Otsuka Study 21‐94‐301.

Methods	Study design: randomised, double‐blind, placebo‐controlled Intention to treat: yes; LOCF method Country: USA
Participants	Number randomised: 370 (cilostazol n = 123; pentoxifylline n = 123; placebo n = 124) Age (mean years): cilostazol = 66; pentoxifylline = 66; placebo = 66 Sex %M: cilostazol = 70; pentoxifylline = 72; placebo = 73 Inclusion criteria: Aged ≥ 40 years (both sexes); intermittent claudication which was chronic (at least 6 months), stable (3 months); Evidence of peripheral occlusive arterial disease; ACD ≤ 450 m in ≤ 8 minutes 28 seconds with no more than 20% variability in two consecutive tests during lead‐in period; ICD of at least 30 m in 34 seconds during lead‐in period; supine ABI of ≤ 0.80 after 10 minutes of rest Exclusion criteria: current use of pentoxifylline or previous discontinuation for inefficacy or adverse event; female of childbearing potential; greater than 60% above ideal body weight; supine arterial BP > 200 mmHg systolic or > 100 mmHg diastolic; sympathectomy or lower extremity arterial reparative surgery within the previous 3 months; DVT within the previous 3 months; termination of treadmill test for reasons other than intermittent claudication; history or current evidence of concomitant exercise‐limiting disease other than intermittent claudication; history of bleeding tendencies; history of cerebrovascular bleed, cerebral or dissecting aortic aneurysm, pericarditis, or pericardial effusion; active peptic disease; recent or anticipated surgical procedures; platelet count < 120 x 109/ litre, twice the normal values for AST or ALT, or serum creatinine > 220 μmol/ litre; current alcohol or other drug abuse, or use of an investigational drug within the past 30 days; a requirement for the uninterrupted use of platelet‐active, anticoagulant, NSAIDs or haemorheologic agents
Interventions	Treatment 1: cilostazol 100 mg, twice daily with third placebo dose to maintain blind, oral administration Treatment 2: pentoxifylline 400 mg, three times daily Control: placebo Duration: 24 weeks
Outcomes	ACD, ICD, subjective claudication improvement by physician and patient; all‐cause death, cardiovascular events, safety endpoints (vital signs, 12‐lead EKG, etc), adverse events; measured at baseline and weeks 2, 4, 8, 12, 16, 20 and 24
Notes	Immediate‐incline treadmill method: incline load started immediately at 10% and remained constant with a constant speed of 3.2 km/h Four‐ to eight‐week lead‐in period
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient description of sequence generation methods
Allocation concealment (selection bias)	Unclear risk	Insufficient description of allocation concealment methods
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"CLZ, PTX and placebo tablets were encapsulated into identical capsule, and blinding of the dose interval was to be preserved by administered [sic] a third daily dose of placebo to CLZ‐randomized subjects"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of assessors is not adequately discussed
Incomplete outcome data (attrition bias) All outcomes	Low risk	Accounted for all dropouts
Selective reporting (reporting bias)	High risk	No reporting of all‐cause death or cardiovascular events
Other bias	Unclear risk	Study supported by Otsuka America Pharmaceutical Inc