| Study characteristics |
| 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); IC which was chronic (at least 6 months), stable (3 months); evidence of POAD; 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 IC; history or current evidence of concomitant exercise‐limiting disease other than IC; 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 ECG, etc.), adverse events; measured at baseline and weeks 2, 4, 8, 12, 16, 20 and 24 |
| Funding |
Otsuka America Pharmaceutical Inc. |
| Declaration of interests |
Not reported ‐ source of the study data was a medical review by the FDA. |
| 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 was 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 |
Low risk |
No evidence of other bias |
