Recent Treatment of Pulmonary Artery Hypertension. Cardiology Division Yonsei University College of Medicine

Transcription

1 Recent Treatment of Pulmonary Artery Hypertension Cardiology Division Yonsei University College of Medicine

2 Definition Raised Pulmonary arterial pressure (PAP) WHO criteria : spap>40 mmhg NIH Criteria : mpap > 25mmHg at rest, Multiple etiologies > 30 mmhg with activity Primary pulmonary hypertension, CTDs (esp. Systemic sclecroderma) Evidence for efficacy of treatment and novel treatments pharmaceutical benefits scheme approved for above two only

3 WHO classification of pulmonary HTN

4 Pathogenesis and Management

5 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

6 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 symptom Avoid pregnancy

7 PAH : Phamacologic Therapy 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

8 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

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

10 Targets for Therapy in PAH

11 Targets for Therapy in PAH Three pathways are considered targets for therapy : nitric oxide, prostacyclin, and endothelin, The nitric oxide pathway increases SMC levels of cgmp causing vasodilation. Prostacyclin increases the level of camp causing vasodilation and preventing proliferation. Endothelin acts upon two receptors on the smooth muscle cell, ETA and ETB. Through these receptors, endothelin drives pulmonary SMC vasoconstriction and proliferation.

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

13 Endothelin is a Key Pathogenic Mediator Proliferation Vascular Smooth Muscle Fibroblasts Hypertrophy Cardiac/Vascular Fibrosis Fibroblast Proliferation Extracellular Matrix Proteins Collagenase Production ET Vasoconstriction Direct Or Via Facilitation Of Other Vasoconstrictor Systems (Renin Angiotensin System, Sympathetic) Inflammation Vascular Permeability Neutrophil / Mast Cell Activation Promotes Cellular Adhesion Cytokine Production

14 Walk Distance (meters) BREATHE-1 study : 6-Minute Walk Test Change From Baseline at Week Placebo (n = 69) Bosentan (n = 144) P = Baseline Week 4 Week 8 Week mg bid 125 or 250 mg bid Mean ± SEM Rubin L et al. NEJM weeks treatment with Bosentan ( endothelin receptor antagonist) improved 6-minute walk.

15 Event-Free (%) BREATHE-1 study:time to Clinical Worsening % p = % 89% p = % 25 0 Bosentan (n = 144) Placebo (n = 69) Time (weeks) Bosentan (n = 35) Placebo (n = 13) * Time to clinical worsening = Shortest time to either death, premature withdrawal or hospitalization due to PHT worsening, or initiation of epoprostenol therapy 16 weeks treatment with Bosentan ( endothelin receptor antagonist) improved clinical outcomes.

16 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

17 Phosphodiesterase-5 inhibitors (PDE5-I): Sildenafil Outcome Sidenafil improved 6-minute walk & pulmonsry vascular resistance

18 Inhalational Iloprost (Ventavis ) Approved for WHO Class III, IV patients with PAH Properties: Selective pulmonary vasodilator Vasodilatory potency similar to PGI2 Exerts preferential vasodilation in wellventilated lung regions Longer duration of vasodilation than PGI 2 (30-90 vs 15 min)

19 Inhalational Iloprost (AIR) Inhaled Placebo N=203 NYHA III or IV PAH, CTPH 2.5 or 5.0 ug (6 or 9 x/d, median 30ug/d) Inhaled Iloprost Baseline 12 weeks 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 1 o End-point 10% 6-min walk & improved NYHA Class w/o clinical deterioration or death Olschewski et al, NEJM 2002, 347:322-9

20 IV Epoprostenol (Flolan ) Sodium epoprostenol (Flolan): short-lived relatively locally acting vasodilator, t1/2 3-5 minutes. Most potent effect -- cardiac output in PAH Resting heart rate, mean right atrial pressure, and a marked improvement in survival. Abrupt cessation can be fatal. Contraindicated in veno-occlusive disease.

21 IV Epoprostenol (Flolan ) Adverse effects 2 delivery system Pump malfunction Catheter related infections Thrombosis Drug-induced side effects Flushing, headache, jaw pain, diarrhea, nausea, myalgias, arthralgias Thrombocytopenia Tolerance Cost Outpatient cost up to $100,000 per year

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

23 Surgical Therapy Atrial septostomy +/- ECMO Improve LV filling and systemic cardiac output Transplantation - lung / heart-lung Reserved for patients who continue to deteriorate with poor QOL despite aggressive pharmacologic therapy 1 year survival % 5 year survival %

24 Treatment of PAH algorithm