Pulmonary Hypertension: We have come a Long Way

Transcription

1 Pulmonary Hypertension: We have come a Long Way Shelley Shapiro M.D. Ph.D Pulmonary Hypertension Program

2 2 Disclosures Grant Support Gilead, United Therapeutics, Actelion, GeNO, Medtonics, Bellerphon, Reata

3 Sometimes it is a zebra: 3

4 4 Objectives 1. To understand the difference between pulmonary hypertension and pulmonary arterial hypertension 2. To understand the causes of PH and how we differentiate them 3. To become acquainted with the range of treatment options and drugs now available for patients with Pulmonary arterial hypertension 4. Pregnancy in women with PAH 5. A few words about Nitric Oxide

5 PAH: Clinical Definition **Mean pulmonary arterial pressure (mpap) mpap >25 mm Hg at rest, Often suspected when echo estimates elevated pulmonary systolic pressure Associated with adverse changes in the pulmonary vasculature (vasculopathy), and at the level of the right ventricle (hypertrophy) PAH is an active proliferative process within the pulmonary arteries Gaine et al. The Lancet,

6 Pulmonary Hypertension Pulmonary hypertension Hemodynamic finding PAP above normal Causes Pulmonary venous congestion, back-up of blood from LV Hypoxia causing pulmonary vasoconstriction Obstruction clots, tumor Arteriopathy diseased pulmonary arteries PH vs. PAH 6

7 7 PH: The Importance of Hemodynamics Pulmonary venous hypertension Elevated PCWP, normal PVR (post-capillary) VC RA RV PA PV PC LA LV Ao PAH Pre-capillary PH with respiratory disease CTEPH Normal PCWP, elevated PVR Other: High CO

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9 Is There a Reason to Suspect PAH? Clinical Presentation Common Initial Symptoms (N=187) Patients (%) Dyspnea 60 Fatigue 19 Syncope or near syncope 13 Chest pain 7 Palpitations 5 Leg edema 3 McGoon M et al for the American College of Chest Physicians. Chest. 2004;126:14S-34S. Rich S et al. Ann Intern Med. 1987;107:

10 Why Treat pulmonary Hypertension? 10

11 REVEAL: Observed 1-year Survival From Time of Enrollment According to Predicted Risk Strata 100 Survival (%) No. at risk: Low Average Mod. high High Very high Risk strata Low Average Moderately high High Very high Months from enrollment Benza RL et al. Circulation. 2010;122:

12 12 Survival from Dx By 6MWD 71.1% 62.5% 41.5% p<.001

13 Plasma BNP as a Prognostic Indicator in Patients With IPAH Survival rate (%) Follow-up BNP BNP <180 pg/ml p BNP 180 pg/ml p Time (mo) By multivariate analysis, higher BNP at follow-up (RR=25.880, p=0.0243) was an independent predictor of mortality. Nagaya N et al. Circulation. 2000;102:

14 Lung/Respiratory Diseases Associated With PH Silicosis Interstitial Lung Disease Emphysema Lymphangioleiomyomatosis 14

15 PH as a Predictor of Survival in Patients With IPF 1.0 Cumulative probability of survival PH N=79 No difference in lung volumes Lower 6-minute walk distance No PH (mpap <25 mm Hg) p<0.001 Lettieri CJ et al. Chest. 2006;129: Days to event 15

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17 ACCF/AHA Diagnostic Algorithm Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam CXR ECG Echocardiogram VQ Scan PFT s Overnight Oximetry HIV ANA LFT s TEE Exercise Echo Pulmonary Angiography Chest CT Angiogram Coagulopathy Profile ABG s Polysomnography Other CTD Serologies Index of Suspicion of PH RVE, RAE, RVSP, RV Function Left Heart Disease VHD, CHD Chronic PE Ventilatory Function Gas Exchange Sleep Disorder HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) Establish Baseline Prognosis RH Cath McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Confirmation of PH Hemodynamic Profile Vasodilator Response 17

18 18 Signs Indicative of PH on ECHO the gateway to the diagnosis Increased RVSP or TR jet Right atrial enlargement & ventricular hypertrophy Flattening of intraventricular septum Small LV dimension Dilated PA RV RA IVS LV LA

19 Measuring TR jet 19

20 20 Cardiac Catheterization The Gold Standard and key to having the correct diagnosis is a right heart catheterization measuring the pressures, saturations and cardiac output

21 What we measure at catheterization and why 1. PA pressures to make the diagnosis 2. RA pressure to assess right sided heart failure and prognosis 3. Wedge pressure and /or LVEDP ***** the key to determine role of LV 4. Cardiac output: prognosis and severity 5. Oxygen saturations to look for shunts 6. Vasoreactivity Has prognostic value- in its absence, no calcium channel blockers!!!!!! 21

22 Algorithm for Assessment of Vasoreactivity in Patients with PH 22 Right Heart Catheterization With Acute Vasoreactivity Testing (ino, prostacyclin, adenosine) Non-responder Responder No Calcium Channel Blockers NONE, NADA!!!!!!!!!!!!!!!!!!!!!! Hemodynamic-monitored Trial of Calcium Channel Blocker Therapy

23 23 Gradients for determining pre vs post capillary PH Trans-pulmonary Gradient: Mean PAP PAWP (can be fooled if Pas is high Diastolic Pulmonary Gradient: PAPd PAWP or LVEDP Abnormal above 5, prognostic 7

24 24 Proposal NICE Combined PCW > 15, DPG 7 2. Isolated Postcapillary PH, PCW > 15, DPG <7

25 Pulmonary Venous Hypertension: A Simplified View- Disproportionate PH (sometimes we have both!) Normal, or mildly elevated trans-pulmonary gradient with readily apparent cause treat underlying cause- left sided disease Substantially elevated trans-pulmonary or diastolic gradient in setting of elevated LVEDP or PCW (PH out of proportion to LHD) Treat left sided pressures aggressively If PA pressures remain elevated and symptoms persist- then treat with PH specific meds? 25

26 Revised Clinical Classification of PH: 2008 Dana Point Who to Treat with PH MEDS I. PAH (IPAH, FPAH, APAH) Treat II. III. IV. Pulmonary hypertension with left heart disease Don t Treat with PH specific medication Pulmonary hypertension associated with lung diseases and/or hypoxemia Under investigation Pulmonary hypertension due to chronic thrombotic and/or embolic disease Treat V. Miscellaneous Treat some- limited data Pub. 26

27 27 Therapy - Standard Care Should START FIRST and should continue! Digoxin Diuretics- for RHF Oxygen if hypoxemic Anticoagulation

28 Less liver congestion and dyspnea and better oxygenation 28 Right Heart Failure Treatment The Most Important!!!! Increase myocardial contractility- digoxin Reduce afterload on RV Reduce volume load- this is key to RV decompensation- DRY IS GOOD!!!!! Lower volume = less wall stress, less TR and less compression of the LV

29 ACC/AHA Guidelines: PAH Determinants of Risk LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>400 m) 6MWD Shorter (<300 m) Peak VO 2 >10.4 ml/kg/min CPET Peak VO 2 <10.4 ml/kg/min Minimal RV dysfunction RAP <10 mm Hg; CI >2.5 L/min/m 2 Echocardiography Hemodynamics Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >20 mm Hg; CI <2.0 L/min/m 2 Minimally elevated BNP Significantly elevated McLaughlin VV et al. JACC. 2009;53:

30 30 Treatments for PAH In 1994 there were none! Now we have many more drugs and devices Other interventions: transplant, bridges to transplant ecmo or vads Being studied: Implantable remodulin pumps, ambulatory nitric oxide DON T GIVE UP Keeping searching for options- referral to expert centers!

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32 Nitric Oxide Pathway: PDE5-I Competitively Inhibits PDE5 Soluble Guanylate Cycle Activated by Riociguat Endothelial cell NO + Riociguat PAP, PVR GTP guanylate cyclase relaxation cgmp Ca 2+ GMP PDE5 - Sildenafil & Tadalafil 32

33 Endothelin Receptor Agonists (ERA s) Indications: WHO Group I PAH Functional Class (FC) II-IV FDA approved ERA s Bosentan (Tracleer) WE DO NOT USE much because of liver issues Ambrisentan (Letaris) Macitentin (Opsumit) newer Mechanism of Action (MoA): Causes vasodilation by blocking endothelin receptors on vascular endothelium and smooth muscle. Antiproliferative and antiinflammatory 33

34 Edema is a Problem with all ERAs and limits therapy Edema and fluid retention are often observed in patients with PAH Edema may develop due to various causes Edema has been observed in nearly all clinical trials of endothelin receptor antagonists (ERAs) Class effect In limited studies these agents don t work in LUNG DISEASE- COPD, ILD DON T USE WHO GROUP 3 Shapiro S, et al., CHEST 2008; Session #

35 Prostacyclins camp mediated Difficult to use but prostacyclins are the gold standard: Epoprostenol showed survival benefit Pumps with inherent problems of malfunction and infection Existing- IV, subcut treprotinil- Remodulin, IV epoprostenolol, Inhaled Ilaprost (VENTAVIS), inhaled Remodulin (TYVASO) Oral prostacyclins and analogs: Orenitram Selexipag Experimental: Implantable pump 35

36 36 Prostacyclin Therapy 1. Parenteral therapy gives consistent levels of medication and is titrated up over time 2. Subcutaneous treprostinil is well absorbed but site pain and inflammation are problems limiting therapy 3. IV has problems with indwelling catheter and infection. Difficult for elderly patients or those with limited support systems 4. Very expensive, cannot be used in SNF or Hospice because of costs- end of life issues 5. Can dramatically improve pts clinical status!!!

37 37 Tyvaso- Inhaled Remodulin Battery-operated (rechargeable) Medication put in pump And used 4 times during the day

38 38 Oral Prostacyclins 1. Just because it s a pill doesn t mean its easy to use of inexpensive 2. Need expertise and nursing support to handle the side effects and titration 3. Not as effective as parenteral agent and perhaps inhaled agents

39 Oral Prostacyclin Analogs There is no free lunch! Selexipag (UPTRAVI) Prostanoid receptor agonist- Now approved but with significant side effects and need to titrate slowly Oral treprostinil (ORENITRAM) Now approved but side effects make it extremely difficult to use and quite expensive in high dose These medications are not as effective as parenteral prostacyclins And are harder to use 39

40 ACCF/AHA Consensus PAH Treatment Algorithm START : Anticoagulate ± Diuretics ± Oxygen ± Digoxin Oral CCB Positive Lower Risk CATH: With Acute Vasoreactivity Testing Negative Higher Risk Sustained Response No ERAs or PDE-5 Is (oral) Epoprostenol or Treprostinil (IV) Iloprost (inhaled) Treprostinil (SC) Epoprostenol or Treprostinil (IV) Iloprost (inhaled) ERAs or PDE-5 Is (oral) Treprostinil (SC) Yes Continue CCB Reassess consider combo-therapy Investigational Protocols McLaughlin VV et al. JACC. 2009;53: Atrial septostomy Lung transplant 40

41 Multi Drug Therapy The norm for treatment- 2/3 of patients in Reveal registry on multi-drug therapy Ambition study looked at Tadalafil and Ambrisentan and compared 2 drugs vs either alone. The results were clear: 2 drug up-front upfront better than either alone and moved us forward to multi-drug therapy. Improvement with second and 3 rd drug are smaller. Expenses wrack up Endpoints for studies (including composites endpoints are problems) in terms of new drug development and treatment strategies Goal directed care- defining goals 41

42 42 Search for the Best Therapy! Multi-Drug therapy First Prostacyclins first! PDE 5 Inhibitors First Endothelin Receptor Blockers First

43 43 How do you pick agents? Cost- range: 10k-150k per year per drug Easy of use: Pill vs Pump, need to monitor, pt support systems Side effects: Prostacylins- pain, GI, bone pain, delivery issues with pumps ERAs- fluid retention, PDE5-I Reflux, back pain, headache, erections Efficacy: Opinion with some facts, head to head comparisons are limited Patient Preferences, Insurance Issues: Who wins?

44 44 Role of PH Centers 1. Expertise dealing with diagnosis and treatment options 2. Nursing support for patient management and drug titration 3. Handling insurance issues which are legendary 4. Advanced and Experimental therapies to get to a CURE

45 PREGNANCY and PAH 1. Previously an absolute No 2. Still extremely high risk with potentially bad outcomes for mother and child 3. However with aggressive therapy usually with parenteral prostacyclins and PDE5-I pts are being taken through 4. Both mother and fetus are at risk 45

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47 Teaching points 1. The hemodynamic changes in pregnancy are particularly destabilizing in pts with PAH, including volume shifts, hypercoagulability and increased demand 2. To get through a preganacy needs intensive coordinated care, frequent follow-up with multispecialty team (including GYN and neonatal heart failure and PH) 3. Monitoring of ECHO, BNP. Control of volume, hospitalization for any deterioration. Prostacyclin therapy 4. Care at specialized PH Center where ECMO and PH therapy can be managed 5. The postpartum period is particularly treacherous as volume shifts back into the intravascular space 47

48 48 NITRIC OXide Vasodilator and may have affects on vascular proliferation. It is inhaled and very short acting and very safe- can be used in a pinch Can stabilize a very sick PH pt while waiting for diuresis and other drugs to kick in Has been limited to inpatient use but that may change. Currently new ambulatory devices are being testes

49 Nitric Oxide Acute Treatment Indications Acute Decompensation, manifested by hypoxia or low cardiac output, or intractable right heart failure Severely ill patients awaiting therapeutic decisions Used to be able to extubate patient with PH on ventilator or post-op I use when pt is undergoing operative procedure, ie GI surgery or flutter ablation both intra-op and post op but there is no literature to support this 49

50 How to Use NO (inpatient) Via nasal cannula- range 5-40ppm Via ET ventilator- up to 80ppm Check for methemoglobin daily Note $125/hr for 1 st 48 hrs I use it in conjunction with PDE5-I but there is no study to support this! Have escape plan!!!! 50

51 Amazing progress in 20 yrs From no drugs to choices Improvement in function, qol, survival (although direct survival studies limited) Patients are living and most importantly breathing!!! No cure yet and treatments are expensive and are often best handles at PH centers 51

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54 Longitudinal Evaluation of the PAH Patient: ACCF/AHA 2009 Expert Consensus CLINICAL COURSE Frequency of Evaluation STABLE No in symptoms and/or decompensation FC I/II 6MWD >400 m No RH failure RV size/function normal RAP normal; CI normal BNP near normal/stable or Oral therapy Q 3 to 6 mos UNSTABLE in symptoms and/or decompensation FC IV 6MWD <300 m Signs of RH failure RV enlargement/dysfunction RAP high; CI low BNP elevated or IV prostacyclin and/or combination tmt Q 1 to 3 mos FC Assessment Every clinic visit Every clinic visit 6MWT Every clinic visit Every clinic visit Echocardiogram Q 12 mo or center-dependent Q 6 to 12 mo or center-dependent BNP Center-dependent Center-dependent RHC Clinical deterioration and centerdependent Q 6 to 12 mo or clinical deterioration For high-risk patients, consider referral to PH specialty center for advanced therapies, clinical trials, and/or lung transplantation. * F/U frequency for patients in FC III and/or 6MWD m depends on composite of detailed assessments on other clinical and objective characteristics listed. For patients who remain stable on established therapy, follow-up assessments can be performed by referring physician(s) or PH specialty centers. McLaughlin VV et al. JACC. 2009; 53:

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56 Goal-directed Therapy Diagnosis of PAH Vasoreactivity test negative NYHA III or IV Baseline examination and 2-6 monthly re-evaluation to assess treatment goals (6MWD >380 m, peak VO 2 >10.4 ml min -1 kg -1, peak systolic BP >120 mm Hg during exercise Treatment goals not met Treatment goals met N=123. If rx goals not met, patients transitioned to next step of algorithm. First-line treatment bosentan Addition of sildenafil Treatment continued Treatment continued 50% required combination therapy Addition of inhaled iloprost Treatment continued Highly urgent lung transplantation Hoeper MM, et al. Eur Respir J. 2005;26:

57 Goal-directed Therapy: Transplantationand IV Prostanoid-Free Survival Transplantation and IV-prostaglandin-free treatment Subjects at risk, n Months *P=0.002 vs historical controls. 43.2% of patients were provided dual therapy, 16.1% triple therapy, 4.2% IV prostanoid. Hoeper MM. Eur Respir J. 2005;26: Goal-directed treatment Expected survival (IPAH only) was calculated according to the NIH equation. * Historical control Patient population Historical control group 57