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Pulmonary Hypertension:

Pulmonary Hypertension Management

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Normal PAP at rest 14 + 3 mmHg, with an upper limit of normal of 20 mmHg. Compliance of pulmonary vascular bed dec with age--mild PH (MPA>20) 13% prev above age 45 and 28% prevalence above age 75.

Severity of Pulmonary Hypertension:

Severity of Pulmonary Hypertension Degree of disease Mild Moderate Severe Mean PAP (mmHg) 25 - 40 41 - 55 >55

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VC RA RV PA PV PC LA LV Ao Post-Capillary PH (PCWP>15 mmHg ; PVR nl) Systemic HTN AoV Disease Myocardial Disease Dilated CMP-ischemic/non-isc. Hypertrophic CMP Restrictive/infiltrative CMP Obesity and others Atrial Myxoma Cor Triatriatum PV compression PVOD PAH Respiratory Diseases PE Pulmonary Hypertension: Define Lesion MV Disease  LVEDP Mixed PH Pre-capillary PH PCWP < 15 mmHg PVR > 3 Wu

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NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE Pathogenesis of Pulmonary Arterial Hypertension

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PAH: Pathophysiology Dilated RV- Intact pericardium  RAP   Intrapericardial pressure (IPP)   LV transmural filling pressure= LVEDP-IPP + Shift of IV septum toward LV   LV preload and  LV distensibility   Systemic Cardiac Output

Blood Test:

Blood Test HIV/Hepatitis ANA, anti-cetromere antibodies Thrombophilia screening Thyroid function test Uric acid / BNP/NT pro BNP

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Ultrasound Imaging HRCT V/Q scan CMRI


ECG Suggestive/ supportive evidence of PH RVH and strain, and RAE. RVH in 87% & RAD in 79% IPAH. Findings does not exclude the presence of PH nor does it exclude severe haemodynamic abnormalities. ECG has insufficient sensitivity(55%) & specificity (70%) to be a screening tool

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Supraventricular arrhythmias in advanced stages,atrial flutter/fibrillation.. further clinical deterioration RAE (P wave >2.5mm in leads II, III, Avf with frontal P axis >75º) has been associated with a 2.8-fold inc risk of mortality over six yrs of observation in pts diagnosed with PH .

Methods of determining RAP:

Methods of determining RAP Jugular vein height IVC appearance Dilated or normal Sniff plesmography Respiratory variation insize Empiric constant value (ie 10 or 14) Floating constant (5, 10, 15, 20mm) Percentage constant (10% of P)

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Bernoulli equation peak pressure gradient of TR = 4 X (TR velocity)2 Contrast echo (e.g. agitated saline) sig inc the doppler signal.. proper measurement of peak TR velocity. Mean PAP =0.61 X PA systolic pressure + 2 mmHg)

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Inaccurate in the individual patient. In patients with severe TR use of the simplified form of the Bernoulli equation may lead to underestimation of PASP. Also overestimations by 10 mmHg

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Echo is an essential component of the diagnostic algorithm of PAH insofar as it makes it possible to confirm the diagnosis. It may also help to exclude PH related to congenital systemic-to pulmonary shunts or sec to pulmonary venous hypertension, thromboembolic disease or obstructed pulmonary vessels, predict the prognosis, monitor the efficacy of specific therapeutic interventions, and detect the preclinical stage of the disease.

Pulmonary function tests and arterial blood gases :

Pulmonary function tests and arterial blood gases Identify the contribution of underlying airway or parenchymal lung disease. …….COPD/ILD .. Evaluated by PFT Severity of emphysema & of ILD.. HRCT. Overnight oximetry or polysomnography.. OSA.

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RHC & vasoreactivity … confirm the diagnosis of PAH, to assess the severity of the haemodynamic impairment,& to test the vasoreactivity . SVC, PA, & systemic arterial blood oxygen saturations should also be determined... needed for the calculation of PVR. Pul angiogram …double lung transplantation or PEA in patients with CTEPH

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Recording of PWP .. PH due to left heart disease. A PWP >15 mmHg excludes the diagnosis of pre-capillary PAH. One of the most challenging differential diagnoses of PAH is heart failure with normal LVEF & diastolic dysfunction

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Vasoreactivity testing.. identify patients who may benefit from long-term therapy with CCBs Acute vasodilator challenge should only be performed with short-acting, safe, and easy to administer drugs with no or limited systemic effects. Current agent.. NO based on previous experience i.v. epoprostenol or i.v. adenosine may also be used as an alternative (but with a risk of systemic vasodilator effects)

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Inhaled iloprost & oral sildenafil may be associated with significant vasodilator effects.. role has not yet been demonstrated. Positive acute response reduction of Mean PAP> 10 mmHg to reach an absolute value of mean <PAP 40 mmHg with an inc or unchanged CO.

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Only 10% of pts with IPAH will meet these criteria. Positive responders.. sustained response to long-term treatment with high doses of CCBs.. safely be treated with this type of therapy. Half acute responders… positive long-term responders to CCBs ..only in these.. CCB as a single treatment warranted.

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?? Usefulness of a/c vasoreactivity tests & treatment with CCBs in pts with other PAH types, such as heritable PAH, CTD, and HIV pts is less clear than in IPAH. … experts recommend performing a/c vasoreactivity studies in these pts and to look for a long-term response to CCBs in those in which the test is positive.

IPAH/FPAH Epidemiology and Natural History Predictors of Prognosis:

IPAH/FPAH Epidemiology and Natural History Predictors of Prognosis  NYHA Class Median Survival I and II 5 years III 2.5 years IV 6 months 5-year survival: 27% NYHA Class III/IV

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50% mortality at 2.5 years if left untreated PAH Survival-NIH registry data 1980’s 0 20 40 60 80 100 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years of Followup Percentage Surviving Adapted from: D’Alonzo GE, Barst RJ, Ayres SM. Survival in patients with PPH: Results from a National Prospective Registry. Ann Internal Med. 1991; 115: 343-349 Time from sx to dx: 2.5 yrs Median: 2.8 yrs 50% survival at 2.5 yrs 68% 48% 34% IPAH/FPAH (PPH): Progressive disorder associated with high mortality rate

Goals of Therapy:

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

PAH Therapy: Life style considerations:

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 syncope sx Avoid pregnancy Psychosocial support

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Infection prevention Elective surgery

PAH: Therapy:

PAH: Therapy Pharmacologic Vasodilators/Vasoremodeling therapy (CCB, oral bosentan, inhaled iloprost; SQ/IV treprostinil; IV epoprostenol, oral sildenafil) Supplemental O 2 Anticoagulation (INR≈ 2-3) Diuretics ( excessive preload) Digoxin IV inotropes (low dose dobutamine, dopamine 1-2 mcg/kg/min ) Rx for RV failure }

Algorithm for Assessment of Vasoreactivity in Patients with PAH:

Algorithm for Assessment of Vasoreactivity in Patients with PAH Right Heart Catheterization With Acute Vasoreactivity Testing (iNO, epoprostenol, adenosine) Non - responder Responder (<15%) and candidate for CCB (no RHF) Consider p.o. Bosentan Consider p.o. Sildenafil Consider Inhaled Iloprost Consider s.q. Treprostinil Consider Continuously-Infused Epoprostenol Hemodynamically-Monitored Trial of Calcium Channel Blocker Therapy mPA  10 mmHg  mPA < 40 mmHg

Strategies to Prevent and Treat Right Heart Failure:

Strategies to Prevent and Treat Right Heart Failure Reduce RV wall stress (  MVO 2 ,  ischemia) Reduce RV afterload Pulmonary vasodilators (O 2 , CCB, ERA’s, prostanoids, nitric oxide) Anticoagulation to prevent thrombosis Reduce RV preload and TR (diuretics: loop, aldosterone antagonists) Improve RV inotropy Chronically: digoxin Acutely:  IV epoprostenol, IV treprostinil  low dose IV dobutamine or dopamine at 1-2 mcg/kg/min

Invasive Treatment of Advanced RV Failure:

Invasive Treatment of Advanced RV Failure Atrial septostomy +/- ECMO Improve LV filling and systemic cardiac output

Surgical Therapy:

Surgical Therapy Transplantation - lung / heart-lung Reserved for patients who continue to deteriorate with poor QOL despite aggressive pharmacologic therapy 1 year survival - 65-70% 5 year survival - 40-50%

Targets of therapy:

Targets of therapy


CCB Nifedipine, diltiazem, and amlodipine. Choice based upon the pt’s HR at baseline, with a relative bradycardia favouring nifedipine & amlodipine & a relative tachycardia favouring diltiazem. Doses high.. 120–240 mg for nifedipine,240–720 mg for diltiazem, & up to 20 mg for amlodipine. Start with a low dose, e.g. 30 mg of slow release nifedipine BID, 60 mg of diltiazem t.i.d., or 2.5 mg of amlodipine OD & inc cautiously & progressively

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Limiting factors for dose inc.. hypotension & LL oedema. Pts followed closely for both safety & efficacy with an initial reassessment after 3–4 months of therapy including RHC. If no adequate response (Figure 2),defined as being in WHO-FC I or II & with a marked haemodynamic improvement, additional PAH therapy should be instituted. Pts who have not undergone a vasoreactivity study or nonresponder.. no CCB.. potential severe SE (e.g. hypotension,syncope, and RV failure).

Prostanoids :

Prostanoids Prostacyclin produced pred by endothelial cells.. induces potent vasodilatation of all vascular beds. Most potent endogenous inhib of platelet aggregation & cytoprotective & antiproliferative activities. Dysregulation of the prostacyclin metabolic pathways in PAH.. red of prostacyclin synthase expression in the PA & of prostacyclin urinary metabolites. Stable analogues.. different pharmacokinetic properties but share qualitatively similar pharmacodynamic effects.


Epoprostenol Synthetic prostacyclin.. short half-life (3–5 min).. stable at room temperature for only 8 h. Administered continuously by infusion pump & a permanent tunnelled catheter. Efficacy of continuous i.v. admin tested in three unblinded RCTs in pts with IPAH and in those with PAH associated with the scleroderma spectrum of diseases. Improves symptoms, exercise capacity, haemodynamics in both clinical conditions, & is the only treatment shown to improve survival in IPAH in a randomized study. Long-term persistence of efficacy in IPAH, as well as in other APAH conditions & and in non operable CTEPH.

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Adverse effects 2˚ delivery system Pump malfunction Catheter related infections Thrombosis Drug-induced side effects Flushing, headache, jaw pain, diarrhea, nausea, myalgias, arthralgias Thrombocytopenia

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Tolerance Cost Outpatient cost up to $100,000 per year Abrupt interruption.. Avoided.. a rebound PH with symptomatic deterioration & even death.

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IV epoprostenol (flolan)


Iloprost Chemically stable prostacyclin analogue available for i.v., oral, & aerosol administration. Selective pulmonary vasodilator Vasodilatory potency similar to PGI 2 Exerts preferential vasodilation in well- ventilated lung regions Longer duration of vasodilation than PGI 2 (30-90 vs 15 min)

Inhalational Iloprost (AIR) Olschewski et al, NEJM 2002, 347:322-9:

Inhalational Iloprost (AIR) Olschewski et al, NEJM 2002, 347:322-9 Inhaled Placebo 2.5 or 5.0 ug (6 or 9 x/d, median 30ug/d) Inhaled Iloprost 12 weeks Baseline 1 o End-point 10% 6-min walk & improved NYHA Class w/o clinical deterioration or death N=203 NYHA III or IV PAH, CTPH ILOPROST Results : Primary endpoint met (17% vs 5%;p=0.007) 6-min walk distance improved (36 m, p=0.004) NYHA class improved (p=0.03) Dyspnea improved (p=0.015) Minimal improvement in cardiopulmonary hemodynamics

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A second RCT (STEP) on 60 pts already treated with bosentan has shown inc in exercise capacity (P ,0.051) in the subjects randomized to the addition of inhaled iloprost in comparison with placebo. Overall, inhaled iloprost was well tolerated, with flushing and jaw pain being the most frequent SE. Oral iloprost have not been assessed in PAH.

Ventavis® (iloprost) Inhalation Solution: Dosage and Administration:

Ventavis ® (iloprost) Inhalation Solution : Dosage and Administration 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


Treprostinil Admin by the i.v. as well as the s.c. route. Admin by pump and a small s/c catheter. Effects studied in the RCT.. showed improvements in exercise capacity, haemodynamics, and symptoms.8 Greatest exercise improvement pts who were more compromised at baseline & in subjects who could tolerate the upper quartile dose (13.8 ng/kg/min). Infusion site pain was the MC AE of treprostinil, discontinuation in 8% of cases

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Optimal dose varies b/w individual pts, ranging in the majority b/w 20 & 80 ng/kg/min. Effects comparable with those of epoprostenol but at a dose which is b/w two & three times higher, however More convenient for the pt because the reservoir can be changed every 48 h as compared with 12 h with epoprostenol.

Subcutaneous Treprostinil (Remodulin ):

Subcutaneous Treprostinil (Remodulin  ) SQ administration Longer half-life than epoprostenol Pre-mixed Stable at room temperature

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A phase III RCT (TRIUMPH) of inhaled treprostinil in pts on background therapy with either the ERA bosentan or the PDE-5 inhibitor sildenafil was recently completed.. improvements in exercise capacity. Oral treprostinil is currently being evaluated in RCTs in PAH


Beraprost. First chemically stable and orally active prostacyclin analogue. The RCT ALPHABET in Europe and a second in the USA.. improvement in exercise capacity that unfortunately persists only up to 3–6 months. No haemodynamic benefits. The most frequent AEs were headache, flushing, jaw pain, and diarrhoea.

Endothelin receptor antagonists :

Endothelin receptor antagonists Activation of the endothelin system has been demonstrated in both plasma and lung tissue of PAH patients. ET-1 exerts vasoconstrictor and mitogenic.. ET-A and ET-B receptors. ET-B receptors in endothelial cells.. Activation..release of vasodilators & antiproliferative substances such as NO and prostacyclin .. Counterbalance ET-1. Efficacy in PAH of the dual ET-A & B receptor antagonist drugs & of the selective ERA compounds appears to be comparable.

Endothelin is increased in IPAH and PAH associated with other Diseases :

Endothelin is increased in IPAH and PAH associated with other Diseases Stewart et al ., Ann Inter Med ,1991 Vancheeswaran et al ., J. Rheum , 1994 Yoshibayashi et al ., Circulation , 1991 Congenital Heart Disease Non-PH PH 0 1 2 3 4 5 P<0.001 Delta ET-LI (PV-RV) (pg/ml) IPAH IrET-1 (pg/ml) Non-PPH PPH 0 2 4 6 8 10 Scleroderma Concentration of ET-1(pg/ml) 4 6 8 10 LcSSc PAH LcSSc Non-PAH P<0.05 P<0.001

Endothelin is a Key Pathogenic Mediator*:

Endothelin is a Key Pathogenic Mediator* Clozel. Ann Med. 2003 * Based on observations reported from in-vitro, in-vivo, or animal models. The clinical significance in humans is unknown. Proliferation Vascular Smooth Muscle Fibroblasts Fibrosis Fibroblast Proliferation  Extracellular Matrix Proteins  Collagenase Production Inflammation  Vascular Permeability Neutrophil / Mast Cell Activation Promotes Cellular Adhesion  Cytokine Production Hypertrophy Cardiac/Vascular Vasoconstriction Direct Or Via Facilitation Of Other Vasoconstrictor Systems ( Renin Angiotensin System , Sympathetic) ET

BREATHE-1: 6-Minute Walk Test Change From Baseline at Week 16:

62.5 mg bid 125 or 250 mg bid -40 -20 0 20 40 60 Bosentan (n = 144) Placebo (n = 69) Baseline Week 4 Week 8 Week 16 P = 0.0002  Walk Distance (meters) Mean ± SEM BREATHE-1: 6-Minute Walk Test Change From Baseline at Week 16 Rubin L et al. NEJM 2002


Bosentan Oral active dual endothelin-A and endothelin-B receptor antagonist and the first molecule of its class that was synthesized. Evaluated in PAH (idiopathic, associated with CTD, and Eisenmenger’s syndrome)in five RCTs (Pilot, BREATHE-1, BREATHE-2, BREATHE-5, and EARLY).. improvement in exercise capacity, functional class, haemodynamics, echocardiographic and Doppler variables, and time to clinical worsening.

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Two RCTs have enrolled exclusively patients with WHO-FC II or pts with Eisenmenger’s syndrome. Resulted in.. regulatory authority approval for the use of bosentan in the treatment of PAH patients in WHO-FC II and also in patients with PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s syndrome. Started at the dose of 62.5 mg twice daily & uptitrated to 125 mg twice daily after 4 weeks.

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Inc in hepatic aminotransferases occurred in 10%of the subjects.. found to be dose dependent & reversible after dose reduction/discontinuation. ..LFT should be performed monthly. Reductions on HB levels and impaired spermatogenesis have also been observed.

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Event-Free (%) Time (weeks) 0 25 50 75 100 0 4 8 12 16 20 24 28 p = 0.0015 p = 0.0038 89% 63% Bosentan (n = 144) Placebo (n = 69) Bosentan (n = 35) Placebo (n = 13) BREATHE-1: Time to Clinical Worsening* 95% 75% * Time to clinical worsening = Shortest time to either death, premature withdrawal or hospitalization due to PHT worsening, or initiation of epoprostenol therapy

Recommended Laboratory Monitoring with Bosentan:

Recommended Laboratory Monitoring with Bosentan  Liver function testing Prior to initiation of treatment Monthly  Hemoglobin Prior to initiation of treatment After 1 month, then every 3 months  HCG Prior to initiation of treatment Monthly


Sitaxentan Selective orally active ET-A receptor antagonist, has been assessed in two RCTs (STRIDE 1 and 2) on pts with WHO-FC II & III PAH. Aetiology included IPAH & PAH associated with CTDs or CHD. The studies demonstrated improvements in exercise capacity & haemodynamics. A 1-year, open-label observational study has demonstrated the durability of the effects of sitaxentan over time.

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The incidence of abn LFT 3–5% for the approved dose of 100 mg once daily. Monthly checking of liver function tests is required. Sitaxentan interacts with warfarin, & co-administration requires dose reductions of warfarin to avoid increases of INR.


Ambrisentan Selective for the ET-A receptor. Evaluated in a pilot study & in two large RCTs ( ARIES 1 and 2 ), which have demonstrated efficacy on symptoms, exercise capacity, haemodynamics, and time to clinical worsening of patients with IPAH and PAH associated with CTD & HIV infection. Durability of the effects of ambrisentan for at least 1 year. Approved for the treatment of WHO-FC II and III patients. Dose 5 mg OD which can be inc to 10 mg OD

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Abn LFTs ranges from 0.8 to 3%. Pts in which treatment with either bosentan or sitaxentan was discontinued due to LFT abn, ambrisentan 5 mg was well tolerated. Nevertheless, pts treated with ambrisentan require monthly liver function test assessment. An increased incidence of peripheral oedema has been reported with ambrisentan use.

Phosphodiesterase type-5 inhibitors :

Phosphodiesterase type-5 inhibitors Inh of cGMP-degrading enzyme PDE-5 results in vasodilatation through the NO/cGMP pathway at sites expressing this enzyme. Pulmonary vasculature contains substantial amounts of PDE-5 Exert antiproliferative effects. All three approved for the treatment of erectile dysfunction, sildenafil, tadalafil, and vardenafil, cause significant pulmonary vasodilation, with maximum effects observed after 60, 75–90, and 40–45 min, respectively.


Sildenafil Orally active, potent, and selective inhibitor of PDE-5. A number of uncontrolled studies have reported favourable effects of sildenafil in IPAH, PAH associated with CTD, CHD, & CTEPH. An RCT (SUPER-1) on 278 PAH patients treated with sildenafil 20, 40, or 80 mg t.i.d. has confirmed favourable results on exercise capacity, symptoms, and haemodynamics. A post hoc analysis of 84 PAH associated with CTD pts in the SUPER-1 trial.. improved exercise capacity, haemodynamic parameters, and functional class at 12 weeks vs placebo.

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The approved dose is 20 mg t.i.d., but the durability of effect up to a year has been demonstrated only with the dose of 80 mg t.i.d. In clinical practice, up-titration beyond 20 mg t.i.d. (mainly 40–80 mg t.i.d.) is needed quite frequently. The PACES trial addressing the effects of adding sildenafil to epoprostenol SE were mild to moderate and mainly related to vasodilation (headache,flushing, epistaxis).


Tadalafil. Tadalafil is a once-daily dispensed, selective PDE-5 inhibitor, currently approved for the treatment of erectile dysfunction. An RCT (PHIRST) 50% pts on background bosentan therapy treated with tadalafil 5, 10, 20, or 40 mg once daily has shown favourable results on exercise capacity, symptoms, haemodynamics, and time to clinical worsening at the largest dose. The durability of the effect has also been shown. The side effect profile was similar to that of sildenafil.

Experimental compounds and alternative medical strategies :

Experimental compounds and alternative medical strategies Despite the progress on the treatment of PAH, the functional limitation and the survival of these patients remain unsatisfactory. For these reasons, additional therapeutic strategies targeted to diverse pathobiological changes are being explored in order to improve symptoms and prognosis further.

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Phase II and III studies are currently being performed with the following compounds: NO-independent stimulators and activators of cGMP, Inhaled VIP, Non-prostanoid prostacyclin receptor agonists, tissular dual ERA-, Tyrosine kinase inhibitors (platelet-derived growth factor inhibitors), and Serotonin antagonists

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The following additional compounds are in an earlier stage of development: Rho-kinase inhibitors, VEGF receptor inhibitors, Angiopoietin-1 inhibitors, and Elastase inhibitors.

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Gene therapy strategies have been tested in animal models. Stem cell therapy has proven to be effective in the rat model & is currently being tested in proof-of-concept & dose-finding studies in PAH pts.

Combination therapy:

Combination therapy Simultaneous use of more than one PAH-specific class of drugs, e.g. ERAs,PDE-5 inhibitors, prostanoids, and novel substances. ..Standard of care in many PAH centres ?? long-term safety & efficacy. Numerous case series have suggested that various drug combinations appear to be safe and effective.

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STEP-1 study.. safety & efficacy of12 weeks therapy inhaled iloprost + bosentan… marginal inc in the post-inhalation 6 MW distance by 26 m (P ¼ 0.051). No improvement in pre-inhalation haemodynamics in the iloprost gp after 12 weeks of treatment, but time to clinical worsening was significantly prolonged in the iloprost gp (0 events vs. 5 events in the placebo group; P ¼ 0.02). In contrast, another RCT, COMBI.. effects of inhaled iloprost + bosentan, was stopped prematurely…no effect on 6 MW distance or time to clinical worsening.

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Results of a few RCTs evaluating combination therapy for PAH have been published. BREATHE-2 study.. better haemodynamic effect of the initial combination epoprostenol-bosentan which also studied the effects of inhaled iloprost added to bosentan, was stopped prematurely no effect on 6 MW distance or time to clinical worsening. Two other RCTs on combination therapy have been concluded: TRIUMPH and PACES.

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TRIUMPH studied the effects of inhaled treprostinil in patients already treated with bosentan or sildenafil. The primary endpoint, change in 6MWT at peak exposure, improved by 20 m compared with placebo (P,0.0006). At trough exposure, i.e. after 4 h post-inhalation,the difference was 14 m in favour of the treprostinil group (P,0.01). There were no significant differences in Borg dyspnoea index, functional class, and time to clinical worsening.

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The PACES trial addressed the effects of adding sildenafil to epoprostenol in 267 PAH patients. The most pertinent findings of this study were significant improvements after 12 weeks in 6MWT and time to clinical worsening. Of note, seven deaths occurred in this trial, all in the placebo group. Additional data from RCTs are available for the combination of ERAs and PDE-5 inhibitors. In the subgp of pts enrolled in the EARLY study (bosentan in WHO-FC II PAH patients) who were already on treatment with sildenafil, the haemodynamic effect of the addition of bosentan was comparable with that achieved in patients without background sildenafil treatment.

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A pharmacokinetic interaction has been described between bosentan and sildenafil, which act as inducers or inhibitors of cytochrome P450 CYP3A4, respectively. The co-administration .. decline of sildenafil plasma levels & inc in bosentan plasma levels. So far there is no indication that these interactions are associated with reduced safety, but the issue of whether the clinical efficacy of sildenafil is significantly reduced is still under debate. No pharmacokinetic interactions have been reported between sildenafil and the two other available ERAs, sitaxentan and ambrisentan.

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In the PHIRST study, the combination of tadalafil and bosentan resulted in an improvement of exercise capacity of borderline statistical significance (subgroup analysis). For these two compounds a pharmacokinetic interaction has also been shown (Table 20).

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There are many open questions regarding combination therapy,including the choice of combination agents, the optimal timing [initial combination (in naive patients) or sequential combination (according to the response to the first drug)], when to switch,and when to combine. When combination therapy is considered, patients should be treated within clinical trials or registries whenever possible. Combination therapy of established PAH drugs is recommended for patients not responding adequately to monotherapy, but combination therapy should be instituted by expert centres only.

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Whether the response to monotherapy is sufficient or not can only be decided on an individual basis. This is judged in an individual patient who, despite monotherapy and optimized background treatment, has an inadequate clinical response(Figure 2 and Table 22). The safety and efficacy of tyrosine kinase inhibitors in PAH must be further evaluated and, at present, the use of these drugs should be restricted to RCTs.

Balloon atrial septostomy :

Balloon atrial septostomy Patients with Eisenmenger’s syndrome & patients with IPAH with a PFO.. survival advantage over those without a PFO, supporting the concept of atrial septostomy as a treatment for IPAH. The creation of an inter-atrial right-to-left shunt can decompress the right heart chambers, and inc LV preload & CO. In addition, this improves systemic O2 transport despite arterial O2 desaturation and dec sympathetic hyperactivity. Recommended tech is graded balloon dilation atrial septostomy, which produces equivalent improvements in haemodynamics and symptoms but reduced risk compared with the original blade technique. Other techniquesare considered to be experimental… l pre-procedure risk assessment ensures reduced mortality.

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BAS should be avoided in end stage pts presenting with a baseline mean RAP of >20 mmHg and O2 saturation at rest of <80% on room air. Pts should be on optimal medical therapy, which may include pre-conditioning with i.v. inotropic drugs, prior to considering BAS. Benefit in pts who are in WHO-FC IV with right heart failure refractory to medical therapy or with severe syncopal symptoms. Considered in pts awaiting transplantation or when medical tt is not available.

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Severe IPAH has been the main indication for BAS in adults, although other indications include PAH associated with surgically corrected CHD, CTD, distal CTEPH, PVOD, and pulmonary capillary haemangiomatosis. Evidence shows improvements in CI, decreases in right atrial pressure with improvement in 6MWT. The impact of BAS on long-term survival has not been established in RCTs. Should be regarded as a palliative or bridging procedure to be performed only by centres with experience in the method.

Treatment of arrhythmias:

Treatment of arrhythmias Increasing clinical problem in PAH patients. In contrast to pts with left heart disease, malignant ventricular arrhythmias such as VT, ventricular flutter, & VF are rare in PAH pts. SV tachyarrhythmias occurred with an annual incidence of 2.8%. Atrial flutter & atrial fibrillation equally common.. Clinical deterioration with signs of right heart failure. Restoration of a stable sinus rhythm was associated with a favourable long-term survival

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Although prospective and controlled data are lacking.. maintenance of a stable sinus rhythm considered an imp treatment goal in pts with PAH. Prophylaxis with anti-arrhythmic drugs without negative inotropic effects such as amiodarone to be considered even if specific data regarding its efficacy are lacking

PAH: Randomized Control Trials of Approved Agents:

PAH: Randomized Control Trials of Approved Agents Class of Drug Study/ Drug N Etiol Class* Design PositiveResults Dis-advantages ET-1 Antagonist BREATHE-1 Oral Bosentan / placebo 213 PAH III,IV Double- Blind 16-wk 6 MWD Symptoms Clinical Worsening CPH Hepatic toxicity (11%; transient, reversible) PDE-5 Inhibitor SUPER Sildenafil Citrate (20, 40 or 80 mg tid) 278 IPAH,CT CHD II, III Double-blind, placebo 12 wks 6 MWD CPH Symptoms Headache, flushing, dyspepsia Prostacyclin analogue Inhalational Iloprost / Placebo 203 PH III-IV Double-blind 12-week Composite Endpoint 6 MWD, sx Administration 6 to 9 times daily Prostacyclin analogue SQ Treprostinil / SQ placebo 470 PAH II-IV Double-blind 12-wk 6 MWD Symptoms CPH Pain, erythema at infusion site Side effects Prostacyclin IV Epoprostenol / Conventional Rx 81 PPH III,IV Open- Label 12-wk 6 MWD Symptoms CPH Survival Indwelling central line Pump ( infection,malf ) Side effects


Conclusion Pulmonary arterial hypertension is a progressive disease with significant morbidity and mortality Right heart failure is an important development which clearly prognosticates and marks disease progression Treatment of right heart failure is essential Therapies with proven benefit in transpulmonary hemodynamics, functional class and exercise tolerance include ET-1 receptor antagonism (bosentan), prostanoids, and oral sildenafil. Continuous IV Flolan is reserved for advanced (class IV) disease where there is a proven survival benefit

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