Brass 2012.

Study characteristics
Methods	Study design: multicentre, randomised, double‐blind, placebo‐controlled Intention‐to‐treat: yes; LOCF method Country: USA and Russia
Participants	Number randomised: 387 (cilostazol, n = 89; K‐134 25 mg, n = 42; K‐134 50 mg, n = 85; K‐134 100 mg, n = 84; placebo, n = 87) Age (mean years): cilostazol = 64.5; K‐134 25 mg = 63.3; K‐134 50 mg = 63.8; K‐134 100 mg = 62.8; placebo = 62.9 Sex (M%): cilostazol = 94.6; K‐134 25 mg = 83.3; K‐134 50 mg = 86.8; K‐134 100 mg = 82.3; placebo = 89.7 Inclusion criteria: aged ≥ 40 years; had PAD as documented by an ABI ≤ 0.90 or an ABI between 0.90 and 1.00 that fell by ≤ 0.20 within one minute following termination of treadmill exercise; patients with a peak walking time at baseline between one and 12 minutes Exclusion criteria: critical limb ischaemia, amputation or other non‐claudication limitation to treadmill performance; revascularisation ≤ 3 months; poorly controlled hyperlipidaemia or hypertension; major surgical procedure ≤ 6 months; myocardial infarction ≤ 4 months; history or evidence of congestive heart failure; electrocardiogram abnormalities; clinically significant laboratory or other medical conditions that pose a safety risk; use of warfarin or aspirin monotherapy, aspirin combined with clopidogrel or ticlopidine, strong inhibitors of cytochrome P3A4, use of other PDE inhibitors, use of pentoxifylline or L‐carnitine
Interventions	Treatment 1: cilostazol 100 mg, twice daily Treatment 2: K‐134 25 mg, twice daily Treatment 3: K‐134 50 mg, twice daily (initially started on 25 mg twice daily and then increased after two weeks) Treatment 4: K‐135 100 mg, twice daily (initially started on 50 mg twice daily and then increased after two weeks) Control: placebo, twice daily Duration: 26 weeks
Outcomes	Peak walking time, claudication onset time, inflammatory bio‐markers, safety and adverse events; measured at baseline (twice) and weeks 2, 4, 14 and 26
Funding	Kowa Research Institute
Declaration of interests	"Dr Morgan is an employee of the study’s sponsor, Kowa Research Institute. Drs Brass, Cooper, and Hiatt were compensated by the study’s sponsor, Kowa Research Institute, for their service on the project’s steering committee. Dr Hiatt is president of the non‐profit Colorado Prevention Center, which provided academic contract research organization services (paid for by Kowa Research Institute) for the reported trial".
Notes	Only data on the cilostazol and placebo groups were included in this review; the K‐134 25 mg, 50 mg and 100 mg groups were excluded from this review because K‐134 is not an alternative antiplatelet agent or medication currently known to increase walking distance. The treadmill test was only described as "graded" with a reference to another study, but we were unable to determine which of the treadmill tests from the referred paper the authors used. The K‐134 arm of 25 mg twice daily was discontinued early because it was found to be minimally informative, and no outcome data were recorded.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was conducted through a central interactive voice response system and used block randomization by site to minimize risk of imbalances".
Allocation concealment (selection bias)	Low risk	"Randomization was conducted through a central interactive voice response system".
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Although the study used a placebo, there was insufficient description to determine if blinding was adequate.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of assessors was not adequately discussed.
Incomplete outcome data (attrition bias) All outcomes	Low risk	"The highest rates of discontinuations were observed in the 100‐mg K‐134 and cilostazol arms... but there were no statistical differences in discontinuation rates across arms". Reasons for discontinuation were similar across treatment groups.
Selective reporting (reporting bias)	Low risk	All outcomes included in the description of methods were reported on.
Other bias	Low risk	No evidence of other bias