Less Simvastatin Safer in Decompensated Cirrhosis

Simvastatin at 40 mg/day in combination with the antibiotic rifaximin (Xifaxan) led to an unexpectedly high proportion of adverse events in decompensated cirrhosis patients, although the statin drug at 20 mg/day plus rifaximin showed no increased risk of adverse events versus placebo, a 44-patient randomized trial indicated.

Pere Ginès, MD, of the Hospital Clinic at the University of Barcelona in Spain, and colleagues ended up stopping treatment with simvastatin 40 mg/day after the first 10 patients showed significant elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) compared with placebo. Levels of creatine kinase (CK) suggestive of muscle damage were also notably higher in the 40-mg group.

The following mean values were found with placebo versus higher-dose rifaximin, in combination with rifaximin.

• AST: 62 vs 191 IU/L, P=0.0009
• ALT: 35 vs 96 IU/L, P=0.0025
• CK: 152 vs 160 IU/L, P=0.014

As well, three of 16 patients in the simvastatin 40-mg group developed liver and muscle toxicity consistent with rhabdomyolysis.

Furthermore, significantly more patients on high-dose simvastatin stopped treatment owing to adverse events: nine of 16 patients versus two of 14 in both of the other groups (P=0.017).

Adverse event rates did not differ markedly between the lower simvastatin dose and placebo.

"In studies investigating the efficacy of simvastatin in patients with decompensated cirrhosis, 20 mg/day should be preferred to a 40 mg/day dose," Ginès and co-authors wrote in The Lancet Gastroenterology and Hepatology.

Accumulating evidence indicates that statins have beneficial effects in cirrhosis, improving intrahepatic circulation and decreasing portal hypertension and possibly reducing mortality, while rifaximin modulates the gut microbiome and may prevent bacterial translocation in cirrhosis patients, the authors explained.

In that context, during July 2017 to January 2018, the LIVERHOPE-SAFETY placebo-controlled trial randomized 50 adults with moderate to severe liver failure at nine hospitals across Italy, France, Holland, Germany, the UK, and Spain to one of the following 12-week regimens: simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Two patients in each group were excluded from the study after randomization after investigators discovered they didn't meet enrollment criteria or never took study medication.

Mean patient age ranged from 49 in the simvastatin 20-mg group to 59 in the placebo group and 60 in the simvastatin 40-mg group. Overall, more than 70% of patients were male and more than 60% had alcohol-related cirrhosis. In excess of 70% were Child-Pugh score B.

The authors noted that while previous small cirrhosis trials reported no liver of muscle toxicity with statins, a multicenter, double-blind, placebo-controlled, randomized trial of 147 patients given simvastatin at 40 mg/day or placebo and followed for up to 2 years found that two of 69 simvastatin patients developed clinically relevant muscle toxicity requiring treatment withdrawal. In support of using a lower dose, a recent large cohort study of more than 70,000 cirrhosis patients showed beneficial effects of simvastatin even with a regimen of less than than 20 mg/day.

In an accompanying editorial, Tracey G. Simon, MD, MPH, of Massachusetts General Hospital in Boston, called the study "a welcome addition to the field" as it appeared to be the first randomized trial to evaluate the safety of two common simvastatin doses in patients with Child-Pugh B or C cirrhosis. "Although the sample size is small, this study is appropriately powered for the primary safety endpoints and provides important and practical evidence that can be readily applied to the design of large-scale phase 3 studies, thus could help inform future simvastatin dosing," wrote Simon, who was not involved in the research.

In her view, the combination of rifaximin with high-dose simvastatin merits scrutiny. "Given the unique study design, which assessed combination simvastatin and rifaximin (rather than simvastatin monotherapy), a potential drug-drug interaction cannot be excluded," she wrote.

Before statins can be incorporated into a prevention strategy for patients with cirrhosis, Simon continued, the safest and most effective statin type, dose, and duration of use must be defined by well-designed prospective studies comparing individual statin types at a range of doses in patients with compensated and decompensated cirrhosis.

A limitation of the safety study, the authors pointed out, was its small sample size, whereas a larger sample might also have yielded efficacy signals for the simvastatin-rifaximin combination in patients with decompensated cirrhosis. In addition, imbalances in some baseline characteristics between patient groups could have affected the study results.