Randomized, double-blind, placebo-controlled, phase ii trial assessing safety of two different doses of simvastatin in combination with rifaximin in decompensated cirrhosis

BACKGROUND: Statins have beneficial effects on the intrahepatic circulation and decrease portal hypertension, while rifaximin modulates gut microbiome and may prevent bacterial translocation in cirrhosis. Therefore, this drug combination may be of therapeutic benefit in decompensated cirrhosis. However, there is concern regarding safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial in patients with decompensated cirrhosis, Child-Pugh B and C, that were randomly assigned to receive simvastatin 40mg/day plus rifaximin 1,200mg/day(n=16) , simvastatin 20mg/day plus rifaximin 1,200mg/day (n=14) or placebo of both medications (n=14) for 12 weeks. Primary endpoint was development of liver or muscle toxicity, as defined by changes in liver transaminases (AST, ALT), alkaline phosphastase and creatine kinase (CK) levels. ITT and PP analysis were performed. FINDINGS: Patients in the simvastatin 40mg/day group but not in the simvastatin 20mg/day group showed a significant increase in AST, ALT and CK levels during treatment, as compared to placebo (191 vs. 62IU/L, 96 vs 35 IU/L and 1160 vs. 152 IU/L for AST, ALT and CK, respectively; p<0.001, p<0.001 and p=0.016) . Moreover, 3 patients (19%) in the simvastatin 40mg/day group developed significant liver and muscle toxicity consistent with rhabdomyolysis. INTERPRETATION: Treatment with simvastatin 40mg/day plus rifaximin in patients with decompensated cirrhosis appears to be associated with significant frequency of adverse events, particularly rhabdomyolysis. By contrast, the dose of simvastatin 20mg/day plus