Simvastatin Addition to Standard of Care Improves Long-Term Survival in Patients With Cirrhosis After Variceal Bleed: An Open Label Randomized Controlled Trial

INTRODUCTION: There is limited evidence about efficacy and safety of simvastatin in decompensated cirrhosis. We assessed whether addition of simvastatin to standard of care improves long-term survival in patients with cirrhosis after variceal bleeding. METHODS: This was a single-center open label randomized controlled trial with superiority design. Patients with cirrhosis (Child-Pugh score 5-12) were randomly assigned to receive either simvastatin (20 mg once-daily) (n = 130) or no drug (n = 138) in addition to standard therapy (carvedilol and band ligation) at day 5 of variceal bleeding episode. Primary outcome was all-cause mortality over 24-month follow-up. Secondary outcomes included individual complications of cirrhosis with death before decompensation as a competing event. RESULTS: Baseline characteristics were similar in both groups with a mean age of 45.0 ± 11.5 years and alcohol (48%) being the predominant etiology. Most patients were of Child-Pugh A (34%) and B (50%) stage. Twenty-four patients (18%) on simvastatin and 44 (31%) on standard therapy died over follow-up (hazard ratio [HR] for simvastatin: 0.48 [95% confidence interval 0.29-0.81]; P = 0.006) with similar results on intention to treat and on per-protocol analysis (excluding 17 patients who stopped simvastatin). Incidence of ascites (subdistributional HR [sHR]) 0.60 (0.39-0.92) and spontaneous bacterial peritonitis (sHR 0.30 [0.11-0.81]) was lower in the simvastatin arm. All cause decompensation (sHR 0.74 [0.52-1.05]), rebleeding (sHR 0.87 [0.57-1.34]), hepatic encephalopathy (sHR 0.71 [0.42-1.19]), and acute-on-chronic liver failure (sHR 0.65 [0.39-1.10]) were comparable in both arms. No heterogeneity of treatment effect was demonstrated across Child-Turcotte-Pugh class ( P = 0.105) or etiology ( P = 0.39). Incidence of serious adverse events was similar (43% in simvastatin and 52% in standard therapy, absolute risk difference: 9.1% [-2.9% to 21.0%]). DISCUSSION: Simvastatin may be associated with improved survival in selected patients with cirrhosis after variceal bleed and reduced incidence of new onset/refractory ascites and its complications (CTRI/2022/07/044263).