Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in December 2013. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

A Cochrane review of low quality studies of prostanoids in people with critical limb ischaemia unsuitable for surgery found that compared with placebo, intravenous iloprost statistically significantly reduced major amputations, improved rest-pain relief, and improved ulcer healing. The benefit of intravenous iloprost on total amputations (major plus minor) was not statistically significant. In a randomised controlled trial (RCT) in people undergoing femorodistal bypass surgery for critical limb ischaemia, perioperative intravenous and intra-graft iloprost did not improve graft patency or clinical status, or reduce amputations at 1‑year follow-up compared with placebo. Adverse events were more common with intravenous iloprost than with placebo and included pain at the infusion site, headache, flushing, nausea and vomiting, and hypotension.

Regulatory status: Iloprost as an infusion solution is not licensed in the UK.

The topic was prioritised because there was a high volume of requests from the NHS for information on this topic and potential for variation in practice.

Effectiveness

  • In a Cochrane review of prostanoids for people with critical limb ischaemia unsuitable for surgery, intravenous iloprost statistically significantly reduced major amputations, improved rest-pain relief and improved ulcer healing compared with placebo. The effect on total amputations (major plus minor) was not statistically significant. The quality of the evidence was graded as low or very low using the GRADE approach.

  • In an RCT in people undergoing femorodistal bypass surgery for critical limb ischaemia; perioperative intravenous and intra-graft iloprost compared with placebo did not improve graft patency, clinical status, or reduce amputations at 1 year follow up.

Safety

  • Common adverse events associated with intravenous iloprost in the Cochrane review and RCT included pain at the infusion site, headache, flushing, nausea and vomiting, and hypotension.

  • A dose-comparison RCT included in the Cochrane review found a significant dose response in adverse events with intravenous iloprost.

  • The RCT in people undergoing femorodistal bypass surgery for critical limb ischaemia reported there was no difference between the placebo and iloprost groups in major adverse events such as myocardial infarction, cerebrovascular accident or death from any cause in the fortnight after surgery.

Patient factors

  • Administered intravenously in secondary care.

Resource implications

  • Iloprost is unlicensed in the UK and can be supplied on request from the manufacturer. No costs could be obtained from standard published sources or the manufacturer1.

1 informal sources suggest that the cost is around £100 for a single 50 microgram ampoule, equating to around £3000 for a 4 week course.

Key points

Iloprost as an infusion solution is not licensed in the UK. It can be supplied on request from the manufacturer, for use by prescribers for individual patients at their sole responsibility. This summary is based on evidence from a Cochrane review of prostanoids for critical limb ischaemia (Ruffolo et al. 2010) and an RCT of perioperative intravenous iloprost in people with critical limb ischaemia undergoing femorodistal bypass grafting surgery (Iloprost Bypass International Study Group [IBISG] 1996).

The Cochrane review included 5 placebo-controlled RCTs of intravenous iloprost in people with critical limb ischaemia unsuitable for rescue or reconstructive intervention (n=604). Meta-analyses of the included RCTs were performed for the outcomes rest pain relief, ulcer healing, total amputations, major amputations and adverse events. Each meta-analysis included 3 of the RCTs, and each RCT contributed to at least 1 meta-analysis. The review found that daily intravenous iloprost infusions given for between 2 and 4 weeks, compared with placebo, statistically significantly:

  • reduced major amputations at a mean follow-up of 21.3 weeks (n=318, 30.6% with intravenous iloprost compared with 44.3% with placebo risk ratio [RR] 0.69, 95% confidence interval [CI] 0.52 to 0.93)

  • improved rest-pain relief at a mean follow-up of 14 weeks (n=318, 56.4% with intravenous iloprost compared with 36.6% with placebo, RR 1.54, 95% CI 1.19 to 1.99)

  • improved ulcer healing at a mean follow-up of 14.7 weeks (n=367, 50.9% with intravenous iloprost compared with 28.3% with placebo, RR 1.80, 95% CI 1.29 to 2.50).

Intravenous iloprost infusions did not statistically significantly reduce total amputations (major plus minor) compared with placebo at a mean follow-up of 21.3 weeks (n=318, 36.6% compared with 46.3% respectively, RR 0.79, 95% CI 0.60 to 1.03).

One large RCT (Iloprost Bypass International Study Group [IBISG] 1996; n=528) assessed intravenous iloprost given for 3 days perioperatively plus an intra-operative intra-graft dose in people having femorodistal bypass surgery for critical limb ischaemia. It found that iloprost did not improve graft patency or clinical status, or reduce amputations at 1‑year follow-up compared with placebo.

Both the Cochrane review and perioperative RCT found that intravenous iloprost was associated with an increased risk of adverse events compared with placebo (absolute rates in the Cochrane review meta-analysis were 83.2% with iloprost compared with 40.6% with placebo; RR 2.05, 95% CI 1.68 to 2.49). Common adverse events with intravenous iloprost included pain at the infusion site, headache, flushing, nausea and vomiting, and hypotension. There was no difference between the iloprost and placebo groups in major adverse events such as myocardial infarction, cerebrovascular accident or death from any cause in the fortnight after surgery in the perioperative RCT of people having bypass surgery.

The Cochrane review also included 1 RCT (n=302) comparing different doses of intravenous iloprost. This RCT found a statistically significant dose response in adverse events with intravenous iloprost, but not in efficacy.

The RCTs in the Cochrane review and the perioperative RCT included varying populations and were mostly carried out in the 1990s, so it is not clear to what extent they would be representative of current clinical practice, including current definitions of critical limb ischaemia. In addition, the trials were of poor methodological quality. The evidence supporting the meta-analysed outcomes in the Cochrane review was graded as low or very low quality using the GRADE approach. The trials did not provide evidence about the longer-term efficacy of intravenous iloprost.

Because intravenous iloprost is unlicensed in the UK, no costs could be obtained from standard published sources or the manufacturer. No data were identified that reported the extent to which intravenous iloprost is currently being used to treat critical limb ischaemia in the UK.

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies.

The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.