Identification of patients who clearly fulfill the diagnostic criteria for HRS is difficult, as is the recruitment of critically ill patients in clinical trials. Accordingly, the largest trials were multicentered and multinational. This increases the clinical

heterogeneity as well as the external validity, making it possible to extrapolate the results to larger patient populations in similar specialized centers. Another important limitation of the present review is related to the methodological quality of the included trials. Our primary meta-analysis was not stable to sensitivity analyses of bias control. Unfortunately, we were unable to perform valid regression analyses to determine the risk of publication bias and other Selumetinib datasheet biases. The risk that such meta-regression analyses would be false-negative was considerable due to the limited number of trials

in individual meta-analyses. Small molecule library Likewise, our results are unlikely to be stable to trial sequential analyses with adjustments for the multiple testing invariably associated with meta-analyses.31 On the other hand, because we included mortality, the results were less susceptible to bias than subjective outcome measures.22 Three of the included trials compared different active treatment regimens.28–30 Although the availability of noradrenalin and lower costs makes this treatment option interesting, the pharmacological effects of this drug are not identical to those of terlipressin. An assessment of whether noradrenalin and

terlipressin have similar effects requires evidence from noninferiority or equivalence trials.32, 33 To demonstrate that the MCE experimental treatment is not worse than the comparator, a pre-specified amount known as the noninferiority or equivalence margin should be defined. The margin should be included in the sample size calculations, and both intention-to-treat and per-protocol analyses should be performed. In accordance with previous epidemiological studies of clinical trials,32, 33 these basic requirements were not met in the trials from the present review. Accordingly, no conclusions regarding noninferiority or equivalence can be made. For several of the included trials, sample size calculations were not reported. Accordingly, we were unable to determine whether sample size calculations were performed and the preset sample size achieved, the trials were terminated prematurely, or the trial was terminated at an arbitrary point. One of the included trials on terlipressin plus albumin versus albumin was terminated after an interim analysis suggested that 2,000 patients would be required to achieve adequate statistical power.17 The specific criteria for the interim analysis were not clearly reported. The control group mortality rates for trials on terlipressin plus albumin were 63% to 100% compared with 83% for the trial terminated prematurely.