Filtering through the Facts: Portopulmonary Hypertension Saturday, September 19, :15 10:05 a.m.

Transcription

1 Filtering through the Facts: Portopulmonary Hypertension Saturday, September 19, :15 10:05 a.m. Joel Wirth, MD Pulmonary & Critical Care Medicine Maine Medical Center, Portland, ME

2 Disclosures Dr. Joel Wirth: Research Funding: Actelion Arena Gilead Reata United Therapeutics This continuing education activity is managed and accredited by Professional Education Services Group in cooperation with the Pulmonary Hypertension Association. Neither PESG, nor PHA, nor any accrediting organization support or endorse any product or service mentioned in the is activity. PESG and PHA staff has no financial interest to disclose. Commercial Support was not received for this activity. 2

3 Learning Objectives At the conclusion of this activity, the participant will be able to: 1. Identify causes for potential complications associated with portopulmonary hypertension (PoPH) 2. Discuss precautions necessary when prescribing PAH medication in patients with PoPH. 3. Discuss strategies to care for PoPH patient in the outpatient setting. 3

4 Overview Portopulmonary hypertension = rare complication of cirrhosis Mortality is higher than predicted by patients MELD* score Severity of PAH is unrelated to the severity or the cause of the liver disease Pathogenesis is unclear: PVR may be chronically increased by pulmonary vasoconstriction, circulating mediators, or shear stress Patients develop classic vascular remodeling with plexiform lesions PAH medications may improve hemodynamics allowing for Liver Transplantation (LT) Excellent outcomes after LT for patients who respond to medical therapy are reported *Model for End-Stage Liver Disease

5 Pulmonary Hypertension Classified I. Pulmonary Arterial Hypertension Idiopathic Hereditary: BMPR2 mutation, ALK-1, other Associated with: Collagen vascular disease Congenital heart disease, HIV, Drugs or toxins, Portal hypertension Chronic hemolytic anemia, Schistosomiasis 1 Pulmonary veno-occlusive disease 1 Pulmonary capillary hemangiomatosis II. Pulmonary venous hypertension Systolic dysfunction, Diastolic dysfunction, Valvular disease III. PH associated with hypoxemia Chronic obstructive pulmonary disease, Interstitial lung disease, Mixed restrictive and obstructive pattern, Sleep-disordered breathing, Alveolar hypoventilation disorders, Chronic exposure to high altitude IV. Chronic thromboembolic PH (CTEPH) V. PH with unclear/multifactorial mechanisms

6 Potential causes of elevated PAP in POPH Safdar, et al., Liver Transplantation :

7 DEFINITION of POPH Liver disease (clinical portal hypertension) MPAP > 25 mm Hg PVR > 240 dyn/sec-cm 5 PCWP < 15 mm Hg

8 GRADING of POPH Safdar, et al., Liver Transplantation :

9 PATHOGENESIS of POPH Affects 6% to 8% of patients with portal hypertension Risk Factors for POPH include: Female sex Autoimmune disease Single-nucleotide polymorphisms in: Estrogen receptor 1 Aromatase Phosphodiesterase 5 (PDE5) Angiopoietin 1 Calcium binding protein A4 Higher levels of circulating Endothelin 1 and Interleukin-6

10 CLINICAL FEATURES of POPH Exertional dyspnea is the usual presenting symptom Loud pulmonic component of 2 nd heart sound in 82% TR systolic murmur in 61% Screening for POPH is necessary in all patients with ESLD undergoing liver transplantation (LT) evaluation Echocardiography is the screening tool of choice Right heart catheterization is required to confirm the diagnosis prior to initiating PAH-specific therapy POPH have higher CO and lower PVR, with similar RAP and mpap compared with Idiopathic PAH

11 NATURAL HISTORY of POPH Mortality relates to: Severity of cirrhosis (Childs Classification) Lower Cardiac Index NYHA FC at diagnosis does not correlate with risk of death In the US (1994 through 2007): 5-year survival rates were: 14% for untreated patients 45% for patients treated with vasodilators 67% for patients undergoing LT In the REVEAL Registry (2012): 5-year survival rate overall was: 40% (versus 64% if Idiopathic PAH)

12 NATURAL HISTORY of POPH Le Pavec et al. Am J Respir Crit Care Med 2008; 178:

13 Survival curves for POPH Patients by the type of treatment (with or without LT) Swanson et al. Am J Transplant 2008;8:

14 MANAGEMENT of POPH Liver Transplantation with severe POPH has a very high mortality rate Most transplant centers consider severe POPH a contraindication to LT LT can be performed safely if the PAH is medically controlled Pulmonary vasodilators are generally effective in the treatment of POPH: Prostanoids Endothelin Receptor Antagonists PDE5 Inhibitors X Beta-Blockers Liver Transplantation Orthotopic Liver Transplantation (OLT) Living Related Donor Liver Transplantation (LDLT)

15 Bandara, et al., Liver Transplantation :

16 Portopulmonary Hypertension: SUMMARY Portopulmonary hypertension = rare complication of PAH associated with cirrhosis/portal hypertension Severity of PAH does not relate to the severity or cause of the underlying liver disease Pathogenesis is still unclear PAH medications may improve hemodynamics which may allow for Liver Transplantation (OLT or LDLT) Excellent outcomes are reported for patients who respond to medical therapy followed by successful OLT or LDLT

17 Filtering Through the Facts: Portopulmonary Hypertension (PoPH) Traci Stewart, RN, MSN, CHFN

18 Disclosures Advisory Board Actelion Bayer This continuing education activity is managed and accredited by Professional Education Services Group in cooperation with the Pulmonary Hypertension Association. Neither PESG, nor PHA, nor any accrediting organization support or endorse any product or service mentioned in this activty. PESG and PHA staff has no financial interest to disclose. Commercial Support was not received for this activity.

19 gray a re a noun grey area; an ill-defined situation or field not readily conforming to a category or to an existing set of rules.

20 PoPH Pulmonary Vasodilators Care Considerations Case Study

21 Child-Pugh Score Originally designed to assess prognosis of patient undergoing surgical treatment of portal hypertension Scoring parameters Bilirubin: <2, 2-3, >3 Albumin: >3.5, , <2.8 INR: >1.7, , >2.2 Ascites: None, present medically controlled, present poorly controlled Encephalopathy: None, present medically controlled, present poorly controlled Score: A (5-6 points), B (7-9 points) or C (10-15 points) Score is a marker of multiorgan changes from cirrhosis

22 MELD Model for end stage liver disease Originally developed to predict 3 mo mortality for TIPS. Validated to predict 3 mo survival Used to prioritize transplant Higher score associated with lower survival Score parameters: Age, cr, bili, INR, dialysis Up to date. 2015

23 Medication Considerations: Phosphodiesterase 5-Inhibitors Sildenafil Hepatic impairment dose adjustment Mild-to-moderate: None Severe: Not studied Tadalafil Hepatic impairment dose adjustment: Mild-to-moderate: Start with 20 mg Severe: Do not use Sildenafil full prescribing information Tadalafil full prescribing information

24 Medication Considerations: Riociguat Use in Specific Populations: Hepatic impairment: Not recommended in patients with severe (Child Pugh C) hepatic impairment. Riociguat Full Prescribing Information. 2014

25 Medication Considerations: Endothelin Receptor Antagonists Bosentan: Warnings and Precautions: Avoid in mod-severe impairment; avoid initiation if elevated aminotransferases (> 3 ULN) Ambrisentan: Use in special populations: Macitentan: Not recommended in patients with moderate or severe hepatic impairment Warnings and Precautions: Other ERAs cause hepatotoxicity and liver failure. Obtain baseline liver enzymes and monitor as clinically indicated Ambrisentan full prescribing information Bosentan full prescribing information Macitentan full prescribing information

26 Oral Treprostinil Contraindications: Severe hepatic impairment (Child Pugh Class C). There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients Hepatic Impairment: In subjects with mild (n=8) hepatic impairment, administration of a single 1 mg dose of Orenitram resulted in a mean Cmax and an AUC0-inf that were 1.6- and 2.1- fold, respectively values seen in healthy subjects. With moderate impairment (n=8), the corresponding ratios were 4.0- and 4.8-fold, and with severe impairment (n=6), they were 4.8- and 7.6-fold Orenitram Full Prescribing Information. 2014

27 Treprostinil Inhaled Warnings and Precautions: Hepatic or renal insufficiency may increase exposure and decrease tolerability. Infused Plasma clearance of treprostinil is reduced in patients with hepatic insufficiency. Patients with hepatic insufficiency may therefore be at increased risk of dose-dependent adverse reactions because of an increase in systemic exposure Special Populations: Remodulin clearance is reduced in patients with hepatic insufficiency. In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to ng/kg/min ideal body weight, and monitor closely. Remodulin has not been studied in patients with severe hepatic insufficiency. Tyvaso Full Prescribing Information Remodulin Full Prescribing Information

28 Epoprostenol Most studied in PoPH Small open label studies Focusing on safety Lack of survival data Consider when liver transplant is necessary to lower mpap Hoeper M, Krowka M, Stassburg C. Lancet. 2004: 363:1461.

29 Special Populations At risk for misdiagnosis Late diagnosis Screening is essential Poor survival

30 Care Considerations Treat underlying liver condition when possible Alcohol abstinence Treat hepatitis Avoid beta blockers/ace-i/arbs Propanolol may prevent variceal hemorrhage, may worsen survival Avoid NSAIDS

31 Care Considerations Fluid retention/ascites Limit sodium 2000mg per day Fluid restrict if hyponatremic <120 Dietician Spironolactone and lasix daily and titrate to response Avoid NSAIDS Monitor electrolytes, BUN, cr! Paracentesis, give albumin for large volume

32 Care Considerations Risk for: Hypotension Spontaneous bacterial peritonitis Bleeding Umbilical hernias Hepatorenal syndrome

33 Care Considerations Confusion Elevated ammonia levels Adherence Complicates infusion therapy

34 Case Study: past history Jack Daniels: 48 yo male Presented in 2010 with pneumonia/septic shock PMH: hep C, liver cirrhosis, recurrent issues with elevated blood ammonia levels and encephalopathy from nonadherence to lactulose Quit drinking five years ago, smoking two years ago, remote marijuana and inhaled substances

35 Case Study: presentation Presents 2011 with chest pain and fluid retention Previously evaluated by liver transplant and didn t require listing due to low MELD score (9) NT-ProBNP 3137 Admitted, diuresed Echo: PASP 87mmHg, normal LA and LV, significantly decreased RV function, enlarged RA, RV (echo in 2010 abnormal)

36 Case Study: evaluation Referred to PH Program, seen 4 days post discharge VS: HR 66, BP 124/66, sat 98% WHO functional class IIIB, dyspnea walking room to room NT-ProBNP 160, Normal TFT, elevated AST/ALT Child Pugh Score B (7-9) 6mw: 213m, no hypoxia PFTs mild obstructive disease Overnight oximetry without desaturations VQ scan negative for PE

37 Case Study: treatment 3/2011 RHC hemodynamics: RA 18; PAP 84/34/50, PAWP 17, LVEDP 14 TCO 3.91, TCI 1.7, PA sat 58%, no step up Social support Discussion

38 Summary PoPH patients are often excluded from clinical trials Data is limited, refer to package inserts. Plan for complications Be cautious Lots of grey areas.

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