Methods

Study design: international, multicenter, randomized, placebo‐controlled, double‐blinded.

Participating centers: Czech Republic, France, Hungary, Russia

Method of randomization:a centralized computer‐generated schedule (1:1 randomization in blocks of 6 and stratified by center and creatinine clearance)

Blinding:double‐blind; buflomedil and placebo were indistinguishable in terms of shape, smell and appearance

Statistical analysis: primary efficacy outcome performed on the intention‐to‐treat population; safety analysis performed on the as‐treated population;

Dropouts:buflomedil: 223 patients permanently stopped treatment prior to study completion (including death) and 5 patients lost to follow‐up; placebo: 219 patients permanently stopped treatment prior to study completion (including death) and 10 patients lost to follow‐up

Participants

Patients > 40 y with documented peripheral arterial obstructive disease, intermittent claudication, and an ankle‐brachial index between 0,30 and 0,80

Patients were excluded from the study if they presented the following characteristics: ischemic rest pain (i.e., Fontaine's stage III PAD), ulceration or gangrene (i.e., Fontaine’s stage IV PAD), iliac or common femoral artery stenosis or occlusion, arterial occlusion of embolic origin, Buerger disease, or any nonatherosclerotic arterial
disease of the lower limbs. Likewise, patients with confounding factor(s) interfering with the evaluation of PAD (e.g., major stroke sequel or major amputation of a lower limb) or the effect of the study treatment (e.g., patients in whom vasoactive treatments could not be discontinued or who were already under treatment with buflomedil
started 1 month previously) were not recruited. Other exclusion criteria were acute myocardial infarction or stroke within the last 45 days, vascular or endovascular surgery within the last 45 days or planned within the next month, active cancer, poor short‐term vital prognosis, and thrombophilia. Finally, pregnant or breast‐feeding
women and women of childbearing age not using effective contraception could not participate in the study.

n = 2078 patients randomized: 1043 to buflomedil, 1035 to placebo

Interventions

Long‐term administration (mean 33 months) of oral buflomedil or placebo

Outcomes

1. The primary efficacy outcome was critical cardiovascular events, defined as the composite of cardiovascular death (including sudden death of presumed cardiac origin), nonfatal myocardial infarction, nonfatal stroke, symptomatic deterioration of peripheral arterial obstructive disease, or leg amputation

2. Secondary efficacy end points included the individual components of the primary efficacy outcome, death resulting from any cause, and all cardiovascular events. Other secondary efficacy endpoints were pain‐free and maximal walking distances (as assessed by patient questioning), ABI values, and quality of life (i.e. ability to perform daily life activities according to the patient using a 0‐ to 100‐mm subjective visual analogue scale)

3. The primary safety outcome was adverse events, with special attention paid to myoclonia and convulsion

Notes

Although this is a large, double‐blind RCT, we excluded this study because PFWD and MWD were not measured by an objective standardized test.

Because of safety reasons, oral buflomedil 300 mg tablets are not anymore on the market

From certain experts in the vascular field (Olin J, NY, USA) criticism has been made on the reliability of the study data

An associated editorial by MS Conte (Boston, MA, USA) (Circulation 2008;117:717‐9)
softened the conclusion of the LIMB study group authors that the use of buflomedil should be considered in addition to an antiplatelet agent in patients with peripheral arterial obstructive disease and intermittent claudication

There was also a letter to the Editor (Letter by De Backer et al regarding article, "Oral buflomedil in the prevention of cardiovascular events in patients with peripheral arterial obstructive disease: a randomized, placebo‐controlled, 4‐year study". Circulation 2008;118;e151)

Methods

Study design: international, multicenter, randomized, placebo‐controlled, double‐blinded.

Participating centers: Czech Republic, France, Hungary, Russia

Method of randomization:a centralized computer‐generated schedule (1:1 randomization in blocks of 6 and stratified by center and creatinine clearance)

Blinding:double‐blind; buflomedil and placebo were indistinguishable in terms of shape, smell and appearance

Statistical analysis: primary efficacy outcome performed on the intention‐to‐treat population; safety analysis performed on the as‐treated population;

Dropouts:buflomedil: 223 patients permanently stopped treatment prior to study completion (including death) and 5 patients lost to follow‐up; placebo: 219 patients permanently stopped treatment prior to study completion (including death) and 10 patients lost to follow‐up

Participants

Patients > 40 y with documented peripheral arterial obstructive disease, intermittent claudication, and an ankle‐brachial index between 0,30 and 0,80

Patients were excluded from the study if they presented the following characteristics: ischemic rest pain (i.e., Fontaine's stage III PAD), ulceration or gangrene (i.e., Fontaine’s stage IV PAD), iliac or common femoral artery stenosis or occlusion, arterial occlusion of embolic origin, Buerger disease, or any nonatherosclerotic arterial
disease of the lower limbs. Likewise, patients with confounding factor(s) interfering with the evaluation of PAD (e.g., major stroke sequel or major amputation of a lower limb) or the effect of the study treatment (e.g., patients in whom vasoactive treatments could not be discontinued or who were already under treatment with buflomedil
started 1 month previously) were not recruited. Other exclusion criteria were acute myocardial infarction or stroke within the last 45 days, vascular or endovascular surgery within the last 45 days or planned within the next month, active cancer, poor short‐term vital prognosis, and thrombophilia. Finally, pregnant or breast‐feeding
women and women of childbearing age not using effective contraception could not participate in the study.

n = 2078 patients randomized: 1043 to buflomedil, 1035 to placebo

Interventions

Long‐term administration (mean 33 months) of oral buflomedil or placebo

Outcomes

1. The primary efficacy outcome was critical cardiovascular events, defined as the composite of cardiovascular death (including sudden death of presumed cardiac origin), nonfatal myocardial infarction, nonfatal stroke, symptomatic deterioration of peripheral arterial obstructive disease, or leg amputation

2. Secondary efficacy end points included the individual components of the primary efficacy outcome, death resulting from any cause, and all cardiovascular events. Other secondary efficacy endpoints were pain‐free and maximal walking distances (as assessed by patient questioning), ABI values, and quality of life (i.e. ability to perform daily life activities according to the patient using a 0‐ to 100‐mm subjective visual analogue scale)

3. The primary safety outcome was adverse events, with special attention paid to myoclonia and convulsion

Notes

Although this is a large, double‐blind RCT, we excluded this study because PFWD and MWD were not measured by an objective standardized test.

Because of safety reasons, oral buflomedil 300 mg tablets are not anymore on the market

From certain experts in the vascular field (Olin J, NY, USA) criticism has been made on the reliability of the study data

An associated editorial by MS Conte (Boston, MA, USA) (Circulation 2008;117:717‐9)
softened the conclusion of the LIMB study group authors that the use of buflomedil should be considered in addition to an antiplatelet agent in patients with peripheral arterial obstructive disease and intermittent claudication

There was also a letter to the Editor (Letter by De Backer et al regarding article, "Oral buflomedil in the prevention of cardiovascular events in patients with peripheral arterial obstructive disease: a randomized, placebo‐controlled, 4‐year study". Circulation 2008;118;e151)