferative effects

• Soluble guanylate cyclase stimulators– Increase cGMP production– Antiproliferative and antiremodeling properties


Sildenafil Oral, IV

Tadalafil Oral

Riociguat Oral

Evidence-Based Treatment Algorithm


WHO FC II WHO FC III WHO FC IV

BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguat

BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguatEpoprostenol IVIloprost inhalationTreprostinil sc, inhalation

Epoprostenol IV

Treprostinil IV BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguatIloprost inhalationTreprostinil sc, inhalation, IV

Initial combination therapy Initial combination therapy

Sequential Combination Therapy

Interventional Procedure

IA/B

IIbC

IIaC

ERA

PA PDE-5isGCS

BAS

Lung Transplantation

Inadequate clinical response

Inadequate clinical response onmaximal therapy

+ +

+

Lung Transplantation

Interventional Procedure

Sequential Combination Therapy

39

Initial Therapy for PAHWHO FC II WHO FC III WHO FC IV

BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguat

BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguatEpoprostenol IVIloprost inhalationTreprostinil sc, inhalation

Epoprostenol IV

Treprostinil IV BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguatIloprost inhalationTreprostinil sc, inhalation, IV

Initial combination therapy Initial combination therapy


IA/B

IIbC

IIaC

Strength of recommendation

and clinical evidence

Epoprostenol for PAH

• Prostacyclin analog

• Indication – functional class III and IV

• Administration– Continuous IV infusion via central venous catheter

– Inhalation form is available in the hospital

• Dosage = 20 – 40 ng/kg/min

• Two branded versions of epoprostenol are available:– One is only stable at room temperature for 8 hours; therefore, it

must be kept cool (ice packs or refrigeration)

– Other is a thermostable formulation

100

80

60

40

20

0Weeks

Epoprostenol (N = 41)

0 2 4 6 8 1210

Conventional therapy (N = 40)

Pat

ien

t S

urv

ival

(%

)

P = 0.003

Barst, et al. N Engl J Med. 1996;334:296-301.

Epoprostenol for PAHPatient Survival

Treprostinil for PAH

• Prostacyclin analog• Indication – functional class II, III, and IV• Administration

– Subcutaneous (SC)– IV– Inhalation– Oral (extended-release tablets; twice daily dosing)

• Dosage– Initial dosage = 1.25 ng/kg/min– Usual dosage = 30 – 100 ng/kg/min

Treprostinil SC for PAH Change in 6-MWD (From Baseline to Week 12)

Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.

0

5

10

15

20

25

30

35

40

< 5.0ng/kg/min

5.0 - 8.1ng/kg/min

8.2 – 13.8ng/kg/min

> 13.8 ng/kg/min

3.31.4

20

36.1

Cha

nge

from

Bas

elin

e (m

eter

s)

P = 0.03

N = 470

Treprostinil IV for PAH

Change in 6-MWD*

Cha

nge

from

Bas

elin

e (m

eter

s)

Tapson, et al. Chest. 2006;129:683-8.

Weeks

Num

ber

of

Pat

ien

ts

Change in Functional Class

12 WeeksBaseline

N = 14*P < 0.05

Treprostinil Inhalation for PAH:TRIUMPH Clinical Trials

RCT1

• N = 212 patients who were

symptomatic on bosentan or

sildenafil

• Addition of treprostinil up to 54 μg,

four times daily for 12 weeks

• Study results – significantly

greater improvement in 6-MWD

and quality of life with combination

therapy

Open-label extension2

• N = 206

• Treprostinil with bosentan (69%)

or sildenafil (31%) for 24 months

• Study results – treatment benefit

and improvements in 6-MWD,

symptoms, functional class, and

quality of life were maintained

for 24 months

1) McLaughlin, et al. J Am Coll Cardiol. 2010;55(18):1915-22. 2) Benza, et al. J Heart Lung Transplant. 2011;30(12):1327-33.

Treprostinil Oral for PAH:FREEDOM-C Clinical Trial

• Study design– Randomized, double-blind, placebo-controlled study

– N = 350 patients with background ERA or PDE-5 inhibitor

– Study duration = 16 weeks

• Study results– High discontinuation rate: 22% of treprostinil-treated patients

and 14% of placebo-treated patients

– Improvement in 6-MWD did not reach statistical significance

– Reduced efficacy may be due to the low dose of treprostinil or presence of background therapy

Tapson, et al. Chest. 2012;142(6):1383-90.

Treprostinil Oral for PAH:FREEDOM-M Clinical Trial

• Study Design– Randomized, double-

blind, placebo-controlled study

– N = 228 treatment-naïve patients, no background therapy permitted

– Study duration = 12 weeks

Jing, et al. Circulation. 2013;127:624-33.Weeks

Change in 6-MWD

Cha

nge

from

Bas

elin

e (m

eter

s)

*P < 0.05

*

*

Iloprost for PAH

• Prostacyclin analog

• Indication – functional class III and IV

• Administration

– Ultrasonic nebulizer used in well-ventilated areas

– Theoretical advantage of pulmonary vs systemic drug delivery

• Dosage

– Usual dosage = 2.5-5 μg, 6 to 9 times daily

– Maximum dosage = 45 μg

Iloprost for PAHComposite Primary Endpoint (at Week 12)

26

43

8

25

13

4 4

19

0

5

10

15

20

25

30

35

40

45

10% Improvementin 6-MWD

Improvement inFunctional Class

Death or ClinicalWorsening

Composite PrimaryEndpoint

Placebo

Iloprost

Olschewski, et al. N Engl J Med. 2002;347:322-9.

Res

pond

ers

(% P

atie

nts)

P = 0.0033N = 203

Bosentan for PAH

• Endothelin receptor antagonist

• Indication – functional class II, III, and IV

• Administration – oral

• Dosage = 62.5 mg twice daily for 4 weeks, then titrate to 125 mg twice daily

62.5 mg twice daily 125 or 250 mg twice daily

-40

-20

0

20

40

60

80

Bosentan (N = 144)

Placebo (N = 69)

4 8 16 Weeks

P = 0.0002

Cha

nge

from

Bas

elin

e (m

eter

s)

Rubin, et al. N Engl J Med. 2002;346:896-903.

Bosentan for PAH:BREATHE Clinical Trial

Change in 6-MWD (From Baseline to Week 16)

Bosentan for PAH:EARLY Clinical Trial

Change in 6-MWD (From Baseline to Week 24)

10

5

0

5

10

15

20

12 Weeks 24 Weeks

Placebo (N = 91)

Bosentan (N = 86)P = 0.076

25

20

15Cha

nge

from

Bas

elin

e (m

eter

s)

Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

11.2

- 7.9

Bosentan for PAH:EARLY Clinical Trial

Time to Clinical Worsening (From Baseline to Week 32)

100

80

60

40

20

00 4 8 12 16 20 2824 32

Eve

nt-F

ree

Pat

ient

s (%

)

Placebo

Bosentan

P < 0.02

Weeks

Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

Ambrisentan for PAH

• Endothelin receptor antagonist



• Dosage = 5 mg and 10 mg daily

Ambrisentan for PAHChange in 6-MWD (From Baseline to Week 12)

Galie, et al. Circulation. 2008;117:3010-9.

-25

0

25

50

4 8 12 Weeks

10 mg

5 mg

Placebo

N = 202

4 8 12 Weeks

5 mg

2.5 mg

Placebo

-20

0

20

40

60 N = 192

Cha

nge

from

Bas

elin

e (m

eter

s)

ARIES-1 ARIES-2 *P < 0.05

44*

23*

-8

49*

22*

-10

Ambrisentan for PAH:ARIES Clinical Trials

Time to Clinical Worsening (From Baseline to Week 12)

--- Placebo

--- 2.5 mg (P = 0.03)

--- 5 mg (P = 0.005)

--- 10 mg (P = 0.03)

70

80

90

100

0 4 8 12 Weeks

Eve

nt-F

ree

Pat

ient

s (%

)

Ambrisentan → 71% relative risk reduction

Galie, et al. Circulation. 2008;117:3010-9.

Ambrisentan for PAH:ARIES-3 Clinical Trial

Study Results• Change in 6-MWD from

baseline to week 24– Increased by 21 meters

(P < 0.05)

• Change in BNP levels from baseline to week 24– Decreased by 26%

Badesch, et al. Cardiovasc Ther. 2012;30(2):93-9.

Patient Population (N = 224)

Ambrisentan for PAH:ARIES-E Clinical Trial

Change in 6-MWD (From Baseline to 24 Months)C

hang

e fr

om B

asel

ine

(met

ers) 2.5 mg (N = 93)

5 mg (N = 186)10 mg (N = 96)

Years

-20

-100

1020

3040

50

60

0.0 0.25 0.5 1.0 1.5 2.0

70

7

23

28

Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.

Macitentan for PAH

• Endothelin receptor antagonist– Sustained receptor binding and enhanced tissue

penetration



• Dosage = 10 mg daily

Macitentan for PAH:SERAPHIN Clinical Trials

RCT1

• N = 742• Macitentan 3 mg or 10 mg

once daily• Study duration = event

driven• Study endpoint = time to

clinical worsening


• N = 550• Macitentan 10 mg once

daily• Study duration = event

driven• Study endpoint = safety

1) www.clinicaltrials.gov/ct2/show/NCT00660179 2) www.clinicaltrials.gov/ct2/show/NCT00667823

http://www.clinicaltrials.gov/ct2/show/NCT01106014


Macitentan for PAH:SERAPHIN Clinical Trial

3 mg 10 mg

N = 250 N = 242

Duration of treatment (event driven) 99.5 weeks 103.9 weeks

Risk reduction in the occurrence of morbidity and mortality events versus placebo (N = 250)

30%(P < 0.05)

45%(P < 0.05)

Overall risk reduction:

With background therapy

Without background therapy

17%

47%

38%

55%

Pulido, et al. NEJM. 2013;369(9):809-18.

Sildenafil for PAH

• Phosphodiesterase-5 inhibitor – targets the nitric oxide pathway


• Administration and dosage

– Oral = 20 mg three times daily

– IV = 10 mg three times daily

Sildenafil for PAH:SUPER-1 Clinical Trial

Galie, et al. N Engl J Med. 2005;353:2148-57.

Pla

ceb

o-A

djus

ted

Cha

nge

from

Bas

elin

e (m

ete

rs)

Change in 6-MWD

P < 0.05

Change in Functional Class

Pat

ient

s W

ith a

n Im

prov

emen

tIn

Fun

ctio

nal C

lass

(%

)

P < 0.05

Sildenafil for PAH:SUPER-2 Clinical Trial

Study Design• Long-term, open-label

extension • N = 170 patients who

completed both studies• Sildenafil 80 mg three times

daily• Second agent added in

18% of patients by end of study period (3 years)

Study Results• 6-MWD

– Maintained or improved in 46% of patients

• Functional class– Maintained or improved

in 60% of patients• Estimated patient survival

rate at 3 years = 79%

Rubin, et al. Chest. 2011:140(5):1274-83.

Sildenafil for PAH:PACES Clinical Trial

Study Design• Randomized, double-blind,

placebo-controlled study• Sildenafil 80 mg three times

daily in combination with epoprostenol (N = 214) compared to epoprostenol monotherapy (N = 53)

• Study duration = 16 weeks


– Placebo-adjusted improvement = 28 meters*

• Clinical worsening event– 6% vs 18.5% of patients on

monotherapy*

• Time to clinical worsening– Significant delay compared

to monotherapy*

Simonneau, et al. Ann Intern Med. 2008;149(8):521-30.

*P < 0.05

Tadalafil for PAH

• Phosphodiesterase-5 inhibitor – targets the nitric oxide pathway

• Indication – functional class II, III, IV


• Dosage = 40 mg daily

Tadalafil for PAH:PHIRST-1 Clinical Trial

Study Design• Randomized, double-blind,

placebo-controlled study• Tadalafil in combination

with bosentan (N = 216) compared to tadalafil monotherapy (N = 189)



– Significant improvement* but less than monotherapy

• Quality of life– Significant improvement

• Clinical worsening events– Significantly less*– 68% relative risk reduction

• Time to clinical worsening– Significant delay*

Galie, et al. Circulation. 2009;119(22):2894-903.Barst, et al. J Heart Lung Transplant. 2011;30(6):632-43.

*P < 0.05(40 mg dose)

Tadalafil for PAH:PHIRST-2 Clinical Trial

Study Design• Long-term, open-label

extension• N = 293 patients from

PHIRST-1• Tadalafil 20 mg or 40 mg

once daily• Background bosentan

permitted (54% of patients)• Study duration = 52 weeks


– Sustained improvement through long-term extension (68 weeks total)

• Clinical worsening events– Significantly less in

patients on combination therapy

Oudiz, et al. J Am Coll Cardiol. 2012;60:768-74.

Riociguat for PAH

• Soluble guanylate cyclase stimulator – targets the nitric oxide pathway



• Dosage = 1 mg – 2.5 mg three times daily

Riociguat for PAH:PATENT Clinical Trials

RCT1

• N = 445• Riociguat 1 mg, 1.5 mg,

2 mg, or 2.5 mg three times daily


• Study endpoint = 6-MWD


• N = 396• Riociguat 1 mg, 1.5

mg, 2 mg, or 2.5 mg three times daily

• Study duration = event driven

• Study endpoint = safety

1) www.clinicaltrials.gov/ct2/show/NCT00810693 2) www.clinicaltrials.gov/ct2/show/NCT00863681



Riociguat for PAH:PATENT Clinical Trial

Significant Improvement*

PVR

NT-proBNP

Functional class

Borg Dyspnea Scale score

Quality of life measures

Time to clinical worsening

Ghofrani, et al. NEJM. 2013;369(4):330-40.

Change in 6-MWD

P < 0.05

Cha

nge

from

Bas

elin

e (m

eter

s)

N = 443*P < 0.05

Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.Badesch, et al. Chest. 2010;137(2):376-87.

Combination Therapy for PAH

• To target multiple disease pathways

• Used when therapy needs to be augmented because response to initial therapy is inadequate

• Sequential combination therapy– Starting in one drug class and adding an agent from

another drug class when necessary

• REVEAL: 34% of patients on 2 or more treatments


Clinical Study Agents N

Study Duration Study Endpoints

Statistical Significance

BREATHE-21 EpoprostenolBosentan 33 16 weeks Hemodynamics, 6-MWD,

functional class No

STEP-12 IloprostBosentan 67 12 weeks Hemodynamics, 6-MWD,

functional class, TTCW Yes

COMBI3 IloprostBosentan 40 12 weeks 6-MWD, functional class,

TTCW No

1) Humbert, et al. Eur Respir J. 2004;24:353-9. 2) McLaughlin, et al. Am J Respir Crit Care Med. 2006;174:1257-63.3) Hoeper, et al. Eur Respir J. 2006;28:691-4.

Early Initiation ofCombination Therapy for PAH

• Combination therapy used in early PAH disease

• Debated by clinicians and researchers

• May improve patient outcomes

• May prevent or slow disease progression

• May reduce costs associated with managing clinical worsening

• Well-controlled studies are needed to test this practice

Affuso, et al. World J Cardiol. 2010;2(3):68-70.


Clinical Study StatusStudy

Design Agents NStudy

DurationStudy

Endpoints

COMPASS-21 Ongoing RCT Sildenafil +/-Bosentan 334 Event

driven TTCW

COMPASS-32 Completed OL Bosentan +/-Sildenafil 100 28 weeks 6-MWD

NCT00323297 Completed RCTBosentan +/-

Sildenafil 104 12 weeks 6-MWDTTCW

FREEDOM-Ev3 Ongoing RCT*• Treprostinil oral +

PDE-5i or ERA• PDE-5i or ERA

858 Event driven

TTCW6-MWD

AMBITION4 Ongoing RCT* Ambrisentan +/-Tadalafil 614 Event

driven TTCW

ATHENA-15 Completed OL Sildenafil or Tadalafil +/- Ambrisentan 38 24 weeks PVR

1) NCT00303459; 2) NCT00433329; 3) NCT01560624; 4) NCT01178073; 5) NCT00617305 *Early combination therapy

Interventional Procedures:Balloon Atrial Septostomy

• In order to:– Decompress right heart chambers

– Increase left ventricle preload

– Increase cardiac output

– Improve systemic oxygen transport

– Decrease sympathetic hyperactivity

• Creation of an interatrial right-to-left shunt

• Considered a palliative or bridging procedure– Patients refractory to medical therapy

– Patients awaiting lung transplantationGalie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Interventional Procedures:Lung Transplantation

• Surgical procedures– Single lung transplant

– Bilateral lung transplant – most common

– Heart-lung transplant – increasingly less common, with about 70 – 90 performed every year*

• Lung transplantation remains the standard of care for patients with PAH who fail aggressive medical therapy, until the age of 75 (depending on the transplant center)

*Long, et al. Pulm Circ. 2011;1(3):327-33.Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

ISHLT Guidelines forLung Transplantation

Persistent functional class III or IV despite maximal medical therapy

Low (< 350 meters) or declining 6-MWD

Failing even while on a parenteral prostacyclin analog

Cardiac index < 2 L/min/m2

Right atrial pressure > 15 mm Hg

ISHLT = International Society for Heart Lung TransplantationLong, et al. Pulm Circ. 2011;1(3):327-33.

Diagnosis of PAH Vasoreactivity test: negative

Baseline exam and 3 - 6 monthly re-evaluation to assess treatment goals:Clinically stable, functional class II, 6-MWD > 400 meters, RAP / CI normal

Treatment goals NOT met Treatment goals met

Start ERA or PDE-5i

Add ERA or PDE-5i

Parenteral PA and / or enrollmentin clinical trials

Urgent lung transplantation

Continue treatment

Continue treatment

Continue treatment

Goal-Directed Therapy

Adapted from: Hoeper, et al. Eur Respir J. 2005;26:858-63.

Low risk Determinants of risk High risk

No Clinical evidence of RV failure Yes

Gradual Disease progression Rapid

II, III WHO functional class IV

Longer (> 400 meters) 6-MWD Shorter (< 300 meters)

Peak VO2 > 10.4 mL/kg/min Cardiopulmonary exercise testing

Peak VO2 < 10.4 mL/kg/min

Minimally elevated and stable BNP / NT-proBNP Significantly elevated

PaCO2 > 34 mm Hg Blood gasses PaCO2 < 32 mm Hg

Minimal RV dysfunction ECHO cardiography Pericardial effusion, RV dysfunction, RA enlargement

RAP < 10 mm Hg;CI > 2.5 L/min/m2

Pulmonary hemodynamicsRAP > 20 mm Hg;

CI < 2 L/min/m2

McLaughlin, et al. Circulation. 2006;114:1417-31. McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.

Prognostication: Determinants of Patient RiskACC / AHA Expert Consensus

REVEAL Risk CalculatorParameter Low risk Score High risk Score

Type of PAHHeritableCTDPortal hypertension

+2+1+2

Demographics/Comorbidities

Male > 60 years oldRenal insufficiency

+2+1

Functional class I -2 IIIIV

+1+2

Vital signs SBP < 110 mm HgHR > 92 bpm

+1+1

6-MWD ≥ 440 meters -1 < 165 meters +1

BNP < 50 pg/mL -2 > 180 pg/mL +1

ECHO Pericardial effusion +1

PFT % pred DLCO ≥ 80% -1 % pred DLCO ≤ 32% +1

RHC mPAP > 20 mm HgPVR > 32 WU

+1+2

Benza, et al. Circulation. 2010;122:164-72. Benza, et al. Chest. 2012;141:354-62.

Clinical Endpoints

Exercise Capacity6-MWDCPET

Treadmill

Functional Class

BiomarkersBNP / NT-proBNPHemodynamics(PVR, PAP, CO)

ImagingCardiac MRI

2D3DE

Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91.

Time to Clinical Worsening

• Composite endpoint of adverse clinical events:

- Death

- Lung transplantation

- Hospitalization for worsening PAH

- Initiation of IV therapy due to worsening PAH

- Worsening of function

- Worsening of PAH symptoms

Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91.

Longitudinal Patient MonitoringACCF / AHA Recommendations

Patient Evaluation 6-MWD

Functional Class BNP ECHO RHC

Stable patient

Every 3-6 months

Every visit Every visit Center

dependentEvery 12 months

If clinical deterioration

Unstable patient

Every 1-3 months

Every visit Every visit Center

dependentEvery 6-12

months

Every 6-12 months or if

clinical deterioration

McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. McLaughlin. Am J Cardiol. 2013;111:S10-5.

Treatment Goals

6-MWD CPETFunctional

Class BNP ECHO Hemodynamics

> 380 – 440 meters

Peak VO2 > 15 mL/min/kg

EqCO2 < 45 L/minI or II Normal

levels

Normal or near normal RV size

and function

RAP < 8 mm HgCI > 2.5 - 3 L/min/m2

McLaughlin, et al. J Am Coll Cardiol. 2013;62(25):S73-81.

Ongoing Clinical Research in PAH

• PAH is a chronic, debilitating disease with significant associated morbidity and mortality

• A cure for PAH has yet to be discovered

• Standard treatment eventually becomes inadequate

• Enrollment in clinical trials posits patients for cutting-edge therapies

Investigational Agents for PAH

Selexipag• Prostacyclin IP

receptor agonist• Targets the

prostacyclin pathway• GRIPHON clinical

trials1,2

• Research is ongoing

Imatinib• Tyrosine kinase inhibitor• PDGF receptor inhibitor

(vascular remodeling)• Antiproliferative• IMPRES clinical trials3,4,5

• Regulatory consideration has been terminated

1) NCT01106014; 2) NCT01112306; 3) NCT00902174; 4) NCT01117987; 5) Hoeper, et al. Circulation. 2013;127(10): 1128-38.

Summary

• Management of patients with PAH involves a complex strategy which includes supportive therapy and disease-targeted medications.

• The evidence-based treatment algorithm for PAH streamlines decision making and drug selection.

• Combination therapy is the standard of care when initial therapy becomes inadequate.

• Prognostication and patient monitoring involves the use of clinically-relevant parameters and endpoints.

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