Treatment Strategies for

Pulmonary Hypertension
Sarfraz Saleemi
MRCP, FCCP, FACP

Section of pulmonary medicine Department of medicine King Faisal Specialist Hospital & Research Center Riyadh, 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: survival correlates with functional class

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

Goals of Therapy

Alleviate symptoms, improve exercise capacity and quality of life Improve cardiopulmonary hemodynamics and prevent right heart failure Delay time to clinical worsening Reduce 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 mean PAP to reach an absolute value of 40 mmHg with an increased or unchanged CO

PAH Therapy: Life style considerations

Sodium restriction Abstinence from smoking Avoid high altitude

<4,000

feet above sea level

Avoid physical exertion in setting of pre- or frank syncopal symptoms Avoid pregnancy

PAH Therapy: General measures

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

Targets Pathophysiology for Current or Emerging Therapies of PAH

Endothelin Pathway
Big Endothelin Endothelinconverting Enzyme

Prostacyclin Pathway
Arachidonic Acid

Nitric Oxide Pathway

Arginine

Prostacyclin Synthase

Nitric Oxide Synthase

Endothelin-1
cAMP
Endothelin Receptor Antagonists

Prostacyclin
cGMP Prostacyclin Prostacyclin Derivatives Derivatives

Nitric Oxide Exogenous Nitric Oxide

Phosphodiesterase Type-5

Endothelin Receptor A

Endothelin Receptor B

Phosphodiesterase Type-5 Inhibitors

Vasoconstriction and Proliferation

Vasodilatation and Antiproliferation

Vasodilatation and Antiproliferation

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

Choice of Initial PAH Therapy

Dependent on many factors Disease severity Approval status Route of administration Side-effect profile Patient preference Physician experience, literature, clinical judgment

Barst RJ, et al. J ACC 2009

PAH Determinants of Risk

Lower Risk No Gradual II, III Longer (>400 m) Minimally elevated Minimal RV dysfunction Normal/near normal RAP and CI Determinants of Risk Clinical evidence of RV failure Progression WHO class 6MW distance BNP Echocardiographic findings Hemodynamics Higher Risk Yes Rapid IV Shorter (<300 m) Very elevated

Pericardial effusion, significant RV dysfunction

High RAP, low CI

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

Choice of Initial PAH Therapy

PAH: Randomized Control Trials of Approved Agents

Class of Drug
Study/ Drug BREATHE-1 Oral Bosentan/ placebo SUPER Sildenafil Citrate (20, 40 or 80 mg tid) Inhalational Iloprost/ Placebo SQ Treprostinil/ SQ placebo N Eunctiona l Class 213 PAH III,IV 278 IPAH,CT CHD II, III 203 PH III-IV 470 PAH II-IV Design Positive Results 6 MWD Symptoms Clinical Worsening CPH 6 MWD CPH Symptoms Composite Endpoint 6 MWD, sx 6 MWD Symptoms CPH Disadvantages

ET-1 Antagonist

DoubleBlind 16-wk Doubleblind, placebo 12 wks Doubleblind 12-week Doubleblind 12-wk

Hepatic toxicity (11%; transient, reversible) Headache, flushing, dyspepsia Administration 6 to 9 times daily Pain, erythema at infusion site Side effects

PDE-5 Inhibitor
Prostacyclin analogue Prostacyclin analogue

Prostacyclin

IV Epoprostenol/ Conventional Rx

81 PPH III,IV

OpenLabel 12-wk

6 MWD Symptoms CPH Survival

Indwelling central line Pump (infection,malf) Side effects

PAH-specific drug therapy

European Heart Journal (2009) 30, 24932537

IV epoprostenol (flolan)

Ventavis (iloprost) Inhalation

Indicated for inhalation via the Prodose AAD system only 2.5 mcg initial dose increase to 5 mcg if 2.5 mcg dose is tolerated maintain at maximum tolerable dose (2.5 mcg or 5 mcg) 6-9 inhalations daily during waking hours; 8-10 minutes each

Subcutaneous Treprostinil (Remodulin

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

Evaluation of Response to therapy

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 R = 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, 24932537

PAH: Composite Score Predicts Disease Progression

Anderson D, et al. AJRCCM 2008

Combination Therapy

Combination Therapy
Concurrent
Drug 1

+
Drug 2

High risk group

Sequential
Drug 1

Drug 2

Low risk group

Combination Therapy: Ongoing or Recently Completed Clinical Trials

Overview of Combination Therapy Trials for PAH

EARLY Bosental and Sildenafil RCT 29 + 19 m

STEP

Iloprost inhalation and Bosentan Iloprost/Beraprost and Bosentan Bosentan and IV Epoprostenol

RCT

67

+ 26 m

COMBI

RCT

40

NS

BREATHE-2

RCT

33

NS

PACES

Sildenafil and IV Epoprostenol

RCT

267

+ 26 m

TRIUMPH-1

Bosentan + Inhaled Treprostinil

RCT

235

+ 20 m

Non-Pharmacological Treatment
- Thrombendartrectomy CTEPH- Chronic thromboembolic pulmonary Hypertension -Atrial Septostomy -Lung Transplant -Heart and Lung Transplant

New Treatments on the Horizon

Pulmonary Arterial Hypertension

Cellular Processes

Newman JH. Circulation 2004;109:2947-2952

Investigational/New Therapies
Tyrosine kinase/growth factor receptor inhibitors Imatinib, sorafenib sorafenib Guanylate cyclase (sGC) stimulators - Riociguat Vasoactive intestinal peptide (VIP) Serotonin transporter agonists Adrenomedullin Rho-kinase inhibitors Cicletanine Endothelial progenitor cells Gene therapy Vectors expressing

THANKS