Abstract: We included 84 RCTs with 8234 participants in this review. Six trials (N = 658) did not report any of the outcomes of interest for this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. The treatments assessed in these 78 trials included antibiotics, antioxidants, aprotinin, atropine, calcitonin, cimetidine, EDTA (ethylenediaminetetraacetic acid), gabexate, glucagon, iniprol, lexipafant, NSAIDs (non-steroidal anti-inflammatory drugs), octreotide, oxyphenonium, probiotics, activated protein C, somatostatin, somatostatin plus omeprazole, somatostatin plus ulinastatin, thymosin, ulinastatin, and inactive control. Apart from the comparison of antibiotics versus control, which included a large proportion of participants with necrotising pancreatitis, the remaining comparisons had only a small proportion of patients with this condition. Most trials included either only participants with severe acute pancreatitis or included a mixture of participants with mild acute pancreatitis and severe acute pancreatitis (75 trials). Overall, the risk of bias in trials was unclear or high for all but one of the trials. Source of funding: seven trials were not funded or funded by agencies without vested interest in results. Pharmaceutical companies partially or fully funded 21 trials. The source of funding was not available from the remaining trials. Since we considered short-term mortality as the most important outcome, we presented only these results in detail in the abstract. Sixty-seven studies including 6638 participants reported short-term mortality. There was no evidence of any differences in short-term mortality in any of the comparisons (very low-quality evidence). With regards to other primary outcomes, serious adverse events (number) were lower than control in participants taking lexipafant (rate ratio 0.67, 95% CI 0.46 to 0.96; N = 290; 1 study; very low-quality evidence), octreotide (rate ratio 0.74, 95% CI 0.60 to 0.89; N = 770; 5 studies; very low-quality evidence), somatostatin plus omeprazole (rate ratio 0.36, 95% CI 0.19 to 0.70; N = 140; 1 study; low-quality evidence), and somatostatin plus ulinastatin (rate ratio 0.30, 95% CI 0.15 to 0.60; N = 122; 1 study; low-quality evidence). The proportion of people with organ failure was lower in octreotide than control (OR 0.51, 95% CI 0.27 to 0.97; N = 430; 3 studies; very low-quality evidence). The proportion of people with sepsis was lower in lexipafant than control (OR 0.26, 95% CI 0.08 to 0.83; N = 290; 1 study; very low-quality evidence). There was no evidence of differences in any of the remaining comparisons in these outcomes or for any of the remaining primary outcomes (the proportion of participants experiencing at least one serious adverse event and the occurrence of infected pancreatic necrosis). None of the trials reported heath-related quality of life. Very low-quality evidence suggests that none of the pharmacological treatments studied decrease short-term mortality in people with acute pancreatitis. However, the confidence intervals were wide and consistent with an increase or decrease in short-term mortality due to the interventions. We did not find consistent clinical benefits with any intervention. Because of the limitations in the prognostic scoring systems and because damage to organs may occur in acute pancreatitis before they are clinically manifest, future trials should consider including pancreatitis of all severity but power the study to measure the differences in the subgroup of people with severe acute pancreatitis. It may be difficult to power the studies based on mortality. Future trials in participants with acute pancreatitis should consider other outcomes such as complications or health-related quality of life as primary outcomes. Such trials should include health-related quality of life, costs, and return to work as outcomes and should follow patients for at least three months (preferably for at least one year).

Plain-language summary: We included 84 RCTs with 8234 participants in this review. Six trials (658 participants) did not report any of the outcomes of interest for this review. In the remaining 78 trials, 210 participants were excluded after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. Apart from the comparison of whether antibiotics should be used, the other comparisons included only a small percentage of people with pancreatic necrosis (an extremely severe form of pancreatitis, which results in pancreatic destruction). Most trials included only the severe form of acute pancreatitis or included both mild and severe forms of pancreatitis. Source of funding: seven trials were not funded or were funded by agencies without vested interest in results. Twenty-one trials were partly or fully funded by pharmaceutical companies. The source of funding was not available from the remaining trials. The overall quality of evidence was low for all the measures because the trials were at unclear or high risk of bias (a systematic error or deviation from the truth that affects the results, favouring one treatment over another) and were small trials. As a result, further studies are required on this topic. Sixty-seven studies including 6638 participants reported short-term deaths. Overall, an average 12% of people who received only supportive care died. There was no evidence that any of the treatments decreased short-term deaths. There was evidence that various treatments might be beneficial in a number of outcomes; however, these results were not consistent, and we cannot make any conclusions as to whether any of the treatments may be beneficial. None of the trials reported health-related quality of life. In conclusion, based on low quality evidence, there is no evidence that any drug treatment added on to supportive care decreases short-term deaths. Future trials in participants with acute pancreatitis should include health-related quality of life, costs, and return to work as outcomes and should follow patients for at least three months (preferably for at least one year).