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Meta-Analysis
. 2018 Jan 10;1(1):CD006544.
doi: 10.1002/14651858.CD006544.pub3.

Prostanoids for critical limb ischaemia

Valeria Vietto  1 , Juan Va Franco, Victoria Saenz, Denise Cytryn, Jose Chas, Agustín Ciapponi
Affiliations
Meta-Analysis

Prostanoids for critical limb ischaemia

Valeria Vietto et al. Cochrane Database Syst Rev. .

Abstract

Background: Peripheral arterial occlusive disease (PAOD) is a common cause of morbidity and mortality due to cardiovascular disease in the general population. Although numerous treatments have been adopted for patients at different disease stages, no option other than amputation is available for patients presenting with critical limb ischaemia (CLI) unsuitable for rescue or reconstructive intervention. In this regard, prostanoids have been proposed as a therapeutic alternative, with the aim of increasing blood supply to the limb with occluded arteries through their vasodilatory, antithrombotic, and anti-inflammatory effects. This is an update of a review first published in 2010.

Objectives: To determine the effectiveness and safety of prostanoids in patients with CLI unsuitable for rescue or reconstructive intervention.

Search methods: For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (January 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1). In addition, we searched trials registries (January 2017) and contacted pharmaceutical manufacturers, in our efforts to identify unpublished data and ongoing trials.

Selection criteria: Randomised controlled trials describing the efficacy and safety of prostanoids compared with placebo or other pharmacological control treatments for patients presenting with CLI without chance of rescue or reconstructive intervention.

Data collection and analysis: Two review authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. We resolved disagreements by consensus or by consultation with a third review author.

Main results: 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.

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

VV: none known. JVAF: none known. VS: none known. DC: none known. JC: none known. AC: none known.

Figures

1
1
Study flow diagram. *Out of 22 excluded studies, nine studies evaluated an inappropriate intervention for control group, seven included participants not fulfilling inclusion criteria with no available disaggregated outcome data, four were abstracts with no available full text, one had a quasi‐randomised design, and another was unpublished and had no available results.
2
2
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
4
4
Funnel plot of comparison: 1 Prostanoids versus placebo, outcome: 1.2 Total amputations.
5
5
Forest plot of comparison: 1 Prostanoids versus placebo, outcome: 1.10 Total amputations. Sensitivity analysis excluding studies at high risk of attrition bias.
1.1
1.1. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 1 Cardiovascular mortality.
1.2
1.2. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 2 Total amputations.
1.3
1.3. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 3 Adverse events (participants).
1.4
1.4. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 4 Rest‐pain relief (dichotomous).
1.5
1.5. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 5 Rest‐pain relief (dichotomous) ‐ sensitivity analysis.
1.6
1.6. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 6 Rest‐pain relief (continuous).
1.7
1.7. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 7 Reduction in analgesics consumption.
1.8
1.8. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 8 Ulcer healing.
1.9
1.9. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 9 Ulcer healing ‐ sensitivity analysis.
1.10
1.10. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 10 Major amputations.
1.11
1.11. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 11 Minor amputations.
1.12
1.12. Analysis
Comparison 1 Prostanoids versus placebo, Outcome 12 All‐cause mortality.
2.1
2.1. Analysis
Comparison 2 Prostanoids versus naftidrofuryl, Outcome 1 Total amputations.
2.2
2.2. Analysis
Comparison 2 Prostanoids versus naftidrofuryl, Outcome 2 Adverse events (participants).
2.3
2.3. Analysis
Comparison 2 Prostanoids versus naftidrofuryl, Outcome 3 Rest‐pain relief.
2.4
2.4. Analysis
Comparison 2 Prostanoids versus naftidrofuryl, Outcome 4 Ulcer healing.
3.1
3.1. Analysis
Comparison 3 PGE1 versus ATP, Outcome 1 Total amputations.
3.2
3.2. Analysis
Comparison 3 PGE1 versus ATP, Outcome 2 Adverse events (participants).
4.1
4.1. Analysis
Comparison 4 Iloprost versus PGE1, Outcome 1 Adverse events (participants).
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Jogestrand 1985 {published data only}
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Karnik 1986 {published data only}
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Linet 1991 {published data only}
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NCT00596752 {unpublished data only}
    1. Alprostadil in Peripheral Arterial Occlusive Disease (PAOD) Stage IV (ESPECIAL) [Multinational, prospective, randomized, double blind, placebo controlled, parallel groups study to assess the efficacy and safety of prostaglandin E1 in subjects with critical limb ischemia (Fontaine Stage IV)]. clinicaltrials.gov/ct2/show/NCT00596752. Date first received: 21 December 2007. [2005‐001970‐29 ( EudraCT Number); SP0777 (Sponsor ID)]
Negus 1987 {published data only}
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Norgren 1990 {published data only}
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Reisin 1997 {published data only}
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Sakaguchi 1984 {published data only}
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Schellong 2004 {published data only}
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Telles 1984 {published data only}
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References to studies excluded from this review

Arosio 1998 {published data only}
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NCT00059644 {published data only}
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Schwarz 1995 {published data only}
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Sert 2008 {published data only}
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