Cochrane Database of Systematic Reviews Pharmacological treatment for Buerger’s disease (Review) Cacione DG, Macedo CR, Baptista-Silva JCC Cacione DG, Macedo CR, Baptista-Silva JCC. Pharmacological treatment for Buerger’s disease. Cochrane Database of Systematic Reviews 2016, Issue 3. Art. No.: CD011033. DOI: 10.1002/14651858.CD011033.pub3. www.cochranelibrary.com Pharmacological treatment for Buerger’s disease (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER....................................... 1 ABSTRACT ...................................... 1 PLAINLANGUAGESUMMARY . 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . ..... 4 BACKGROUND .................................... 7 OBJECTIVES ..................................... 8 METHODS ...................................... 8 RESULTS....................................... 10 Figure1. ..................................... 11 Figure2. ..................................... 12 Figure3. ..................................... 13 Figure4. ..................................... 16 ADDITIONALSUMMARYOFFINDINGS . 17 DISCUSSION ..................................... 24 AUTHORS’CONCLUSIONS . 25 ACKNOWLEDGEMENTS . 25 REFERENCES ..................................... 26 CHARACTERISTICSOFSTUDIES . 28 DATAANDANALYSES. 37 Analysis 1.1. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 1 Ulcer healing (8 weeks) - iloprost200mcg. ................................ 38 Analysis 1.2. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 2 Ulcer healing (8 weeks) - iloprost400mcg. ................................ 39 Analysis 1.3. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 3 Ulcer healing (6 months) - iloprost200mcg. ................................ 39 Analysis 1.4. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 4 Ulcer healing (6 months) - iloprost400mcg. ................................ 40 Analysis 1.5. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 5 Complete relief of rest pain (8 weeks)-iloprost200mcg. 40 Analysis 1.6. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 6 Complete relief of rest pain (8 weeks)-iloprost400mcg. 41 Analysis 1.7. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 7 Complete relief of rest pain (6 months)-iloprost200mcg.. 41 Analysis 1.8. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 8 Complete relief of rest pain (6 months)-iloprost400mcg.. 42 Analysis 1.9. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 9 Rate of amputation - iloprost 200mcg. ................................... 42 Analysis 1.10. Comparison 1 Oral prostacyclin analogue (iloprost) versus placebo, Outcome 10 Rate of amputation - iloprost400mcg. ................................ 43 Analysis 2.1. Comparison 2 Intravenous prostacyclin analogue (iloprost) versus oral aspirin, Outcome 1 Ulcer healing (4 weeks)..................................... 43 Analysis 2.2. Comparison 2 Intravenous prostacyclin analogue (iloprost) versus oral aspirin, Outcome 2 Ulcer healing (6 months). ................................... 44 Analysis 2.3. Comparison 2 Intravenous prostacyclin analogue (iloprost) versus oral aspirin, Outcome 3 Complete relief of restpain(4weeks)................................. 44 Analysis 2.4. Comparison 2 Intravenous prostacyclin analogue (iloprost) versus oral aspirin, Outcome 4 Rate of amputation. .................................. 45 Analysis 3.1. Comparison 3 Prostacyclin versus prostaglandinE1,Outcome1Ulcerhealing. 45 Analysis 3.2. Comparison 3 Prostacyclin versus prostaglandin E1, Outcome 2 Complete relief of pain. 46 Analysis 4.1. Comparison 4 Folic acid versus placebo, Outcome 1 Pain (0 month). 46 Analysis 4.2. Comparison 4 Folic acid versus placebo, Outcome 2 Pain (2 months). 47 Pharmacological treatment for Buerger’s disease (Review) i Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 4.3. Comparison 4 Folic acid versus placebo, Outcome 3 Pain (6 months). 47 Analysis 4.4. Comparison 4 Folic acid versus placebo, Outcome 4 Change in rate of amputation (2 months). 48 Analysis 4.5. Comparison 4 Folic acid versus placebo, Outcome 5 Change in rate of amputation (6 months). 48 APPENDICES ..................................... 48 FEEDBACK...................................... 51 WHAT’SNEW..................................... 52 CONTRIBUTIONSOFAUTHORS . 53 DECLARATIONSOFINTEREST . 53 SOURCESOFSUPPORT . 53 DIFFERENCES BETWEEN PROTOCOL AND REVIEW . .... 54 INDEXTERMS .................................... 54 Pharmacological treatment for Buerger’s disease (Review) ii Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Pharmacological treatment for Buerger’s disease Daniel G Cacione1, Cristiane R Macedo2, Jose CC Baptista-Silva3 1Department of Surgery, UNIFESP - Escola Paulista de Medicina, São Paulo, Brazil. 2Brazilian Cochrane Centre, Centro de Estudos de Saúde Baseada em Evidências e Avaliação Tecnológica em Saúde, São Paulo, Brazil. 3Evidence Based Medicine, Cochrane Brazil, Universidade Federal de São Paulo, São Paulo, Brazil Contact address: Daniel G Cacione, Department of Surgery, UNIFESP - Escola Paulista de Medicina, Rua Borges Lagoa, 564 cj 124, Vila Clementino, São Paulo, 04038000, Brazil. [email protected]. [email protected]. Editorial group: Cochrane Vascular Group. Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 3, 2016. Review content assessed as up-to-date: 13 April 2015. Citation: Cacione DG, Macedo CR, Baptista-Silva JCC. Pharmacological treatment for Buerger’s disease. Cochrane Database of Systematic Reviews 2016, Issue 3. Art. No.: CD011033. DOI: 10.1002/14651858.CD011033.pub3. Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT Background Buerger’s disease (thromboangiitis obliterans) is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small and medium sized arteries, veins, and nerves in the upper and lower extremities. The etiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularization to improve the condition. Pharmacological treatment is an option for patients with severe complications, such as ischaemic ulcers or rest pain. Objectives To assess the effectiveness of any pharmacological agent (intravenous or oral) compared with placebo or any other pharmacological agent in patients with Buerger’s disease. Search methods The Cochrane Vascular Trials Search Co-ordinator searched their Specialised Register (last searched in April 2015) and the Cochrane Register of Studies (Issue 3, 2015). The review authors searched trial registers and the European grey literature; screened reference lists of relevant studies, and contacted study authors and major pharmaceutical companies. Selection criteria Randomised controlled trials (RCTs) involving pharmacological agents used in the treatment of Buerger’s disease. Data collection and analysis Two review authors, independently assessed the studies, extracted data and performed data analysis. Main results Five randomised controlled trials (total 602 participants) compared prostacyclin analogue with placebo, aspirin, or a prostaglandin analogue, and folic acid with placebo. No studies assessed other pharmacological agents such as cilostazol, clopidogrel and pentoxifylline or compared oral versus intravenous prostanoid. Compared with aspirin, intravenous prostacyclin analogue iloprost improved ulcer healing (risk ratio (RR) 2.65; 95% confidence interval (CI) 1.15 to 6.11; 98 participants; one study; moderate quality evidence), and helped to eradicate rest pain after 28 days Pharmacological treatment for Buerger’s disease (Review) 1 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (RR 2.28; 95% CI 1.48 to 3.52; 133 participants; one study; moderate quality evidence), although amputation rates were similar six months after treatment (RR 0.32; 95% CI 0.09 to 1.15; 95 participants; one study; moderate quality evidence). When comparing prostacyclin (iloprost and clinprost) with prostaglandin (alprostadil) analogues, ulcer healing was similar (RR 1.13; 95% CI 0.76 to 1.69; 89 participants; two studies; I² = 0%; very low quality evidence), as was the eradication of rest pain after 28 days (RR 1.57; 95% CI 0.72 to 3.44; 38 participants; one study; low quality evidence), while amputation rates were not measured. Compared with placebo, the effects of oral prostacyclin analogue iloprost were similar for: healing ischaemic ulcers (iloprost 200 mcg: RR 1.11; 95% CI 0.54 to 2.29; 133 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 0.90; 95% CI 0.42 to 1.93; 135 participants; one study; moderate quality evidence), eradication of rest pain after eight weeks (iloprost 200 mcg: RR 1.14; 95% CI 0.79 to 1.63; 207 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 1.11; 95% CI 0.77 to 1.59; 201 participants; one study; moderate quality evidence), and amputation rates after six months (iloprost 200 mcg: RR 0.54; 95% CI 0.19 to 1.56; 209 participants; one study, and iloprost 400 mcg: RR 0.42; 95% CI 0.13 to 1.31; 213 participants; one study). When comparing folic