Treatment Strategies for

Pulmonary Pulmonary HypertensionHypertensionSarfraz Saleemi Sarfraz Saleemi MRCP, FCCP, FACPMRCP, FCCP, FACP

Section of pulmonary medicineSection of pulmonary medicineDepartment of medicineDepartment of medicine

King Faisal Specialist Hospital & Research King Faisal Specialist Hospital & Research CenterCenter

Riyadh, Saudi ArabiaRiyadh, Saudi Arabia

Treatment of Pulmonary Hypertension

Currently there is no cure for PAH

Those who start therapy in WHO FC I or II demonstrate a better prognosis than those whose therapy is started in the more severe stages

By recognising and treating patients as early as possible, disease progression may be delayed

Sitbon O et al. J Am Coll Cardiol 2002

PAH: Screening high risk population

Key to early diagnosis – screening high risk populations: Family members of a patient with familial Pulmonary

Arterial Hypertension (FPAH) Patients with systemic sclerosis (SSc) Patients with HIV Patients with chronic liver disease and portal

hypertension International guidelines recommend annual

screening with Doppler echocardiography. Right heart catheterisation still the only

method for definitive diagnosis• Hachulla E et al Ann Rheum Dis 2004• Galie N et al. Eur Heart J 2004• McGoon M et al. Chest 2004

Without treatment:Without treatment:survival correlates with survival correlates with

functional classfunctional class

McLaughlin VV, et al. Chest 2004;126:78S-92S

Goals of TherapyGoals of Therapy

Alleviate symptoms, improve Alleviate symptoms, improve exercise capacity and quality of exercise capacity and quality of lifelife

Improve cardiopulmonary Improve cardiopulmonary hemodynamics and prevent right hemodynamics and prevent right heart failureheart failure

Delay time to clinical worseningDelay time to clinical worsening Reduce morbidity and mortalityReduce morbidity and mortality

PH treatment algorithm

Badesch D. B. et.al. Chest 2007;131:1917-1928

Acute vasoreactivity test

Reduction of at least 10 mmHg in Reduction of at least 10 mmHg in mean PAP to reach an absolute value mean PAP to reach an absolute value of 40 mmHg with an increased or of 40 mmHg with an increased or unchanged COunchanged CO

PAH Therapy: Life style PAH Therapy: Life style considerationsconsiderations

Sodium restrictionSodium restriction Abstinence from smokingAbstinence from smoking Avoid high altitudeAvoid high altitude

<4,000 feet above sea level<4,000 feet above sea level Avoid physical exertion in Avoid physical exertion in

setting of pre- or frank syncopal setting of pre- or frank syncopal

symptomssymptoms Avoid pregnancyAvoid pregnancy

PAH Therapy: PAH Therapy: General General measuresmeasures

Diuretic treatment is indicated in PAH patients with signs of RV failure and fluid retention

Continuous long-term O2 therapy is indicated in PAH patients when arterial blood O2 pressure is consistently less than 8 kPa (60 mmHg)c

Oral anticoagulant treatment should be considered in patients with IPAH, heritable PAH, and PAH due to use of anorexigens

Oral anticoagulant treatment may be considered in patients with APAH

Digoxin may be considered in patients with PAH who develop atrial tachyarrhythmias to slow ventricular rate

Humbert M et al. N Engl J Med. 2004;351:1425-1436.

Targets for Current or Emerging Targets for Current or Emerging TherapiesTherapies

Big EndothelinBig Endothelin

Endothelin-Endothelin-convertingconverting

EnzymeEnzyme

EndothelinEndothelinReceptor AReceptor A

EndothelinEndothelinReceptor BReceptor B

Vasoconstrictionand

Proliferation

EndothelinReceptor

Antagonists

Endothelin-1Endothelin-1

Endothelin PathwayEndothelin Pathway

ArginineArginine

Nitric OxideNitric OxideSynthaseSynthase

Vasodilatationand

Antiproliferation

Nitric OxideNitric Oxide

cGMPcGMP ExogenousNitric Oxide

Phosphodiesterase Type-5Phosphodiesterase Type-5

PhosphodiesteraseType-5 Inhibitors

Nitric Oxide PathwayNitric Oxide Pathway

Arachidonic AcidArachidonic Acid

ProstacyclinProstacyclinSynthaseSynthase

Vasodilatationand

Antiproliferation

ProstacyclinProstacyclin

cAMPcAMP

ProstacyclinProstacyclinDerivativesDerivatives

ProstacyclinDerivatives

Prostacyclin PathwayProstacyclin Pathway

Pathophysiology of PAHPathophysiology of PAH

Choice of Initial PAH Choice of Initial PAH TherapyTherapy

Dependent on many factorsDependent on many factors– – Disease severityDisease severity– – Approval statusApproval status– – Route of administrationRoute of administration– – Side-effect profileSide-effect profile– – Patient preferencePatient preference– – Physician experience, literature, Physician experience, literature,

clinical judgmentclinical judgment

Barst RJ, et al. J ACC 2009

PAH Determinants of PAH Determinants of RiskRiskLower Risk Determinants of Risk Higher Risk

NoClinical evidence of

RV failureYes

Gradual Progression Rapid

II, III WHO class IV

Longer (>400 m) 6MW distance Shorter (<300 m)

Minimally elevated BNP Very elevated

Minimal RV dysfunctionEchocardiographic

findings

Pericardial effusion,significant RV dysfunction

Normal/near normalRAP and CI

Hemodynamics High RAP, low CI

McLaughlin VV, McGoon MD. Circulation. 2006;114:1417-1431.

Choice of Initial PAH Choice of Initial PAH TherapyTherapy

PAH: Randomized Control Trials of PAH: Randomized Control Trials of ApprovedApproved Agents Agents

Class of Drug Study/Drug

NEunctiona

lClass

Design Positive Results

Disadvantages

ET-1Antagonist

BREATHE-1Oral Bosentan/placebo

213PAHIII,IV

Double-Blind16-wk

6 MWDSymptoms Clinical WorseningCPH

Hepatic toxicity (11%;transient, reversible)

PDE-5 Inhibitor

SUPERSildenafil Citrate (20, 40 or 80 mg tid)

278IPAH,CTCHDII, III

Double-blind, placebo12 wks

6 MWDCPHSymptoms

Headache, flushing, dyspepsia

Prostacyclinanalogue

InhalationalIloprost/Placebo

203PHIII-IV

Double-blind12-week

Composite Endpoint6 MWD, sx

Administration6 to 9 times daily

Prostacyclinanalogue

SQ Treprostinil/SQ placebo

470PAHII-IV

Double-blind12-wk

6 MWDSymptomsCPH

Pain, erythemaat infusion siteSide effects

Prostacyclin IV Epoprostenol/Conventional Rx

81PPHIII,IV

Open-Label12-wk

6 MWDSymptomsCPHSurvival

Indwelling central linePump(infection,malf)Side effects

PAH-specific drug therapyPAH-specific drug therapy

European Heart Journal (2009) 30, 2493–2537

IV epoprostenol (flolan)

VentavisVentavis®® (iloprost) (iloprost) Inhalation Inhalation

Indicated for inhalation via the ProdoseIndicated for inhalation via the Prodose®® AAD AAD®® system only system only 2.5 mcg initial dose2.5 mcg initial dose

increase to 5 mcg if 2.5 mcg dose is toleratedincrease to 5 mcg if 2.5 mcg dose is tolerated maintain at maximum tolerable dose (2.5 mcg or 5 mcg)maintain at maximum tolerable dose (2.5 mcg or 5 mcg)

6-9 inhalations daily during waking hours; 8-10 minutes each6-9 inhalations daily during waking hours; 8-10 minutes each

Subcutaneous Treprostinil Subcutaneous Treprostinil (Remodulin(Remodulin ))

•SQ administration•Longer half-life than epoprostenol•Pre-mixed•Stable at room temperature

Evaluation of Response to Evaluation of Response to therapytherapy

◙ Physical exam – JVP, murmurs, edema, ascites, liver enlargement, hypotension◙ Functional – history (WHO or NYHA functional classification, 6 minute walk, exercise test◙ Labs - BNP, renal and hepatic function◙ Echocardiography – RV function,

pericardial effusion◙ Right heart catheterization – RAP, CI

Relationship Between The Mean 6 MWD at Baseline

and Rate of Fatal Events During 3-Month Follow Up

(Adjusted R² = 0.5519, P = .0109)

Macchia, et al. Am Heart J 2007; 153:1037-1047

Suggested assessments and timing for the follow-up of patients with

PAH

European Heart Journal (2009) 30, 2493–2537

PAH: Composite Score PredictsDisease Progression

Anderson D, et al. AJRCCM 2008

Combination Therapy

Combination TherapyCombination Therapy

ConcurrentConcurrent

++

++

Drug 1

Drug 2

Drug 2Drug 1

Sequential

High risk group

Low risk group

Combination Therapy: Ongoing orRecently Completed Clinical Trials

Overview of Combination Therapy Trials for PAH

EARLY Bosental and Sildenafil RCT 29 + 19 m

STEP Iloprost inhalation and Bosentan

RCT 67 + 26 m

COMBI Iloprost/Beraprost and Bosentan

RCT 40 NS

BREATHE-2 Bosentan and IV Epoprostenol RCT 33 NS

PACES Sildenafil and IV Epoprostenol RCT 267 + 26 m

TRIUMPH-1 Bosentan + Inhaled Treprostinil

RCT 235 + 20 m

- - Thrombendartrectomy CTEPH- Chronic CTEPH- Chronic thromboembolic thromboembolic pulmonary pulmonary Hypertension Hypertension

-Atrial Septostomy-Lung Transplant-Heart and Lung

Transplant

Non-Pharmacological Treatment

New Treatments on the New Treatments on the HorizonHorizon

Pulmonary Arterial HypertensionCellular Processes

Newman JH. Circulation 2004;109:2947-2952

• • Tyrosine kinase/growth factor receptor Tyrosine kinase/growth factor receptor inhibitors inhibitors

– – Imatinib, sorafenib sorafenibImatinib, sorafenib sorafenib• • Guanylate cyclase (sGC) stimulatorsGuanylate cyclase (sGC) stimulators - - RiociguatRiociguat• • Vasoactive intestinal peptide (VIP) Vasoactive intestinal peptide (VIP) • • Serotonin transporter agonists Serotonin transporter agonists • • AdrenomedullinAdrenomedullin• • Rho-kinase inhibitors Rho-kinase inhibitors • • Cicletanine Cicletanine • • Endothelial progenitor cells Endothelial progenitor cells • • Gene therapy Gene therapy – – Vectors expressingVectors expressing

Investigational/New Investigational/New TherapiesTherapies

THANKS