Efficacy of L-Ornithine L-Aspartate for the prevention and Treatment of Hepatic Encephalopathy in Cirrhosis: An Update of the Evidence Base

Abstract

The advent of well-established procedures for the determination of clinical trial quality based on risk of bias assessments has resulted insubstantial improvements in the quality of systematic reviews and meta-analyses relating to the assessment of Randomized Controlled Trials (RCTs) on the efficacy of treatments for a range of clinical conditions. In the current review, manual and electronic searches of databases using appropriate keywords were used to assess the evidence base for the use of L-ornithine L-aspartate (LOLA) for the prevention and treatment of Hepatic Encephalopathy (HE), a common neuropsychiatric complication of liver cirrhosis. Making use of current risk of bias techniques, seven systematic reviews with accompanying meta-analyses were identified in which the results of RCTs on the efficacy of LOLA for the treatment of HE were analyzed. A clear consensus of opinion was observed in support of the efficacy of LOLA for lowering of blood ammonia and for the concomitant improvement of mental status in patients with overt HE (OHE) and in five of the six meta-analyses in patients with minimal HE (MHE). Evidence in support of a beneficial effect of LOLA for the prevention of OHE in patients with cirrhosis was reported in a novel systematic review and meta-analysis involving the analysis of six RCTs in patients with cirrhosis and a range of clinical presentations where successful OHE prevention/prophylaxis was accompanied in all cases by significant reductions of blood ammonia. Both, intravenous and oral formulations of LOLA were found to be effective. Reduction in the progression of MHE to OHE was independently confirmed in a subsequent meta-analysis. Two systematic reviews with network meta-analyses compared the efficacy of LOLA to other available agents. Only treatment with LOLA or branched-chain amino acids (BCAAs) resulted in significant improvements in mental status and LOLA was judged to be the most effective agent with respect to clinical improvement and concomitant reduction of blood ammonia. In the case of MHE, rifaximin, lactulose and LOLA were equivalent in clinical efficacy and were each superior to probiotics. LOLA was superior to lactulose or probiotics for the prevention of episodes of OHE in patients with MHE compared to placebo/no treatment; rifaximin was ineffective in this regard. databases, conference proceedings and correspondence with investigators and pharmaceutical companies yielded 22 RCTs involving 1375 patients with cirrhosis and HE or risk of development of HE for which outcome data was available. LOLA had a beneficial effect on HE compared to placebo/no intervention for all trials [RR: 0.70, 95% CI: 0.59–0.88] but evidence was judged to be very low quality leading investigators to conclude that outcomes were uncertain. However, subsequent sub-group analyses of completed RCTs and/or RCTs with findings published as full papers demonstrated significant improvements in mental state: 12 completed trials, 994 patients : RR:0.63, 95% CI: 0.48–0.83, p<0.001], 12 published trials, 1032 patients: RR:0.65,95% CI: 0.50–0.85, p<0.0017]. Both iv and oral formulations appeared to be effective in this analysis. Searches of databases revealed 8 RCTs that assessed the LOLA for of 646 with cirrhosis. LOLA was significantly more effective than placebo/no intervention for improvement in all types of [RR: as well as for with OHE or MHE analysed separately. These improvements were accompanied by significant reductions in fasting blood ammonia [MD: p<0.01].