Statin Order The use of Statins in Chronic Liver Disease Laura M. Stinton, MD MSc FRCPC Clinical Assistant Professor, University of Calgary Disclosures Advisory Board : Abbvie Clinical funding: Abbvie, Gilead No financial disclosures related to this talk Off-Label use of medications will be discussed 1
Cases -??Use of Statin 50 M GP wants to start patient on Statin as 10 year cardiac risk is high (Framingham >20%). Checks baseline ALT = 60. Patient has been on statin for 6 weeks, ALT = 100. US shows steatosis, fibroscan = 15 kpa, CP-A. First variceal bleed. Decompensated with ascites. Statin use in CLD - Swinging Pendulum Statins Contraindicated - Fear of DILI - Elevation of liver enzymes - Risk of decompensation Statins Indicated - Decrease Portal HTN - Improve Fibrosis - HCC risk reduction 2
Goals Review safety of Statins in liver disease Overview of recent studies: Portal HTN Fibrosis regression & survival HCC chemoprevention Statins - Pharmacology HMG Co-A reductase inhibitors Block hepatic cholesterol synthesis At least 7 statins on the market In top 5 classes of drugs Rx per year US $ 19.7 Billion in 2005 2003 Atorvastatin became #1 best selling pharmaceutical in history at $ 12.4 Billion Taylor FC, et al, JAMA, 2013 Deichmann, et al, Oshsner Journal 2015 3
Statins Adverse Drug Reactions Muscle: Rhabdomyolysis Liver: Transaminitis True Liver Injury Statins - Transaminitis Asymptomatic & usually temporary rise in liver enzymes Occurs in early stages of treatment Secondary to changes in lipid content of hepatocytes leading to increased permeability and enzyme leakage NOT direct liver injury <3% of patients on Statins Only ~3% of these patients have persistent elevation >3X ULN Corrected with dose decrease Usually does not recur with re-introduction Bjornsson E, et al, J Hepatology. 2012 Black DM, et al, Arch Intern Med, 1998 4
Statins True Liver Injury Idiosyncratic liver injury 1% Cholestatic (atorvastatin) Hepatocellular (simvastatin) Immunoallergic Reaction isolated cases of drug induced AIH 3-4 months after initiation Recur on re-introduction Chang CY, et al, Aliment Pharmacol Ther, 2007 Statins - DILI Multiple studies to evaluate risk of liver injury due to statins Overall no association between statin use & liver related mortality Liver related mortality lower with Statin use Many physicians reluctant to start statin or will readily stop if increase in liver enzymes FDA & Liver Expert Panel: healthcare professionals should perform liver enzyme tests only before initiating statin therapy and as clinically indicated thereafter www.fda.gov/drugs/drugsafety/ucm292101 5
Statins in Pre-existing Liver Disease Overall no increased risk of idiosyncratic reaction NAFLD, PBC, HCV Compensated cirrhosis Not associated with increased mortality may delay decompensation Animal studies show decrease in portal HTN?? Severely Decompensated Cirrhosis?impaired drug metabolism Cohen DE, et al, Am J Cardiol, 2006 Kumar S, et al, Dig Dis Sci, 2014 Abraldes JG, et al, Hepatology, 2003 Trebicka J, et al, Hepatology, 2007 Portal HTN & Variceal bleeding 6 week mortality rate of 10-20% Risk of re-bleeding with no treatment 60% in first year First line standard treatment: Combination of NSBBs and EVL 6
Reducing Portal HTN HVPG goal in patients with cirrhosis >20% from baseline or to <12mmHG Good outcome measurement Ideal drug for Portal HTN: Decrease intrahepatic vascular resistance Maintain or improve hepatic blood flow Selective to the hepatic circulation Minimal effects on systemic hemodynamics Anti-Fibrotic effects Statins in the Liver: Pleiotropic Effects Targets dysfunctional pathways in cirrhosis Inhibits RhoA/Rho-kinase Increases enos phosphorylation - Improvement in endothelial function - Increase in NO production in endothelial cells Liver Selective - True liver only vasodilators Trebicka J, et al, Hepatology 2007 Abraldes JG, et al, J Hepatology 2007 Trebicka J et al, J Hepatology 2010 Zafra C, et al, Gastroenterology 2004 Moreno M, et al, Am J Physiol Gastrointest Liver, 2009 Improved liver microvascular function Decrease portal pressure Anti-inflammatory effects Anti-fibrotic effects 7
Proof of Concept Aim Examine effects of simvastatin on HVPG and safety RCT, simvastatin vs. placebo, 59 patients, 1 month HVPG measured by HV catheterization Simvastatin decreased HVPG and improved liver perfusion in patients with cirrhosis Effects were additive to β-blockers No increase in adverse effects (18.5 to 17.1mmHg) RCT, simvastatin vs. placebo, 34 patients, 3 months HVPG measured by color Doppler EUS Simvastatin lowered portal pressure No adverse side effects Simvastatin group had improvement in liver function Decrease in Child-Pugh score and ALT 8
BLEPS: Bleeding Prevention with Simvastatin Study Methods Multicenter 14 Spanish Academic Centers Randomized (1:1) Placebo-controlled Double-Blind Parallel Group 9
Methods Inclusion Criteria: Age 18-80 yrs Previous diagnosis of liver cirrhosis Index variceal bleed within previous 5-10 days Exclusion Criteria: Pregnancy/Lactation Multifocal HCC or single lesion >5cm Creatinine >2 mg/dl HIV on treatment Previously treated with portosystemic shunt Child-Pugh >13 PVT Previous treatment with EVL and NSBB Previous treatment with Statins within 1 month Intervention All patients received standard secondary prophylaxis: EVL and NSBB Randomized 1:1 Simvastatin 20mg/day 40mg/day at day 15 Placebo Treated for 24 months 10
Outcome Measures Primary End Points: All-cause re-bleeding or All-cause Death Secondary End Points: Recurrent variceal bleeding # of patients requiring alternative treatment (eg. TIPS) Development of: SPB, HRS, PVT, death, transplantation 11
Primary Outcome Primary end point (re-bleeding or death) 39% Placebo 32% Simvastatin Addition of Simvastatin to standard therapy was not statistically superior to placebo in preventing re-bleeding or death after a variceal bleed 12
Secondary Outcomes Mortality: 22% Placebo 9% Simvastatin Treatment with Simvastatin was associated with a 61% reduction in the relative risk of death compared to placebo. Re-bleeding: 28% Placebo 25% Simvastatin Re-bleeding rate was not significantly decreased by the addition of simvastatin to standard therapy. Mortality with Simvastatin was only decreased in CP A/B not CP C 13
Safety of Simvastatin No significant difference in adverse events between placebo and simvastatin Definition of significant drug toxicity Asymptomatic increase in ALT, AST or CK >3x baseline 1 patient in Simvastatin group with ALT, AST >3x ULN Asymptomatic No worsening of liver function tests Returned to baseline after stopping simvastatin 2 patients in Simvastatin group with rhabodomyolisis Symptomatic (myalgias) Neither developed kidney injury Fully recovered after stopping simvastatin Additional Secondary Outcomes 14
Conclusion BLEPS Trial In cirrhotic patients post variceal bleed the addition of Simvastatin to NSBB & EVL: Improved overall survival No reduction in rate of other complications of cirrhosis including re-bleeding Overall survival was NOT primary endpoint of this trial so future validation is required in a wider cirrhotic population (ie. Not just previous variceal bleed) - Retrospective cohort 15
Statins in HCC Conclusion Statins should be used for cardiovascular indications in patients with chronic liver disease, including cirrhosis FDA recommends baseline liver enzyme testing but not routine measurement Further studies are needed to determine off-label use of statins in liver disease: Variceal bleeding Cirrhosis progression Death HCC???? Will there one day be a Standing (Statin) Order for all liver patients???? 16
Thank you 17