PULMONARY HYPERTENSION UPDATE Dianne L. Zwicke, MD Clinical Associate Professor of Medicine University of Wisconsin School of Medicine and Public Health Milwaukee Clinical Campus Milwaukee, Wisconsin FINANCIAL DISCLOSURE Dianne L. Zwicke, MD Dianne L. Zwicke, MD I have been an investigator and received study grants from the following companies: Glaxo – Welcome Myogen PRE-DIX Lilly * Participated in Advisory Boards *United Therapeutics Encysive *Gilead Bayer *Pfizer Medtronic Co Therix Ikaria Actileon Novartis GENO PULMONARY HYPERTENSION Vascular (PAH) Non-Vascular Mixed Idiopathic COPD Congenital Collagen Vascular OSA ? COPD Sickle Cell ILD ? ILD HIV PE ? PE Hepatopulmonary Restrictive Clinical Classification: Where Is the Lesion? VC RA RV PA PC PV LA LV Ao ALK-1, activin receptor-like kinase 1; Ao, aorta; BMPR2, bone morphogenetic receptor type 2; HHT, hereditary hemorrhagic telangiectasia; HIV, human immunodeficiency virus; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PC, pulmonary capillary bed; PV, pulmonary vein; RA, right atrium; RV, right ventricle; VC, vena cava. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54. Graphic adapted from http://cme.medscape.com/viewarticle/530730. PULMONARY ARTERIAL HYPERTENSION ►Mean PA pressure > 24 mmHg ►PCWP < 15mmHg ►PVR > 2.5 / 3.0 PATHOLOGIC CHANGES Vascular PH ► Smooth muscle hypertrophy ► Intimal hyperplasia ► In situ thrombosis ► Arteritis ► Plexogenic lesion PULMONARY HYPERTENSION Severity by Mean PAP 26-35 Mild 36-45 Moderate 46-55 Severe > 55 Systemic Epidemiology of PAH (WHO Group 1)1 ► Prevalence of PAH in associated conditions: Distribution of PAH in French Registry8 CTDa: 8%-12%2,3 Appetite suppressant CHD: 15%-30%4 >1 Risk factor IPAH HIV PoPH: 2%-6%5,6 HIV: 0.5%7 PoPH CHD FPAH a Systemic sclerosis. CTD CHD, congenital heart disease; CTD, connective tissue disease; FPAH, familial pulmonary arterial hypertension; HIV, human immunodeficiency virus; IPAH, idiopathic pulmonary arterial hypertension; PoPH, portopulmonary hypertension. 1. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54. 2. Hachulla et al. Arthritis Rheum. 2009;60:1831-1839. 3. Mukerjee et al. Ann Rheum Dis. 2003;62:1088-1093. 4. Landzberg. Clin Chest Med. 2007;28:243-253. 5. Hadengue et al. Gastroenterology. 1991;100:520-528. 6. Krowka et al. Hepatology. 2006;44:1502-1510. 7. Sitbon et al. Am J Respir Crit Care Med. 2008;177:108-113. 8. Humbert et al. Am J Respir Crit Care Med. 2006;173:1023-1030. VASCULAR PH EPIDEMIOLOGY ► Idiopathic ► Idiopathic (Necropsy) ► Idiopathic (Familial) ► Connective Tissue ► HIV ► Hepatopulmonary ► Anorexic drug 1/500,000 750/500,000 191/1926 1-100/1000 5/100 5-8/100 12-25/500,000 1-Year Mortality Remains High in FC IV Patients1,2 1-Year mortality (%) 50 N=782 46 <30% on prostanoid 40 29 30 20 10 9 0 II III IV WHO FC FC, functional class; QuERI, Quality Enhancement Research Initiative; WHO, World Health Organization. 1. McLaughlin et al. Am J Respir Crit Care Med. 2009;179:A1043. 2. Mathier et al. Am J Respir Crit Care Med. 2009;179:A2658. PULMONARY HYPERTENSION RIGHT HEART FAILURE SYMPTOMS ► DOE - 2 Years - 70% ► Ascites - 20% ► CP - RV ischemia - 30% ► Peripheral edema - 10% ► Syncope / near syncope – 30% ► Early satiety - 50% ► Fatigue - 90% ► Hoarseness - 10% ► Raynauds phenomonon – 10% PULMONARY HYPERTENSION Diagnostics - Basics ► History & Physical ► Labs- CBC, CMP, TSH, ANA, RF, CRP, ESR, HIV, ANTICARDIOLIPIN AB ► EKG, CXR ► Full PFT’S ► Lung scan ► Echo with contrast / TEE PULMONARY HYPERTENSION Diagnostics - Advanced ► ► ► ► ► HR Chest CT Pulmonary Angiography Sleep study / screen 6 minute walk Cardiac cath with pharmacologic challenge -- LAST STUDY! Hemodynamic Progression of PAH Pre-symptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated CO Symptom Threshold PAP PVR RAP Right Heart Dysfunction Time CO, cardiac output; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure. Vasoactive Mediators Involved In PAH ABNORMALITIES Nitric oxide deficiency Prostacyclin deficiency Endothelin overexpression THERAPIES PDE-5 inhibitors Block the activity of PDE-5, restoring vasodilation through an increase in cGMP1 Prostacyclin Supplement the deficiency in PGI2, resulting in vasodilation and inhibition of platelet aggregation2 ERAs Block the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-13 cGMP, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET-1, endothelin; PDE-5, phosphodiesterase type 5; PGI2, prostacyclin. 1. Humbert et al. J Am Coll Cardiol. 2004;43(suppl S):13S-24S. 2. Humbert et al. N Engl J Med. 2004;351:1425-1436. 3. Galiè et al. Eur Heart J. 2004;25:2243-2278. Overall PAH Therapy Use in Enrolled Population1,2 50 N=782 43 Patients (%) 40 30 28 25 22 20 10 0 PDE-5I ERA Prostanoid Combination ERA, endothelin receptor antagonist; PDE-5I, phosphodiesterase type 5 inhibitor; QuERI, Quality Enhancement Research Initiative. 1. McLaughlin et al. Am J Respir Crit Care Med. 2009;179:A1043. 2. Mathier et al. Am J Respir Crit Care Med. 2009;179:A2658. Has Survival Meaningfully Improved With Modern Therapies? IPAH, HPAH, and anorexigen-associated PAH 100 After 2000 (current therapies) 1992-1999 (only IV PGI2) Before 1992 (no specific Tx) 75 n=269 NS n=260 50 25 n=118 P<0.05, log-rank test 0 0 12 24 36 48 60 Months HPAH, hereditary pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; NS, not significant; PGI2, prostacyclin; Tx, treatment. Sitbon et al. Slides presented at European Respiratory Society; September 16-18, 2007; Stockholm, Sweden. PULMONARY ARTERIAL HYPERTENSION MEDICAL THERAPIES EPOPROSTINIL (Flolan, Veletri) ► Prostacyclin ► 75% sustained in PVR ► 10% are non responders ► Double lumen catheter ► Requires continuous infusion BOSENTAN (Tracleer) ► ET – 1 antagonist ► Binds ETA – ETB receptors in endothelium and vascular smooth muscle ► P450 pathway (2C9, 3A4) ► 3-5 hour max plasma concentration ► t½ is five hours ► 95% bound to albumin, excreted in bile ► 62.5 – 125 mg bid orally, 1-2 month Rx TREPROSTINIL (Remodulin) ► UT – 15 ► Prostacyclin ► SQ analogue or IV infusion ► Modified insulin pump – SQ INHALED NITRIC OXIDE ► Endothelial derived relaxing factor ► Endogenous mediator for smooth muscle relaxation ► Selective pulmonary vasodilator through cGMP pathway ► Increases oxygenation SILDENAFIL (Revatio) ► PDE – 5 Inhibitor ► Found abundantly in pulmonary vasculature ► Inhibits proliferation ► Potent pulmonary vasodilation ► Increased epistaxis and GI bleed ► Can’t prescribe nitrates ILOPROST (Ventavis) ► Inhaled ► 6-9 prostacyclin derivative treatments/day ► 10-15 ► Mini minutes/treatment Nebulizer AMBRISENTAN (Letairis) ► Endothelin receptor blocker ► WHO group 1-3, WHO class 2 or 3 symptoms ► 5 or 10mg daily, tablet ► IPH, CTD, HIV, diet drugs ► Caution=pregnancy; liver toxicity (Label removed) INHALED EPOPROSTINIL (Flolan) ► 30-80ng ► Special / kg / min delivery system INHALED EPOPROSTENOL AS SOLO OR ADJUNCTIVE THERAPY FOR PULMONARY ARTERY HYPERTENSION Dianne Zwicke MD, Krishna Nagendran MD, Faisal Hayat MD, Theodore Gronski MD, Jonathan Kay MD, Frank Spexarth RPH, Wende Moline NP, Andrea Krause NP, Mori Naoyo PHD University of Wisconsin School of Medicine and Public Health-Milwaukee Clinical Campus Study Data Introduction Pulmonary arterial hypertension (PAH) is a common finding in patients with significant valvular heart disease. Post operative mortality is increased in these patients. Currently, the most commonly used drug to rapidly decrease pulmonary artery pressure is nitric oxide. Epoprostenol (EPO) is less expensive, less toxic, and easier to administer when compared to inhaled nitric oxide. Inhaled EPO may be an alternative to IV EPO, as it has selective pulmonary vasodilator properties and less systemic side effects. Hache, et al, studied the effect of inhaled EPO compared to a placebo in twenty patients undergoing cardiothoracic surgery and concluded it was safe. In our study, we treated patients with increased pulmonary artery pressure, undergoing cardiothoracic surgery, with inhaled EPO to determine efficacy. Methods The selected study population was patients undergoing cardiothoracic surgery, at St Lukes Medical Center, in Milwaukee, Wisconsin, between July 2008 and April 2009. Anesthesiologists prospectively initiated inhaled EPO therapy, using the AccuNeb, on the vasodilated and fully anesthetized patients, with a measured PA systolic pressure greater than 60mmHg by Swan-Ganz catheter. We collected data by chart review of the identified study population. Pulmonary artery pressure and cardiac index were compared using two sample paired t-test, respectively (two-tailed). Results Of all patients, seventy two (82.8%) underwent valve surgeries, seven (8.1%) had LVAD’s, and two (2.3%) had heart transplants. Inhaled EPO was used as adjuvant therapy in 6 (6.7%) medical patients. No adverse effects from this therapy was observed. Hemodynamic parameters are statistically significant. Population demographics are presented in the table. Number of Patients SET UP n=87 Average age 67 sex M= 54 , F= 33 ( Range 31-88 ) Heart Failure (EF < 40) 51 Average days on Ventilator 5 (58.6%) Valve Disorders Mitral Regurgitation (Total ) 54 Severe / Moderate / Mild 27 / 17 /10 Tricuspid Regurgitation (Total) 30 Severe / Moderate /Mild 17 / 9 / 4 Aortic Stenosis 14 (Total) Severe / Moderate 12 / 2 Aortic Regurgitation 10 Figure 2. Sulfur granule with surrounding lymphocytic infiltrate Surgeries Mitral valve Replacement 16 Mitral Valve Repair 28 Aortic Valve Replacement 21 Cardiac Index (Pre) (n=52) 2.12 +/- 0.5 Cardiac Index (Post) PAP pre-op (Mean) 2.92 +/- 0.7 (p<0.001) (n=56) 39 +/- 0.52 PAP Post-op (Mean) 25.1 +/- 0.5 (p<0.001) Average cost inhaled EPO $19/hour Average cost inhaled NO $132/hour Conclusion Inhaled Epoprostenol demonstrated excellent clinical and hemodynamic results and was well tolerated in this critically ill subgroup of patients. It was a cost effective alternative to inhaled nitric oxide with a net savings more than $875,000 . CLINICAL IMPLICATION Based on this preliminary subset population analysis, inhaled epoprostenol may be efficacious in wider clinical settings for patients with pulmonary artery hypertension. It is more cost effective. Further studies are warranted to guide therapy in other clinical subsets of patients. TREPROSTINIL (Tyvaso) ► Prostaglandin ► 2-12 – inhaled. breaths / treatment qid ► Same side effects as any Prostaglandin during titration TADALAFIL (Adcirca) ► PDE-5 inhibitor ► 20-40mg ► 36 daily po hour ½ life ► Avoid with Rifampin and Antifungals PERCUTANEOUS INTERVENTION IN PULMONARY HYPERTENSION ► Coil Closure of PDA ► ASD Closure ► VSD Closure ► Atrial Septostomy SURGICAL PROCEDURES IN PULMONARY HYPERTENSION ► ASD / VSD Closure ► Mitral Valve Repair / Replacement ► Anomolous Pulmonary Venous Return ► Pulmonary Thrombo-Endarterectomy ► Open Lung Biopsy ► Pericardial Window / Drainage CURRENT CLINICAL TRIALS - Oral Remodulin - (United Therapeutics) - Selexipag - (Actileon) - Combo Study vs single drug - Adcirca +/-Letairis (United Therapeutics / Gilead) - Riociguat with LV Failure and PHTN - (Bayer) - Tyvaso Registry - (United Therapeutics) - Implantable pump / continuous infusion Remodulin - (Medtronics) - Inhaled nitric oxide - (GENO) - Inhaled Nitric Oxide via Ambulatory Device (Ikaria) - Taladafil with LV Failure and PHTN (NIH) - Oral Beraprost (LungRx) ▪ Prostacyclins ▪ Nitric Oxide ▪ PD’s ▪ ERA ▪ Combo CASES 48 y/o female PAH / ICM ► CREST syndrome x 6 years ► Anterior wall MI → LVEF 15-20% ► PAH – RA-18, RV-86/22, PA-88/22 (55), W-16, CI-1.8, PA-Sat 48%, Ao-92%, PVR-12.18 WU ► IV Remodulin titrated to 100ng/kg/min ► Ambrisentan ► Digoxin 5→10mg po daily 0.25mg daily 48 y/o female PAH / ICM – (continued) ► Lasix 40mg daily ► K/Mg replacement ► Lisinopril 20mg daily / DC Coreg ► More Aggressive immunosuppression ___________________________________________ * LVAD – Heartmate II for 6-7 months * Successfully transplanted (heart) * Weaned off Remodulin 42 y/o male - Hep C ETOH Liver Dz ► Massive ► Normal ascites, LE edema, severe RH failure LV, no significant valve disease ► Right Heart Cath…. Hepatic wedge - 18 RA – 18 RV – 19 / 22 PA – 92 / 25 (54) CI – 1.9 PVR – 9 WU 42 y/o male - Hep C ETOH Liver Dz (continued) IV Lasix, Dobutamine, Flolan ► Digoxin 0.25mg daily, K/Mg replacement ► Flolan changed to Veletri for home infusion ► Revatio 20mg tid added ________________________________________________ ► Liver transplant after PVR ↓ to 5 WU, CI >2.8 ► ECHO = marked improvement of RVEF ________________________________________________ ► * 3 months after transplant – weaned off IV Veletri * 9 months after transplant – weaned from Revatio * Stable 1 year after cessation of all PAH drugs 69 y/o old female - HCM ► NYHA 3, 3+ edema to mid thighs, + ascites ► Severe DOE and muscle wasting ► ECHO – mild RVH, mod LVH, RVSP 55, LVEF 65% ► PHTN work up – negative ► Cath – RA-18, RV-58/19, PA-55/22, CI-2.8, W-20, PA-Sat 55%, PVR3.2 WU, ► Treatment – IV Lasix → CVVH ________________________________________________________________ * Home on peritoneal dialysis x 9 months * Evaluate for transplant – status 7 PAH – Pulmonary Emboli 56 year old female with PE after Hysterectomy ► Well until 3 years ago, 02 6L NC now ► Denied PTE at another institution ► Reviewed Pulmonary Angiogram ► RHC – RA 8, RV 65/20(35), CI 2.3, Sat-62% ► Coronary Angiogram ► Sent to San Diego Vague Symptoms Major presenting symptoms are syncope, shortness of breath and fatigue Syncope is prodrome to death Correct diagnosis must be established Empiric vasodilator therapy is not recommended Treatment options are frequently available if not seen at end stage