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Cardiff Masterclass November 2019

Supportive Care in Liver Disease and Prescribing Considerations in Hepatic

Failure

Dr Aoife LowneyConsultant in Palliative Medicine

King’s – Dr Polly Edmonds and Dr Wendy Prentice

• 80% of deaths within the liver unit occur in intensive care– 4-10 deaths per month

– Proactive Supportive and Palliative Care Service for Patients with Chronic Liver Disease

– a hospital with a tertiary liver service, biggest HCC service and transplant programme in UK.

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What makes Liver Disease so special?

• Unpredictability

• Challenging symptoms often requiring

admission to hospital

• Patient Profile- Young, addiction, homelessness

• Maintaining hope (transplant etc)

• Lack of evidence base; prognostication, symptom management and service configuration

• Complex pharmacology

Chronic Liver Disease• 5th highest cause of mortality after heart, cancer, stroke and

respiratory disease; only major cause of death increasing year onyear– In England 2% all deaths; 4% all deaths if any mention of liver disease

included from death certification– 9000 deaths /yr England and Wales

• Disproportionately affects younger age groups– 40-49yr old age group ALD most common cause of death, 1 in 10 all deaths– 70% deaths occur in hospital. More likely to be from deprived background

National End of Life Care Intelligence Network, Deaths from liver disease, implications for end of life care inEngland. March 2012Volk ML et al. Hospital readmissions among patients with decompensated cirrhosis. Am J Gastro. 2011 Sept 20.Verne J, Pring A. Raising the profile of end of life care needs for patients dying from liver disease –using nationalmortality data.Public Health England/ www.gov.uk/phe 2013

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Most Common Causes

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• Alcohol over many years

• Being infected with hepatitis for a long time, particularly hepatitis C

• Non-alcoholic steatohepatitis – a more severe form of non-alcoholic fatty liver disease, where the liver becomes inflamed as the result of a build-up of excess fat

In the UK, the most common causes of cirrhosis are:

Impact of therapy on mortality HCV

Deaths from HCV or HCC in patients with HCV(PHE report on HCV 2016)

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Chronic Liver Disease in the UK

Source: Adapted from ONS mortality data presented in ‘NHS Atlas of Variation in Healthcare for People with Liver Disease’ 2013. London: NHS Liver Care

Variable access to services

Variable quality…

Worldwide prevalence: 4.5-9%

Place of death for patients dying of liver disease

Source: Adapted from ONS data presented in “Deaths from Liver Disease”, National End of Life Care

Intelligence Network, London, 2012.

Distribution of liver disease deaths by place of death, England 2001-2009

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HCCVillanueva A. Hepatocellular Carcinoma. N Engl J Med 2019; 380:1450-1462

Fig 2: Barcelona Clinic Liver Cancer (BCLC) StagingThe Lancet 2018 391, 1301-1314DOI: (10.1016/S0140-6736(18)30010-2)

Identification of advanced disease

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• Synthetic and excretory function

• INR > 2, albumin < 20mmol/l

• Bilirubin > 100µmol/l

• Thrombocytopaenia is a sensitive indicator of liverfibrosis

• Performance status over time

• De-compensation

• Child Pugh /MELD/UKELD score

• SPICT: PS↓, ≥2 unplanned hospital admissions in 6/12, wt↓,symptoms, ascites,encephalophathy, bleeds, hepatorenal, bacterial peritonitis

Medici V, Rossaro L, Wegelin JA, Kamboj A, Nakai J, Fisher K, Meyers F. The Utility of the Model for End-Stage LiverDisease Score: A reliable guide for liver transplant candidacy and, for select patients, simultaneous hospice referral.Liver Transplantation 2008;14: 1100-1106

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Clinical course of cirrhosis: 1-year outcome probabilities according to clinical signs & events

No VaricesNo AscitesNo VaricesNo Ascites

VaricesNo Ascites

VaricesNo Ascites

Ascites+/- Varices

Ascites+/- Varices

BleedingAscites

BleedingAscites

7%

6.6%

7.6%

4.4%

4%

DeathDeath

1%1%

3.4%3.4%

20%20%

57%57%

Source: Adapted from D’Amico G et al. J Hepatol. 2006; 44: 217 – 231

Complications of Advanced Disease

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Refractory ascites• Mortality of 50% at 6 months

• Transjugular intrahepatic portosystemic shunt (TIPS)

• Paracentesis

– Risks of precipitating hepatorenal syndrome– Colloid volume expansion is probably unnecessary for safe withdrawal of < 5

L ascitic fluid– Implanted, externally draining peritoneal catheter

• Challenge regarding place of care

EASL. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis and hepatorenalsyndrome in cirrhosis. J of Hepatol 2010 vol. 53:397-417Runyon BA. Treatment of patients with cirrhosis and ascites. Sem Liver Dis 1997;17(3):249-260Reisfield GM, Wilson GR. Management of intractable, cirrhotic ascites with an indwelling drainage catheter. J ofPall Med, 2003. Vol 6 (5): 787-791

Refractory ascites• Co-ordinated care

– Planned follow up by MDT in OP

– Reduced readmissions, 12 month mortality & costs

• The alfapump® system

– IP catheter connected to a subcut implanted battery powered device that moves fluid from peritoneal cavity & a 2nd that connects the pump to the urinary bladder

– 2019 NICE – not approved for routine use ‘serious and well recognised safety concerns’

Ge PS and Runyon BA. Care coordination for patients with cirrhosis: a ‘win-win’ solution for

patients, caregivers, providers, and healthcare expenditures. J Hepatol 2013 vol 59. 203

204 https://www.nice.org.uk/guidance/IPG631Nov18

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Implantable tunnelled catheters

• NICE approval in malignant setting

• Established guidance in place at King’s but variable use

• REDUCe (Reduced Drainage Untreatable Cirrhosis) trial – feasibility study completed

• Anecdotal use across UK

Macklan L. Palliative long-term abdominal drains versus repeated drainage in individuals with

untreatable ascites due to advanced cirrhosis: study protocol for feasibility randomised

controlled trail. BMC Open Access 2018 19:401

REDUCEe Macken L et al. Long term palliative abdominal drains versus large volume

paracentesis in refractory ascites due to cirrhosis: a multi-centre feasibility randomised controlled trial (the REDUCe Study). J Hepatol 2019; Suppl 70:e660

• Feasibility study

– 12 wk feasibility RCT, LVP vs. LTAD

– 36 pts randomised (19 LVP, 17 LTAD)

– Plans for multi-centre RCT but challenges regarding funding and agreement of primary outcome measure

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Spontaneous Bacterial Peritonitis

• Patients with SBP have an in hospital mortalityof 20%

• Cumulative recurrence rates are 70%, mediansurvival of nine months

• Prophylaxis

– If suffered recurrent episodes then long termantibiotics may be appropriate

Variceal bleeding

• Mortality from first presentation varicealbleed is about 50%, although influenced byseverity of underlying liver disease

• Crisis planning, patient preferences

• Child-Pugh class, one year mortality rates fromsubsequent variceal haemorrhage:– A 5%

– B 25%

– C 50%

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Encephalopathy

• Metabolically induced, potentially reversible, functionaldisturbance of brain– Severe intrinsic hepatic dysfunction– Portosystemic shunts leading to the diversion of portal blood to the

systemic circulation before removal of toxic intestinal substances

• Personality changes, impaired intellect, disturbed sleeppattern and depressed level of consciousness

• Marker of decompensation

• Laxative therapy NB along with rifaximin for resistant cases(reduces ammonia production by eliminating ammoniaproducing colonic bacteria)Cash WJ et al. Current concepts in the assessment and treatment of Hepatic Encephalopathy. QJMed2010; 103:9-16

Pharmacological Impact of Hepatic Impairment

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Hepatic Impairment

• Increasingly common in the end of life population• Unlike renal failure – no single parameter

indicating the extent to which drug clearance will be affected

• Do not rely solely on LFTs…• Main site of metabolism for most drugs• Generally impairment must be severe for drug

metabolism to be altered to a clinically important extent (large reserve)

• Unpredictable impacts

Pharmacokinetic Considerations

• Decreased absorption

• Altered distribution and protein binding

• Altered metabolism

• Reduced elimination

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Prescribing in Hepatic Impairment

General rules to live by:

• Reduce starting dose and frequency of administration

• Titrate slowly

• Beware of constipation and sedation

Red Flags for considering dose reduction

• Drugs with:

– Low systemic PO bio-availability due to high first pass hepatic extraction

– Highly protein bound

– Cleared mainly by phase 1 metabolism e.g. CYP enzymes and has a narrow therapeutic window or a long half-life

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Analgesia – non opioidsDrug Oral bio-

availabilityProteinbinding

Active metabolite

Increase in half-life in severe hepatic impairment

Dose

Paracetamol <90% 20-30% Toxic <50% Start with 500mg 8hourly and monitor LFTs if using above 500mg 6hourly. Max dose 1g 8hourly.

Diclofenac 50% >99% No No data Dose unchanged –check LFTs after 1-2months

Ibuprofen 90% 90-99% No Nil Dose unchanged

Naproxen 95% 99% No <50% Maximum 250mg BD

Avoid celecoxib if possible

Analgesia - opioidsDrug Oral bio-

availabilityProteinbinding

Active metabolite

Increase in half-life in severe hepatic impairment

Dose

Fentanyl - 80-85% No No Dose unchanged

Alfentanil - 92% No Yes Lower doses may be sufficient

Buprenorphine 50% 96% No Probably Lower doses may be needed

Diamorphine No data - Yes No Prescribe as for morphine

Methadone 40-100% 60-90% No No data Use cautiously with specialist advice

Morphine 15-64% 20-35% Yes <100% Titrate slowly, decrease frequency of IR products

Avoid codeine, dihydrocodeine, oxycodone and tramadol if possible

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Anti-emetics

Drug Oral bio-availability

Proteinbinding

Active metabolite

Increase in half-life in severe hepatic impairment

Dose

Cyclizine No data No data No No data Dose unchanged

Haloperidol 45-75% 92% Yes No data Start with low dose, titrate slowly

Levomepromazine 20-40% No data No No data Start with low dose, titrate slowly

Metoclopramide 50-80% 13-22% No >100% Start with 5mg BD, maximum 10mg BD

Ondansetron 56-71% 70-76% No >300% Maximum 8mg/24hours

Benzos and Z drugs

Drug Oral bio-availability

Proteinbinding

Active metabolite

Increase in half-life in severe hepatic impairment

Dose

Lorazepam 90% 85% No <50% Unchanged

Temazepam 90% 96% No No Unchanged

Midazolam - 96-98% Yes <100% Start with low dose

Zopiclone 75% 45-80% Yes <50% Start with 3.75mg

Avoid clonazepam and diazepam if possible

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Anti-psychoticsDrug Oral bio-

availabilityProteinbinding

Active metabolite

Increase in half-life in severe hepatic impairment

Dose

Haloperidol 45-75% 92% Yes No data Start low and titrate slowly

Olanzapine 60% 93% No No data Start low and titrate slowly

Quetiapine 100% 83% Yes Probably Start with 25mg/24hours and increase daily by 25-50mg/24hours

Risperidone 99% 90% Yes No data Start low and titrate slowly

Avoid chlorpromazine if possible

Anti-depressants

Avoid duloxetine, sertraline and venlafaxine if possible

Drug Oral bio-availability

Proteinbinding

Active metabolite

Increase in half-life in severe hepatic impairment

Dose

Amitriptyline 45% 96% Yes No Start with 10mg On and titrate slowly

Citalopram 80% <80% Yes >200% Start with 10mg OD, max dose 20mg OD

Mirtazapine 50% 85% Yes No data Start with 15mg OD, max dose 30mg OD

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Anti-epilepticsDrug Oral bio-

availabilityProteinbinding

Active metabolite

Increase in half-life in severe hepatic impairment

Dose

Levetiracetam >95% <10% No Probably Unchanged

Oxcarbazepine >95% 40-60% Yes No data Pro-drug: reduced transformation and thus reduced effect

Carbamazepine 85-100% 70-80% Yes No data Start low and titrate slowly

Gabapentin 30-75% <3% No No data Start low and titrate slowly

Pregabalin >90% 0 No No data Start low and titrate slowly

Valproate 95% 90-95% No No data Start low and titrate slowly

Avoid clonazepam, phenobarbital and phenytoin if possible

Proactive Palliative and Supportive Care in Liver Failure

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Proactive approach• Increasing evidence that early palliative care

intervention can improve symptom management and quality of life

– Improved symptom burden and mood

– Improved survival?

– Less aggressive treatment and less hospitalization• Greer JA et al. Early integration of palliative care services with standard oncology care for patients with

advanced cancer. CA Cancer J Clin. 2013;63(5):349-63

• Temel JS et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N ENGL J Med. 2010:363(8):733-42

• Baumann AJ et al. Benefit of early palliative care intervention in End-Stage Liver Disease Patients awaiting liver transplantation. JPSM 2015:Dec 50(6);882-6 e2

• Walling AM et al. Impact of consideration of transplantation on end-of-life care for patients during a terminal hospitalization. Transplantation. 2013;95(4):641-6

• Early palliative care for adults with advanced cancer (Review) 2017 The Cochrane Collaboration

Integration in practiceHudson BE et al. Frontline Gastroenterology 2017;8:45-52

Screening criteria Supportive care intervention

Childs Pugh C Consultant led poor prognosis discussion

>2 liver related admissions in last 6 months

Poor prognosis letter to GP

Ongoing alcohol use in known ALD Opportunity for advance care planning

Currently unsuitable for transplantation Specialist palliative care review if complex symptomatic/social/psychological needs

WHO PS 3-4 Allocation of hepatology specialist nurse

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Take Home Messages

• Deaths from CLD are on the rise

• There are multiple parameters to consider when thinking about the severity of CLD

• Look at synthetic function as well as complications of CLD

• Pharmacology is complex- consult the PCF

‘Is life worth living? It all depends on the liver’William James, American Philosopher, 1842-1910

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Any questions?

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