Abstract: For this update, 15 additional studies fulfilled selection criteria. We included in this review 33 randomised controlled trials with 4477 participants; 21 compared different prostanoids versus placebo, seven compared prostanoids versus other agents, and five conducted head-to-head comparisons using two different prostanoids. We found low-quality evidence that suggests no clear difference in the incidence of cardiovascular mortality between patients receiving prostanoids and those given placebo (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.41 to 1.58). We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared with placebo (RR 0.97, 95% CI 0.86 to 1.09). Adverse events were more frequent with prostanoids than with placebo (RR 2.11, 95% CI 1.79 to 2.50; moderate-quality evidence). The most commonly reported adverse events were headache, nausea, vomiting, diarrhoea, flushing, and hypotension. We found moderate-quality evidence showing that prostanoids reduced rest-pain (RR 1.30, 95% CI 1.06 to 1.59) and promoted ulcer healing (RR 1.24, 95% CI 1.04 to 1.48) when compared with placebo, although these small beneficial effects were diluted when we performed a sensitivity analysis that excluded studies at high risk of bias. Additionally, we found evidence of low to very low quality suggesting the effects of prostanoids versus other active agents or versus other prostanoids because studies conducting these comparisons were few and we judged them to be at high risk of bias. None of the included studies assessed quality of life. We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared against placebo. Moderate-quality evidence showed small beneficial effects of prostanoids for rest-pain relief and ulcer healing when compared with placebo. Additionally, moderate-quality evidence showed a greater incidence of adverse effects with the use of prostanoids, and low-quality evidence suggests that prostanoids have no effect on cardiovascular mortality when compared with placebo. None of the included studies reported quality of life measurements. The balance between benefits and harms associated with use of prostanoids in patients with critical limb ischaemia with no chance of reconstructive intervention is uncertain; therefore careful assessment of therapeutic alternatives should be considered. Main reasons for downgrading the quality of evidence were high risk of attrition bias and imprecision of effect estimates.

Plain-language summary: We searched published and unpublished studies up to January 2017. We found 33 clinical trials with a total of 4477 participants; most were published in the 1980s and 1990s and were carried out in European countries. Eleven out of 33 studies received funding from pharmaceutical companies. Most studies included patients over 60 years old who had severe blocking of arteries of the leg; many also had diabetes. Follow-up was usually less than 1 year. We found that, when compared with placebo, prostanoids provided a small beneficial effect by alleviating pain in the leg at rest and improving ulcer healing. Prostanoids did not reduce deaths or the need for an amputation. We found that no studies evaluated the quality of life of people with this condition. We found insufficient evidence to compare effects of prostanoids against those of other medications or other prostanoids. Our findings suggest that taking prostanoids does cause harm. When 1000 patients are treated with prostanoids, on average 674 (572 to 798) will experience adverse events, compared with 319 given placebo. Adverse events usually include nausea, vomiting, diarrhoea, headache, dizziness, and flushing. More severe adverse events include low blood pressure, chest pain, and abnormalities in heart rhythm. When evaluating effects of prostanoids on rest-pain, ulcer healing, and adverse events, researchers provided moderate-quality evidence; review authors downgraded this in most cases because of loss of participants to follow-up. Evaluating cardiovascular mortality yielded evidence of low quality related to loss of participants to follow-up and small numbers of reported events. On the other hand, the quality of evidence on risk of amputation was high.