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Meta-Analysis
. 2021 Jun 30;6(6):CD003748.
doi: 10.1002/14651858.CD003748.pub5.

Cilostazol for intermittent claudication

Tamara Brown  1 , Rachel B Forster  2 , Marcus Cleanthis  3 , Dimitri P Mikhailidis  4 , Gerard Stansby  5 , Marlene Stewart  1   6
Affiliations
Meta-Analysis

Cilostazol for intermittent claudication

Tamara Brown et al. Cochrane Database Syst Rev. .

Abstract

Background: Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent claudication (exercise-induced lower limb pain relieved by rest). These patients have a three- to six-fold increase in cardiovascular mortality. Cilostazol is a drug licensed for the use of improving claudication distance and, if shown to reduce cardiovascular risk, could offer additional clinical benefits. This is an update of the review first published in 2007.

Objectives: To determine the effect of cilostazol on initial and absolute claudication distances, mortality and vascular events in patients with stable intermittent claudication.

Search methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries, on 9 November 2020.

Selection criteria: We considered double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other drugs used to improve claudication distance in patients with stable intermittent claudication.

Data collection and analysis: Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We assessed the risk of bias with the Cochrane risk of bias tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) and for continuous outcomes we used mean differences (MDs) and 95% CIs. We pooled data using a fixed-effect model, or a random-effects model when heterogeneity was identified. Primary outcomes were initial claudication distance (ICD) and quality of life (QoL). Secondary outcomes were absolute claudication distance (ACD), revascularisation, amputation, adverse events and cardiovascular events.

Main results: We included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies also compared cilostazol with pentoxifylline. Treatment duration ranged from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Cilostazol dose ranged from 100 mg to 300 mg; pentoxifylline dose ranged from 800 mg to 1200 mg. The certainty of the evidence was downgraded by one level for all studies because publication bias was strongly suspected. Other reasons for downgrading were imprecision, inconsistency and selective reporting. Cilostazol versus placebo Participants taking cilostazol had a higher ICD compared with those taking placebo (MD 26.49 metres; 95% CI 18.93 to 34.05; 1722 participants; six studies; low-certainty evidence). We reported QoL measures descriptively due to insufficient statistical detail within the studies to combine the results; there was a possible indication in improvement of QoL in the cilostazol treatment groups (low-certainty evidence). Participants taking cilostazol had a higher ACD compared with those taking placebo (39.57 metres; 95% CI 21.80 to 57.33; 2360 participants; eight studies; very-low certainty evidence). The most commonly reported adverse events were headache, diarrhoea, abnormal stools, dizziness, pain and palpitations. Participants taking cilostazol had an increased odds of experiencing headache compared to participants taking placebo (OR 2.83; 95% CI 2.26 to 3.55; 2584 participants; eight studies; moderate-certainty evidence).Very few studies reported on other outcomes so conclusions on revascularisation, amputation, or cardiovascular events could not be made. Cilostazol versus pentoxifylline There was no difference detected between cilostazol and pentoxifylline for improving walking distance, both in terms of ICD (MD 20.0 metres, 95% CI -2.57 to 42.57; 417 participants; one study; low-certainty evidence); and ACD (MD 13.4 metres, 95% CI -43.50 to 70.36; 866 participants; two studies; very low-certainty evidence). One study reported on QoL; the study authors reported no difference in QoL between the treatment groups (very low-certainty evidence). No study reported on revascularisation, amputation or cardiovascular events. Cilostazol participants had an increased odds of experiencing headache compared with participants taking pentoxifylline at 24 weeks (OR 2.20, 95% CI 1.16 to 4.17; 982 participants; two studies; low-certainty evidence).

Authors' conclusions: Cilostazol has been shown to improve walking distance in people with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache. There is insufficient evidence about the effectiveness of cilostazol for serious events such as amputation, revascularisation, and cardiovascular events. Despite the importance of QoL to patients, meta-analysis could not be undertaken because of differences in measures used and reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance and data were too limited for any conclusions on other outcomes.

PubMed Disclaimer

Conflict of interest statement

TB: none.

RBF: none.

MC: none.

DPM: declared that he received payment to attend meetings (Amgen, Novo Nordisk), advisory boards (Novo Nordisk), and present lectures on lipids and cilostazol (Amgen, Novo Nordisk and Libytec). It is five years since his last lecture on cilostazol (Libytec). As Editor‐in‐Chief; royalties were paid to him (Informa, SAGE and Bentham publications). He has published peer‐reviewed material regarding cilostazol.

GS: none.

MS: MS is a member of the Cochrane Vascular editorial base. In order to maintain integrity, editorial tasks for this review have been carried out by other members of the editorial team.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 1: Initial claudication distance (ICD)
1.2
1.2. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 2: Absolute claudication distance (ACD)
1.3
1.3. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 3: Arterial revascularisation
1.4
1.4. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 4: Amputation
1.5
1.5. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 5: Adverse event related to study medication ‐ headache
1.6
1.6. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 6: Adverse event related to study medication ‐ diarrhoea
1.7
1.7. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 7: Adverse event related to study medication ‐ abnormal stools
1.8
1.8. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 8: Adverse event related to study medication ‐ dizziness
1.9
1.9. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 9: Adverse event related to study medication ‐ pain
1.10
1.10. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 10: Adverse event related to study medication ‐ palpitations
1.11
1.11. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 11: Cardiovascular event
1.12
1.12. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 12: All‐cause mortality
1.13
1.13. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 13: Ankle brachial index (ABI)
1.14
1.14. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 14: Initial claudication distance (ICD) sensitivity analysis
1.15
1.15. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 15: Absolute claudication distance (ACD) sensitivity analysis
1.16
1.16. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 16: Adverse event related to study medication ‐ headache, sensitivity analysis
1.17
1.17. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 17: Adverse event related to study medication ‐ diarrhoea, sensitivity analysis
1.18
1.18. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 18: Adverse event related to study medication ‐ pain, sensitivity analysis
1.19
1.19. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 19: Adverse event related to study medication ‐ palpitations, sensitivity analysis
1.20
1.20. Analysis
Comparison 1: Cilostazol versus placebo, Outcome 20: All‐cause mortality sensitivity analysis
2.1
2.1. Analysis
Comparison 2: Cilostazol 100 mg twice daily versus pentoxifylline 400 mg three times daily, Outcome 1: Initial claudication distance (ICD)
2.2
2.2. Analysis
Comparison 2: Cilostazol 100 mg twice daily versus pentoxifylline 400 mg three times daily, Outcome 2: Absolute claudication distance (ACD)
2.3
2.3. Analysis
Comparison 2: Cilostazol 100 mg twice daily versus pentoxifylline 400 mg three times daily, Outcome 3: Adverse event related to study medication ‐ headache
2.4
2.4. Analysis
Comparison 2: Cilostazol 100 mg twice daily versus pentoxifylline 400 mg three times daily, Outcome 4: Adverse event related to study medication ‐ diarrhoea
2.5
2.5. Analysis
Comparison 2: Cilostazol 100 mg twice daily versus pentoxifylline 400 mg three times daily, Outcome 5: Adverse event related to study medication ‐ abnormal stools
2.6
2.6. Analysis
Comparison 2: Cilostazol 100 mg twice daily versus pentoxifylline 400 mg three times daily, Outcome 6: Adverse event related to study medication ‐ pain
2.7
2.7. Analysis
Comparison 2: Cilostazol 100 mg twice daily versus pentoxifylline 400 mg three times daily, Outcome 7: Adverse event related to study medication ‐ palpitations
2.8
2.8. Analysis
Comparison 2: Cilostazol 100 mg twice daily versus pentoxifylline 400 mg three times daily, Outcome 8: All‐cause mortality
2.9
2.9. Analysis
Comparison 2: Cilostazol 100 mg twice daily versus pentoxifylline 400 mg three times daily, Outcome 9: Ankle brachial index (ABI)
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Beebe 1999 {published data only}
    1. Beebe HG, Dawson DL, Cutler BS, Herd JA, Strandness DE Jr, Bortey EB, et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Archives of Internal Medicine 1999;159(17):2041-50. - PubMed
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study 21-92-202. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Brass 2012 {published data only}
    1. Brass EP, Cooper LT, Morgan RE, Hiatt WR. A phase II dose-ranging study of the phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication. Journal of Vascular Surgery 2012;55(2):381-9. - PubMed
    1. Hiatt WR, Cooper LT, Morgan RE, Brass EP. Clinical effects of the phosphodiesterase inhibitor K-134 in peripheral artery disease and claudication. Circulation 2011;124(Suppl 21):A9800. - PubMed
    1. Lewis RJC. Application of adaptive design and decision making to a phase II trial of a phosphodiesterase inhibitor for the treatment of intermittent claudication. Trials 2011;12:134. - PMC - PubMed
    1. NCT00783081. Safety and efficacy of K-134 for the treatment of intermittent claudication. www.clinicaltrials.gov/ct2/show/NCT00783081 (first posted 31 October 2008).
Dawson 1998 {published data only}
    1. Dawson DL, Cutler BS, Meissner MH, Strandness DE Jr. Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial. Circulation 1998;98(7):678-86. - PubMed
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study 21-90-201. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Dawson 2000 {published data only}
    1. Dawson DL, Cutler BS, Hiatt WR, Hobson RW 2nd, Martin JD, Bortey EB, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. American Journal of Medicine 2000;109(7):523-30. - PubMed
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study 21-96-202. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
De Albuquerque 2008 {published data only}
    1. De Albuquerque RM, Virgini-Magalhães CE, Lencastre SF, Bottino DA, Bouskela E. Effects of cilostazol and pentoxifylline on forearm reactive hyperemia response, lipid profile, oxidative stress, and inflammatory markers in patients with intermittent claudication. Angiology 2008;59(5):549-58. - PubMed
Elam 1998 {published data only}
    1. Elam MB, Heckman J, Crouse JR, Hunninghake DB, Herd JA, Davidson M, et al. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arteriosclerosis, Thrombosis, and Vascular Biology 1998;18(12):1942-7. - PubMed
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study 21-93-201. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Lee 2001 {published data only}
    1. Lee TM, Su SF, Hwang JJ, Tseng CD, Chen MF, Lee YT, et al. Differential lipogenic effects of cilostazol and pentoxifylline in patients with intermittent claudication: potential role for interleukin-6. Atherosclerosis 2001;158(2):471-6. - PubMed
    1. Lee TM, Su SF, Tsai CH, Lee YT, Wang SS. Differential effects of cilostazol and pentoxifylline on vascular endothelial growth factor in patients with intermittent claudication. Clinical Science 2001;101(3):305-11. - PubMed
Money 1998 {published data only}
    1. Money SR, Herd JA, Isaacsohn JL, Davidson M, Cutler B, Heckman J, et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. Journal of Vascular Surgery 1998;27(2):267-74. - PubMed
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study 21-94-203. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
O'Donnell 2009 {published data only}
    1. O'Donnell M, Badger SA, Sharif MA, Young IS, Lau LL, Lee B, et al. Randomised controlled trial assessing the effects of cilostazol on exercise-induced ischaemia-reperfusion in patients with peripheral arterial disease. In: European Society for Vascular Surgery Annual Meeting; 2008 Sep 4-7; Nice, France. 2008:43.
    1. O'Donnell ME, Badger SA, Makar RR, McEneny J, Young IS, Lau LL, et al. The effects of cilostazol on the attenuation of inflammatory response in patients with peripheral arterial disease. The Vascular Society of Great Britain and Ireland Yearbook 2007:49.
    1. O'Donnell ME, Badger SA, Makar RR, Young IS, Lau LL, Lee B, et al. The effects of cilostazol in diabetic patients. The Vascular Society of Great Britain and Ireland Yearbook 2007:82.
    1. O'Donnell ME, Badger SA, Sharif MA, Makar RR, McEneny J, Young IS, et al. The effects of cilostazol on exercise-induced ischaemia-reperfusion injury in patients with peripheral arterial disease. European Journal of Vascular and Endovascular Surgery 2009;37(3):326-35. - PubMed
    1. O'Donnell ME, Badger SA, Sharif MA, Makar RR, Young IS, Lee B, et al. The effects of cilostazol on peripheral neuropathy in diabetic patients with peripheral arterial disease. Angiology 2008;59(6):695-704. - PubMed
Otsuka Study 21‐86‐101 {unpublished data only}
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study 21-86-101. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Otsuka Study 21‐86‐103 {unpublished data only}
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study 21-86-103. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Otsuka Study 21‐87‐101 {unpublished data only}
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study 21-87-101. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Otsuka Study 21‐94‐301 {unpublished data only}
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study 21-94-301. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Otsuka Study 21‐95‐201 {unpublished data only}
    1. Otsuka 21-95-201. A randomised double-blind study of the safety and efficacy of two different doses of cilostazol versus placebo in patients with intermittent claudication secondary to peripheral vascular disease. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Otsuka Study 21‐98‐213 {unpublished data only}
    1. Anon. Pletal (cilostazol). Study 21-98-213 PACE. Otsuka Pharmaceuticals Submission to NICE: Cilostazol for the symptomatic treatment of intermittent claudication secondary to peripheral arterial disease (accessed prior to 16 June 2021).
    1. European Medicines Agency. Assessment report for Cilostazol containing medicinal products. ema.europa.eu/docs/en_GB/document_library/Referrals_document/Cilostazol_... (accessed prior to 22 June 2021).
Strandness 2002 {published data only}
    1. Otsuka 21-94-201. A randomised double blind study of the effect of cilostazol versus placebo on walking distances in patients with intermittent claudication secondary to peripheral vascular disease. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
    1. Strandness DE Jr, Dalman RL, Panian S, Rendell MS, Comp PC, Zhang P, et al. Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. Vascular and Endovascular Surgery 2002;36(2):83-91. - PubMed

References to studies excluded from this review

CASTLE 2008 {published data only}
    1. Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: a study in long-term effects). Journal of Vascular Surgery 2008;47(2):330-6. - PubMed
    1. Otsuka 21-98-214-01. CASTLE. A randomized, double-blind, placebo-controlled, multicenter, parallel-arm, study to assess the long-term effects of Pletal® (Cilostazol) versus placebo administered orally to patients with intermittent claudication secondary to peripheral arterial disease. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
    1. Stone WM, Demaerschalk BM, Fowl RJ, Money SR. Type 3 phosphodiesterase inhibitors may be protective against cerebrovascular events in patients with claudication. Journal of Stroke and Cerebrovascular Diseases 2008;17(3):129-33. - PubMed
    1. Stone WM, Fowl RJ, Money SR. Type 3 phosphodiesterase inhibitors may be protective against cerebrovascular events in patients with claudication. In: Vascular Annual Meeting; 2007 Jun 6-10; Baltimore. 2007. - PubMed
Chao 2014 {published data only}
    1. Chao TH, Tseng SY, Chen IC, Tsai YS, Huang YY, Liu PY, et al. Cilostazol enhances mobilization and proliferation of endothelial progenitor cells and collateral formation by modifying vasculo-angiogenic biomarkers in peripheral arterial disease. International Journal of Cardiology 2014;172(2):e371-4. [DOI: 10.1016/j.ijcard.2013.12.295] - DOI - PubMed
Chao 2016 {published data only}
    1. Chao TH, Chen IC, Lee CH, Chen JY, Tsai WC, Li YH, et al. Cilostazol enhances mobilization of circulating endothelial progenitor cells and improves endothelium-dependent function in patients at high risk of cardiovascular disease. Angiology 2016;67(7):638-46. [DOI: 10.1177/0003319715606249] - DOI - PubMed
    1. Chao TH, Chen IC, Liu PY, Tsai WC, Li YH, Tseng SY, et al. Cilostazol enhances mobilization of circulating endothelial progenitor cells and improves endothelium-dependent function mediated by modifying metabolic and angiogenic markers in patients with high risk for cardiovascular disease. Journal of the American College of Cardiology 2015;65(10):A1650.
    1. Chao TH, Liu PY, Tsai WC, Tseng SY, Li YH. The vasculo-angiogenic and vaso-protective effects of cilostazol in patients with high risk for cardiovascular disease. European Heart Journal 2015;36(Suppl 1):229. [DOI: 10.1093/eurheartj/ehv399] - DOI
    1. Chao TH, Tseng SY, Tsai YS, Huang YY, Liu PY, Ou HY, et al. Cilostazol enhances mobilization and proliferation of circulating endothelial progenitor cells and collateral formation mediated by modifying vasculo-angiogenic biomarkers in patients with peripheral arterial occlusive disease. Journal of the American College of Cardiology 2013;61(10):E2052. [DOI: ] - PubMed
Chen 2017 {published data only}
    1. Chao TH, Li YH, Tseng SY, Liu PY. The associations between the effect of cilostazol on the proprotein convertase subtilisin/kexin type 9 concentrations and circulating endothelial progenitor cells and vasculo-angiogenesis factors. European Heart Journal 2018;39(Suppl 1):523. [DOI: 10.1093/eurheartj/ehy565.P2620] - DOI
    1. Chen IC, Tseng WK, Li YH, Tseng SY, Liu PY, Chao TH. Effect of cilostazol on plasma levels of proprotein convertase subtilisin/kexin type 9. Oncotarget 2017;8(64):108042-53. - PMC - PubMed
ChiCTR‐TRC‐09000441 {published data only}
    1. ChiCTR-TRC-09000441. Evaluation of efficacy of cilostazol on type 2 diabetes with ischemic disease of lower extremity by transcutaneous oxygen pressure measurement. who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-TRC-09000441 (retrospectively registered 24 June 2009).
Chisari 2019 {published data only}
    1. Chisari LM, Malaguarnera S, Grasso A, Malaguarnera M, Chisari G, Borzì AM, et al. Cilostazol reduces dry eye symptoms and improve walking distance in patients with peripheral artery disease. La Clinica Terapeutica 2019;170(5):e357-63. [DOI: 10.7417/CT.2019.2160] - DOI - PubMed
Goldenberg 2012 {published data only}
    1. Goldenberg NA, Krantz MJ, Hiatt WR. L-Carnitine plus cilostazol versus cilostazol alone for the treatment of claudication in patients with peripheral artery disease: a multicenter, randomized, double-blind, placebo-controlled trial. Vascular Medicine 2012;17(3):145-54. [DOI: 10.1177/1358863X12442264] - DOI - PubMed
Hsieh 2009 {published data only}
    1. Hsieh CJ, Wang PW. Effect of cilostazol treatment on adiponectin and soluble CD40 ligand levels in diabetic patients with peripheral arterial occlusion disease. Circulation Journal 2009;73(5):948-54. - PubMed
JPRN‐C000000215 {published data only}
    1. JPRN-C000000215. Study on therapeutic effects of antiplatelet drugs in prevention of occurrence and inhibition of progression of diabetic atherosclerosis. who.int/trialsearch/Trial2.aspx?TrialID=JPRN-C000000215 (first posted 2005).
JPRN‐UMIN000001198 {published data only}
    1. JPRN-UMIN000001198. Cilostazol trial. http://www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000001198 (first posted 20 June 2008).
JPRN‐UMIN000011869 {published data only}
    1. JPRN-UMIN000011869. Relationship between arteriosclerosis obliterans and serum level of eicosapentaenoic acid as prospective interventional study. http://www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000011869 (first posted 26 September 2013).
JPRN‐UMIN000014307 {published data only}
    1. JPRN-UMIN000014307. Phase IIb double blinded parallel group dose response study for DVC1-0101 to treat severe intermittent claudication. http://www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000014307 (first posted 1 September 2014).
Kim 2013 {published data only}
    1. Kim NH, Kim HY, An H, Seo JA, Kim NH, Choi KM, et al. Effect of cilostazol on arterial stiffness and vascular adhesion molecules in type 2 diabetic patients with metabolic syndrome: a randomised, double-blind, placebo-controlled, crossover trial. Diabetology and Metabolic Syndrome 2013;5(1):41. - PMC - PubMed
Mazzone 2013 {published data only}
    1. Mazzone A, Di Salvo M, Mazzuca S, Valerio A, Gussoni G, Bonizzoni E, et al. Effects of iloprost on pain-free walking distance and clinical outcome in patients with severe stage IIb peripheral arterial disease: the FADOI 2b PILOT Study. European Journal of Clinical Investigation 2013;43(11):1163-70. [DOI: 10.1111/eci.12159] - DOI - PubMed
NCT00102050 {published data only}
    1. NCT00102050. Efficacy and safety of NM-702 tablets for the treatment of intermittent claudication. clinicaltrials.gov/show/NCT00102050 (first received 19 January 2005).
NCT00300339 {published and unpublished data}
    1. NCT00300339. MASCOT: mixed antagonist of serotonin for claudication optimal therapy. clinicaltrials.gov/ct2/show/NCT00300339 (first received 8 March 2006).
NCT00443287 {published and unpublished data}
    1. NCT00443287. Efficacy and safety of HMR1766 in patients with Fontaine Stage II peripheral arterial disease. www.clinicaltrials.gov/ct2/show/NCT00443287 (first posted 5 March 2007).
NCT00573950 {published data only}
    1. NCT00573950. Effects of cilostazol on plasma adipocytokine and arterial stiffness. clinicaltrials.gov/show/NCT00573950 (first posted 14 December 2007).
NCT00886574 {published data only}
    1. NCT00886574. Cilostazol versus aspirin for primary prevention of atherosclerotic events (CAPPA). clinicaltrials.gov/show/NCT00886574 (first posted 22 April 2009).
NCT00912756 {published data only}
    1. NCT00912756. Sufficient treatment of peripheral intervention by cilostazol (STOP-IC). clinicaltrials.gov/ct2/show/NCT00912756 (first posted 2 June 2009).
NCT01188824 {published data only}
    1. NCT01188824. The safety and efficacy of cilostazol in ischemic stroke patients with peripheral arterial disease (SPAD study). clinicaltrials.gov/ct2/show/NCT01188824 (first posted 26 August 2010).
NCT01952756 {published data only}
    1. NCT01952756. Effect of cilostazol endothelial progenitor cells and collateral formation in peripheral occlusive artery disease (PAOD). clinicaltrials.gov/show/NCT01952756 (first posted 21 September 2013).
NCT02373462 {published data only}
    1. NCT02373462. Effect of olmesaRtan on walking distancE and quaLIty of lifE in peripheral artery disease patients with hypertension treated for intermittent claudication (RELIEF). clinicaltrials.gov/show/NCT02373462 (first posted 14 February 2015).
NCT02407314 {published data only}
    1. NCT02407314. Ticagrelor and peripheral arterial disease. clinicaltrials.gov/ct2/show/NCT02407314 (first posted 18 March 2015).
NCT02636283 {published data only}
    1. NCT02636283. Use of entresto sacubitril/valsartan for the treatment of peripheral arterial disease. clinicaltrials.gov/show/NCT02636283 (first posted 29 October 2015).
NCT02930811 {published data only}
    1. NCT02930811. Efficacy of sildenafil on the morbi-mortality of peripheral arterial diseased patients with intermittent claudication (VALSTAR). clinicaltrials.gov/show/NCT02930811 (first posted 10 October 2016).
NCT03318276 {published data only}
    1. NCT03318276. Clinical trial to evaluate efficacy and safety of SID142 in patients with chronic artery occlusive disease. clinicaltrials.gov/show/NCT03318276 (first posted 18 October 2017).
NCT03686306 {published data only}
    1. NCT03686306. VIRTUOSE: efficiency of sildenafil on the absolute claudication distance of peripheral arterial disease patients with intermittent claudication (VIRTUOSE). clinicalTrials.gov/show/NCT03686306 (first posted 24 September 2018).
Otsuka Study PUIC‐1 {published data only}
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study PUIC-1. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Otsuka Study PUIC‐2 {published data only}
    1. Otsuka America. Pletal (Cilostazol) Tablets. Study PUIC-2. www.accessdata.fda.gov/drugsatfda_docs/nda/99/20863.cfm (accessed May 2014).
Xiao 2010 {published data only}
    1. Xiao Z, Chen L, Yang C, Yang H, Luo B, Mai L, et al. Evaluation of cilostazol efficacy on type 2 diabetes with lower limb ischemic disease by transcutaneous oxygen pressure measurement. In: American Diabetes Association. 70th Scientific Sessions; 2010. Guangdong, China (professional.diabetes.org/abstract/evaluation-cilostazol-efficacy-type-2... American Diabetes Association, 2010 (accessed 1 April 2021).

References to studies awaiting assessment

Sapelkin 2013 {published data only}
    1. Sapelkin SV, Kharazov AF. Advanced position in the conservative treatment of patients with peripheral arterial disease. Khirurgiia 2013;4:68-73. - PubMed

Additional references

Aboyans 2018
    1. Aboyans V, Ricco JB, Bartelink ME, Björck M, Brodmann M, Cohnert T, et al, ESC Scientific Document Group. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Endorsed by: the European Stroke Organization (ESO), The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). European Heart Journal 2018;39(9):763-816. - PubMed
ATT 2002
    1. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324(7329):71-86. - PMC - PubMed
Barriocanal 2016
    1. Barriocanal AM, Lopez AM, Farre M, Montane E. Recommendations of intermittent claudication symptomatic treatment in peripheral arterial disease clinical practice guidelines. Basic and Clinical Pharmacology and Toxicology 2016;119(Suppl 1):53.
Broderick 2020
    1. Broderick C, Forster R, Abdel-Hadi M, Salhiyyah K. Pentoxifylline for intermittent claudication. Cochrane Database of Systematic Reviews 2020, Issue 10. Art. No: CD005262. [DOI: 10.1002/14651858.CD005262.pub4] - DOI - PMC - PubMed
Chapman 2003
    1. Chapman TM, Goa KL. Cilostazol: a review of its use in intermittent claudication. American Journal of Cardiovascular Drugs 2003;3(2):117-38. - PubMed
Cosmi 2014
    1. Cosmi B, Conti E, Coccheri S. Anticoagulants (heparin, low molecular weight heparin and oral anticoagulants) for intermittent claudication. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No: CD001999. [DOI: 10.1002/14651858.CD001999.pub2] - DOI - PMC - PubMed
Dawson 2001
    1. Dawson DL. Comparative effects of cilostazol and other therapies for intermittent claudication. American Journal of Cardiology 2001;87(12A):19D-27D. - PubMed
Dormandy 1999
    1. Dormandy J, Heeck L, Vig S. The natural history of claudication: risk to life and limb. Seminars in Vascular Surgery 1999;12(2):123-37. - PubMed
Fakhry 2018
    1. Fakhry F, Fokkenrood HJP, Spronk S, Teijink JAW, Rouwet EV, Hunink MGM. Endovascular revascularisation versus conservative management for intermittent claudication. Cochrane Database of Systematic Reviews 2018, Issue 3. Art. No: CD010512. [DOI: 10.1002/14651858.CD010512.pub2] - DOI - PMC - PubMed
Gerhard‐Herman 2017
    1. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. 2016 AHA/ACC Guidelines on the Management of Patients with Lower Extremity Peripheral Artery Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology 2017;69:e71-e126. - PubMed
GRADEpro [Computer program]
    1. McMaster University (developed by Evidence Prime) GRADEpro GDT. Version accessed 14 January 2021. Hamilton (ON): McMaster University (developed by Evidence Prime). Available at gradepro.org.
Haile 2020
    1. Haile S, Linné A, Johansson UB, Joelsson-Alm E. Follow-up after surgical treatment for intermittent claudication (FASTIC): a study protocol for a multicentre randomised controlled clinical trial. BMC Nursing 2020;19(45):1-12. [DOI: 10.1186/s12912-020-00437-7] - DOI - PMC - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from training.cochrane.org/handbook/archive/v5.1.
Higgins 2021
    1. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.
Higgins 2021a
    1. Higgins JPT , Eldridge S, Li T. Chapter 23: Including variants on randomized trials. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane 2021. Available from www.training.cochrane.org/handbook.
Iida 2008
    1. Iida O, Nanto S, Uematsu M, Morozumi T, Kitakaze M, Nagata S. Cilostazol reduces restenosis after endovascular therapy in patients with femoropopliteal lesions. Journal of Vascular Surgery 2008;48(1):144-9. - PubMed
Khan 2005
    1. Khan S, Cleanthis M, Smout J, Flather M, Stansby G. Life-style modification in peripheral arterial disease. European Journal of Vascular and Endovascular Surgery 2005;29(1):2-9. - PubMed
Lane 2017
    1. Lane R, Harwood A, Watson L, Leng GC. Exercise for intermittent claudication. Cochrane Database of Systematic Reviews 2017, Issue 12. Art. No: CD000990. [DOI: 10.1002/14651858.CD000990.pub4] - DOI - PMC - PubMed
Lee 2013
    1. Lee SW, Ahn JM, Han S, Park GM, Cho YR, Lee WS, et al. Differential impact of cilostazol on restenosis according to implanted stent type (from a pooled analysis of three DECLARE randomized trials). American Journal of Cardiology 2013;112(9):1328-34. - PubMed
Lefebvre 2011
    1. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from training.cochrane.org/handbook/archive/v5.1.
Leng 1996
    1. Leng GC, Lee AJ, Fowkes FG, Whiteman M, Dunbar J, Housley E, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral artery disease in the general population. International Journal of Epidemiology 1996;25(6):1172-81. - PubMed
NICE 2011
    1. National Institute for Health and Care Excellence (NICE). Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease. nice.org.uk/guidance/TA223/chapter/2-Clinical-need-and-practice (accessed 11 July 2014).
NICE 2012
    1. National Institute for Health and Care Excellence (NICE). Peripheral arterial disease: diagnosis and management (last updated December 2020). nice.org.uk/Guidance/CG147 (accessed 12 March 2021).
Niu 2016
    1. Niu PP, Guo ZN, Jin H, Xing YQ, Yang Y. Antiplatelet regimens in the long-term secondary prevention of transient ischaemic attack and ischaemic stroke: an updated network meta-analysis. BMJ Open 2016;6(3):e009013. [DOI: 10.1136/bmjopen-2015-009013] - DOI - PMC - PubMed
PAD 2003
    1. Peripheral Arterial Diseases Antiplatelet Consensus Group. Antiplatelet therapy in peripheral arterial disease. Consensus statement. European Journal of Vascular and Endovascular Surgery 2003;26(1):1-16. - PubMed
Regensteiner 2002
    1. Regensteiner JG, Ware JE Jr, McCarthy WJ, Zhang P, Forbes WP, Heckman J, et al. Effect of cilostazol on treadmill walking, community-based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease: meta-analysis of six randomized controlled trials. Journal of the American Geriatrics Society 2002;50(12):1939-46. - PubMed
RevMan Web 2019 [Computer program]
    1. The Cochrane Collaboration Review Manager Web (RevMan Web). The Cochrane Collaboration, 2019. Available at revman.cochrane.org.
Rizzo 2011
    1. Rizzo M, Corrado E, Patti AM, Rini GB, Mikhailidis DP. Cilostazol and atherogenic dyslipidemia: a clinically relevant effect? Expert Opinion on Pharmacotherapy 2011;12(4):647-55. - PubMed
Robless 2001
    1. Robless P, Mikhailidis D, Stansby G. Systematic review of antiplatelet therapy for prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease. British Journal of Surgery 2001;88(6):787-800. - PubMed
Sallustio 2010
    1. Sallustio F, Rotondo F, Di Legge S, Stanzione P. Cilostazol in the management of atherosclerosis. Current Vascular Pharmacology 2010;8(3):363-72. - PubMed
Schünemann 2021
    1. Schünemann HJ, Higgins JPT, Vist GE, Glasziou P, Akl EA, Skoetz N, et al. Chapter 14: Completing ‘Summary of findings’ tables and grading the certainty of the evidence. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.
Squires 2010
    1. Squires H, Simpson E, Meng Y, Harnan S, Stevens J, Wong R, National Institute for Health and Clinical Excellence. Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for intermittent claudication in people with peripheral arterial disease. Technology Assessment Report commissioned by the NIHR HTA Programme. www.guidance.nice.org.uk/nicemedia/live/12265/51580/51580.pdf (accessed May 2014). - PubMed
Squires 2011
    1. Squires H, Simpson E, Meng Y, Harnan S, Stevens J, Wong R, et al. A systematic review and economic evaluation of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease. Health Technology Assessment 2011;15(40):1-210. [DOI: 10.3310/hta15400] - DOI - PMC - PubMed
Stevens 2012
    1. Stevens JW, Simpson E, Harnan S, Squires H, Meng Y, Thomas S, et al. Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication. British Journal of Surgery 2012;99(12):1630-8. - PubMed
Thompson 2002
    1. Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. American Journal of Cardiology 2002;90(12):1314-9. - PubMed
Ueno 2011
    1. Ueno H, Koyama H, Mima Y, Fukumoto S, Tanaka S, Shoji T, et al. Comparison of the effect of cilostazol with aspirin on circulating endothelial progenitor cells and small-dense LDL cholesterol in diabetic patients with cerebral ischemia: a randomized controlled pilot trial. Journal of Atherosclerosis and Thrombosis 2011;18(10):883-90. - PubMed
Wong 2011
    1. Wong PF, Chong LY, Mikhailidis DP, Robless P, Stansby G. Antiplatelet agents for intermittent claudication. Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No: CD001272. [DOI: 10.1002/14651858.CD001272.pub2] - DOI - PubMed

References to other published versions of this review

Bedenis 2014
    1. Bedenis R, Stewart M, Cleanthis M, Robless P, Mikhailidis DP, Stansby G. Cilostazol for intermittent claudication. Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No: CD003748. [DOI: 10.1002/14651858.CD003748.pub4] - DOI - PMC - PubMed
Robless 2007
    1. Robless P, Mikhailidis DP, Stansby GP. Cilostazol for peripheral arterial disease. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No: CD003748. [DOI: 10.1002/14651858.CD003748.pub2] - DOI - PubMed
Robless 2008
    1. Robless P, Mikhailidis DP, Stansby GP. Cilostazol for peripheral arterial disease. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No: CD003748. [DOI: 10.1002/14651858.CD003748.pub3] - DOI - PubMed

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