The RCTs included were all assessed to be at low risk of bias with respect to randomization and allocation concealment except for 3 trials [25, 31, 32] for which selection bias was deemed unclear. The same 3 trials also were assessed to be at unclear risk of bias with regard to blinded outcome assessment, completeness of outcomes data, selective outcomes reporting, and other potential sources of bias [25, 31, 32]. All trials were deemed to be at high risk of performance bias as blinding of patients, physicians, and research personnel to treatment allocation was not feasible (Fig. 2).