Published online before print January 22, 2008, doi: 10.1161/CIRCULATIONAHA.107.706374
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(Circulation. 2008;117:816-822.)
© 2008 American Heart Association, Inc.
Vascular Medicine |
Oral Buflomedil in the Prevention of Cardiovascular Events in Patients With Peripheral Arterial Obstructive Disease
A Randomized, Placebo-Controlled, 4-Year Study
Reprint requests to Alain Leizorovicz, MD, Service de Pharmacologie Clinique, EA 3736, Faculté R.T.H. Laennec, Rue Guillaume Paradin, BP 8071–69376 Lyon Cedex 08, France. E-mail al{at}upcl.univ-lyon1.fr
Received April 1, 2007; accepted November 21, 2007.
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Abstract |
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Background— Cardiovascular-related morbidity and mortality in patients with peripheral arterial obstructive disease remain high. We performed an international, multicenter, randomized, double-blind, placebo-controlled trial to investigate whether long-term administration of oral buflomedil could reduce the rate of cardiovascular events in patients with intermittent claudication.
Methods and Results— Patients >40 years of age with documented peripheral arterial obstructive disease, intermittent claudication, and an ankle-brachial index between 0.30 and 0.80 were eligible for inclusion and were randomized to receive orally either buflomedil or placebo for 2 to 4 years. Aspirin was recommended for all patients (unless they were receiving other antithrombotic treatments at inclusion). The primary efficacy outcome was critical cardiovascular events, defined as the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, symptomatic deterioration of peripheral arterial obstructive disease, or leg amputation. A total of 2078 patients were recruited. Mean treatment duration was 33 months. The rate of critical cardiovascular events was significantly lower in buflomedil-randomized patients than in placebo-randomized patients (9.1% versus 12.4%; hazard ratio, 0.742; 95% confidence interval, 0.603 to 0.915; P=0.0163). Ankle-brachial index increased by 9.2% in buflomedil-randomized patients and decreased by 3.6% in placebo-randomized patients (P<0.001). Tolerance of buflomedil and placebo was comparable.
Conclusions— Compared with placebo, buflomedil administered for 3 years reduced the occurrence of symptomatic cardiovascular events by 26%. The main contributor to the difference in the composite outcome was the reduction in symptomatic deterioration of peripheral arterial disease. The use of buflomedil should be considered in addition to an antiplatelet agent in patients with peripheral arterial obstructive disease and intermittent claudication.
Key Words: cardiovascular diseases • peripheral vascular disease • prevention • trials • vasodilatation
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Introduction |
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Peripheral arterial disease (PAD) of the lower limbs is a common age-related disorder.1,2 Based on intermittent claudication, its cardinal symptom, its prevalence in Western societies is 0.5% to 1% in patients 40 to 50 years of age and 7% to 9% in patients 65 to 75 years.3 PAD generally results from atherosclerosis and therefore frequently is associated with coronary and cerebrovascular ischemic diseases.1,4 Optimal treatment of PAD combines various strategies designed to prevent local progression of the disease, to relieve clinical symptoms, to improve quality of daily life, and overall to avert cardiovascular complications associated with a high level of morbidity and mortality.1 This treatment associates lifestyle changes, surgical procedures, and medical treatment, mainly antiplatelet agents, and therapies for high blood pressure, diabetes, and dyslipidemia.1 Despite such treatment, mortality in patients with symptomatic PAD remains high, with a rate of
20% within 5 years after diagnosis5; 80% of deaths are the result of cardiovascular events.6 Therefore, additional therapies are needed.
Editorial p 717
Clinical Perspective p 822
Buflomedil is an 
1-, 2-adrenolytic agent with vasoactive and hemorheologic properties.7–10 Compared with placebo, it appears to improve the walking ability of patients with intermittent claudication.11 On the grounds of its overall effect at the microcirculatory level and its potential benefit on walking distance, we hypothesized that long-term administration of buflomedil also would reduce cardiovascular events. We therefore performed an international, multicenter, randomized, double-blind trial comparing the effect of long-term administration of oral buflomedil with that of placebo on the occurrence of cardiovascular events in patients with PAD-related intermittent claudication. Follow-up extended for up to 4 years after randomization.
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Methods |
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Patients
Patients >40 years of age with documented PAD, intermittent claudication (ie, Fontaine’s stage II PAD), and an ankle-brachial index (ABI) at rest between 0.30 (exclusive) and 0.80 (inclusive) were eligible for the study. ABI was measured on the arms and ankles with a blood pressure cuff and a continuous-wave Doppler probe (8 to 10 MHz). It was calculated by dividing the ankle pressure (measured on the affected lower limb at rest and taking into account the higher of the posterior tibial or fibular artery pressures, except in the case of a clearly false value resulting from mediacalcosis) by the brachial systolic pressure (the higher of the 2 arm pressures). Ultrasound or angiography was performed to confirm the atherosclerotic origin of PAD and to exclude significant proximal lesions (>50%).
Patients were excluded from the study if they presented the following characteristics: ischemic rest pain (ie, Fontaine’s stage III PAD), ulceration or gangrene (ie, 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 (eg, major stroke sequel or major amputation of a lower limb) or the effect of the study treatment (eg, 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.
Study Design
The Limbs International Medicinal Buflomedil (LIMB) study was a randomized, double-blind, placebo-controlled study. Patients were randomly assigned using a centralized computer-generated schedule (1:1 randomization in blocks of 6 and stratified by center and creatinine clearance) to receive orally either buflomedil (Fonzylane, Cephalon France, Maisons-Alfort, France) or placebo for 2 to 4 years. The dosage of buflomedil was adjusted to creatinine clearance: 300 mg twice daily in patients with a creatinine clearance of 
40 mL/min and 150 mg twice daily in patients with a creatinine clearance of <40 mL/min. The day of randomization was defined as day 1. Follow-up visits were scheduled at 1 and 3 months after randomization and then every 6 months up to 48 months.
The study was conducted under the supervision of the Steering Committee. A Data Safety and Monitoring Board was established to evaluate the progress of the trial, including periodic assessments of efficacy and safety data, to make recommendations to the Steering Committee as to whether the study was to be continued or to propose any amendments in relation to the results. The members were independent of the Steering Committee. As indicated below, the Data Safety and Monitoring Board conducted a planned interim analysis.
The study was conducted in accordance with the ethics principles stated in the Declaration of Helsinki and local regulations. The protocol was approved by independent local institutional review boards, and written informed consent was obtained from all patients before randomization.
Treatments
The study medications consisted of round, white, coated tablets. Buflomedil and placebo tablets were indistinguishable in terms of shape, smell, and appearance. Patients not receiving any antithrombotic treatment at trial initiation were advised to take an antiplatelet agent (low-dose aspirin 75 to 100 mg) or vitamin K antagonist during the study period. Peripheral vasodilators (including prostacyclin) were prohibited and were to be discontinued before trial initiation.
Outcome Measures
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 PAD (defined as clinical worsening of the symptoms reported by the patient, ie, invalidating claudication or stage III/IV disease, or acute/subacute homolateral or contralateral ischemia requiring the implementation of new therapeutic strategies, including administration of an intravenous vasoactive treatment, physiotherapy under medical supervision at a specialized center, vascular or endovascular surgery, or angioplasty), or leg amputation. Secondary efficacy end points included the individual components of the primary efficacy outcome, death resulting from any cause, and all cardiovascular events. The pain-free and maximal walking distances (as assessed by patient questioning), ABI values, and quality of life (ie, ability to perform daily life activities according to the patient using a 0- to 100-mm subjective visual analogue scale) were other secondary efficacy end points. The primary safety outcome was adverse events, with special attention paid to myoclonia and convulsion. All critical cardiovascular events and all cases of neurological symptoms and serious adverse events were reviewed and validated by the independent Critical Event Committee, the members of which were unaware of the patients’ treatment assignments.
Statistical Analysis
The trial was designed to demonstrate that buflomedil was superior to placebo in preventing critical cardiovascular events. Assuming an incidence of critical cardiovascular events without vasoactive treatment of 20% to 24% over a median period of 3 years,2,4 it was estimated that a total of 2000 patients would give a power of 90% to detect a 25% risk reduction with buflomedil at an risk of 0.05. As outlined in its charter, the Data Safety and Monitoring Board conducted a planned interim analysis 6 months after the inclusion of the 1000th patient to make recommendations on the continuation of the study based on efficacy, safety, and futility (using conditional power calculations) considerations. This analysis was performed in a semiblinded fashion, with treatment groups coded as A or B. The significance level for efficacy was set according to the Peto rule at 0.001 to keep an overall significance level of 0.05 for the final analysis. From this analysis, the recommendation was to continue the study as planned.
Analysis of the primary efficacy outcome was performed on the intention-to-treat population, defined as the population of all randomized patients; patients were analyzed in the treatment group to which they had been assigned. The safety analysis was performed on data from patients who had received at least 1 dose of study medication, with patients analyzed according to the treatment actually received (as-treated population). All patients had to have completed a follow-up of at least 24 months.
Qualitative data were reported as numbers and percentages. Quantitative data were reported as mean values (SD) or as median values with range or first and third quartiles. Fisher’s exact test (categorical variables) and Student’s t test (continuous variables) were used to compare groups. For nonnormal data, the Wilcoxon test was used. Critical event-free curves were computed with the Kaplan-Meier method and were compared by use of the log-rank test. Efficacy analyses were performed unadjusted and adjusted for age, sex, renal clearance, ABI, prior myocardial infarction, prior stroke, or diabetes at baseline with the regression-adjustment Cox model. All statistical tests were 2 sided, with the type I error set at 5%. All analyses were performed with SAS software (version 8.02, SAS Institute, Cary, NC).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Study Population
Between February 2000 and May 2002, 2078 patients were enrolled in 123 centers in 4 countries to receive either buflomedil or placebo (Figure 1). All randomized patients received at least 1 dose of study treatment and were analyzed for efficacy and safety. The follow-up was completed in March 2004, with 15 patients (0.7%) lost to follow-up. The median duration of follow-up was comparable in both groups, ie, 2.75 years.
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Demographic variables, medical history, severity of PAD, and concomitant treatments at baseline were comparable in the 2 study groups (Table 1; P=not significant for each comparison). Before inclusion, 24 patients (1.2%) had experienced rest pain in the right or left limb. Thirteen patients (0.6%) had suffered from ischemic ulcers; 5 patients (0.2%) had suffered from gangrene.
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The mean±SD duration of treatment was 30±11 months (range, 0 to 50 months) and 30±11 months (0 to 48 months) in patients treated with buflomedil and placebo, respectively. Thirty-six patients received either 150 mg buflomedil (n=18) or placebo (n=18) twice daily. Overall, including deaths, 442 patients (21.3%) permanently discontinued study treatments before study completion, with no difference between the 2 groups. The most frequent motive for discontinuation was patient decision (239 patients, 11.5%) (Table 2). In addition, 172 patients (8.3%) temporarily discontinued study treatments before study completion, with no difference between the 2 groups.
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Cardiovascular Events
The rate of the primary outcome was significantly lower in buflomedil-randomized patients than in placebo-randomized patients (9.1% versus 12.4%; absolute risk reduction, 3.26%; 95% confidence interval, 0.50 to 6.01; hazard ratio, 0.742; 95% confidence interval, 0.603 to 0.915; P=0.0163; Table 3 and Figure 2). The benefit of buflomedil remained significant after adjustment of the treatment effect for covariates (age, presence of diabetes, baseline ABI) influencing the risk of critical cardiovascular events (P=0.005). Favorable but not statistically significant differences were observed between the treatment groups for any of the individual components of the primary efficacy outcome and all-cause mortality. In patients with symptomatic deterioration of PAD, an invasive therapeutic strategy (vascular or endovascular surgery or angioplasty) was performed in 77.2% of the patients; overall, this therapeutic approach was performed in 30 buflomedil-randomized patients (2.9%) and in 41 placebo-randomized patients (4.0%).
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Parameters Assessing Disease Progression
Over the whole study period, median ABI increased by 9.2% (range, –0.6% to 23.4%) in buflomedil-randomized patients and decreased by 3.6% (range, –15.6% to 12.0%) in placebo-randomized patients (P<0.001, Wilcoxon test) (Figure 3). Median pain-free walking distance and maximal walking distance increased by 43% (range, 0% to 163%) and 33% (range, 0% to 133%) in buflomedil-randomized patients, respectively, compared with placebo-randomized patients (P<0.001, Wilcoxon test) (Figure 4).
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In the buflomedil group, 73% of patients (n=762) reported that claudication of the most affected lower limb improved at least once during the study period compared with 60% of placebo-randomized patients (n=623) (P<0.001, Fisher’s exact test). Conversely, worsening of claudication of the most affected limb, at least once during the study period, was more frequent in patients randomized to placebo (n=368, 36%) than in those randomized to buflomedil (n=229, 22%) (P<0.001, Fisher’s exact test). Discomfort during daily life activities decreased significantly more in the buflomedil group than in the placebo group (P=0.033, Wilcoxon’s test).
Safety
No difference was observed between the number of patients experiencing serious adverse events among those receiving buflomedil (n=224, 21.5%) and those receiving placebo (n=238, 23.0%). Most serious adverse events were related to disease progression and associated cardiovascular ischemic events. The total mortality rates were comparable between the 2 study groups (Table 3). Only 11 serious adverse events were related to buflomedil and 11 to placebo. No treatment-related cases of convulsion or myoclonia were reported. Excluding deaths, 359 patients (17.3%) withdrew from treatment before study completion. The proportions of patients discontinuing the treatment because of adverse events were similar in the 2 treatment groups (Table 2). By the end of follow-up, 149 patients (7.2%) had died, with death being of cardiovascular origin in 81 patients.
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Discussion |
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This randomized study showed that after a median treatment duration of 33 months, buflomedil reduced the occurrence of a composite outcome of critical cardiovascular events and worsening of clinical symptoms by 26% compared with placebo in patients with PAD-related intermittent claudication. The main benefit of buflomedil was that it prevented the worsening of clinical symptoms, thereby decreasing or delaying recourse to invasive therapy (surgery or angioplasty). A positive trend also was observed in other major components of the composite outcome, eg, cardiovascular death (decreasing from 4.4% in placebo patients to 3.4% in buflomedil patients) and amputation of lower limb (decreasing from 1.5% to 1.0%). Although the rate of the composite outcome was lower than originally expected (10.7% versus 20% to 22%), the 26% risk reduction obtained with buflomedil was significant and in accordance with the initial hypothesis. This amplitude of risk reduction is comparable to that observed with other effective drugs classically administered to patients with PAD: Aspirin and angiotensin-converting enzyme inhibitors reduce the risk of serious vascular events by
25% and statins by 20% per 1-mmol/L reduction in low-density lipoprotein cholesterol.12–15 In light of the high prevalence of PAD, the benefit observed in buflomedil-treated patients also may have a markedly important impact in terms of health economy. It is also important to note that the beneficial effect of buflomedil was demonstrated while most patients were concomitantly receiving an antiplatelet drug (76%), and a number of them were treated with an angiotensin-converting enzyme inhibitor (34%) or a hypolipemic drug (16%). Of note, the relatively low percentage of patients treated with angiotensin-converting enzyme inhibitors or a hypolipemic drug reflects clinical practice at the time of the trial, during which the administration of these drugs was not yet widespread. This combination of various effective treatments may explain why the rate of cardiovascular events observed in the LIMB study was lower than expected. Buflomedil also increased the walking distance of patients and, in a modest but significant manner, ABI. We have no clear explanation as to why median ABI increased in buflomedil-randomized patients, but it is possible that this result may be due to an effect of buflomedil on the collateral pathway and/or a buflomedil-induced decrease in arm blood pressure because the drug exhibits vasoactive properties.16,17 The safety profile of buflomedil was comparable to that of placebo, and compliance was good; the percentage of patients who withdrew over the 3-year study period was low compared with that observed with other drugs tested in this setting.18–21
Although conceived before the release of guidelines for the clinical investigation of medication in PAD,22 many characteristics of the general design and study outcomes of the LIMB study are in agreement with these recommendations. The results were obtained in a large patient population (n=2078), with very few patients lost to follow-up (0.7%), and over a long period of time (48 months). The study population was homogeneous, including only patients with intermittent claudication. It reflects well the demographic and medical characteristics generally observed in such patients.4,19–21,23–25 The beneficial effect of buflomedil was demonstrated using a composite end point evaluating cardiovascular morbidity and mortality. Furthermore, buflomedil positively influenced all components of the composite primary efficacy end point, excluding nonfatal myocardial infarction and stroke; in particular, it reduced cardiovascular mortality by 30%. Importantly, the results in terms of reduction of critical cardiovascular events were comparable regardless of whether patients had diabetes (post hoc analysis not shown; P=0.32; Breslow-Day test).
This is the first clinical trial to examine the effect of buflomedil on cardiovascular events. Previous studies have focused on symptoms of intermittent claudication only.11 The positive effect of buflomedil on both symptoms of intermittent claudication and cardiovascular events may be explained by common underlying mechanisms. Buflomedil has been shown to reduce platelet aggregation, to prevent leukocyte adhesion to the endothelium during hypoxia, and to increase tissue tolerance to ischemia,7–10 all known to be involved in the development of atherogenesis.3 Moreover, we showed that buflomedil significantly increased ABI, which is known to be a strong independent predictor of cardiovascular mortality.26 Interestingly, the beneficial effect of buflomedil on ABI was already evidenced after 6 months of treatment. The magnitude of the effect of buflomedil on cardiovascular events relative to that of placebo tended to increase up to the end of the study at 48 months of treatment. Whether a longer treatment duration would lead to a greater benefit remains to be investigated. The results obtained in previous studies also suggested that other agents with vasodilatory activities such as synthetic prostacyclin analogues may have beneficial effects not only on local symptoms but also on overall cardiovascular events.20,23 However, these were small studies not primarily designed to evaluate vascular events. Buflomedil is an -blocker with vasoactive and hemorheologic properties,7–10,16,17 but whether it would be effective in patients already treated with other vasodilator (eg, angiotensin-converting enzyme inhibitors or calcium blockers) or rheological (eg, cilastazol) drugs is currently unknown.
The inclusion criteria limit the applicability of the results to patients with PAD and intermittent claudication. The study was performed in Europe; thus, the ethnicity of the population was relatively homogeneous. The beneficial effect of buflomedil in patients with more severe disease, ie, ischemic rest pain, ulceration, or gangrene, remains to be determined.
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Conclusions |
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Although the exact mechanism of action of buflomedil remains to be elucidated, the present placebo-controlled study showed for the first time that, apart from improving walking ability, buflomedil treatment for 3 years in addition to antiplatelet therapy reduced the occurrence of symptomatic cardiovascular events by 26%. The main contributor to the difference in the composite outcome was the reduction of symptomatic deterioration of PAD. The use of buflomedil should be considered in addition to an antiplatelet agent in patients with PAD and intermittent claudication.
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LIMB Group Members
Steering Committee: A. Leizorovicz (chair), F. Becker (co-chair), M. Keltai, Y. Lukjanov, K. Roztocil, and P. Vivet (Cephalon France). Critical Event Committee: J.-L. Guilmot (chair), Y. Kerdiles, and P. Lacroix. Data Safety and Monitoring Board: F. Kohler (chair), B. Charbonnier, R. Leverge, and J. Ninet. Writing Committee: A. Leizorovicz (chair) and F. Becker (co-chair). Participating centers: Czech Republic, 7; France, 97; Hungary, 10; and Russia, 9.
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Acknowledgments |
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Source of Funding
This study was supported by an unrestricted grant from Cephalon France, Maisons-Alfort, France.
Disclosures
A. Leizorovicz and F. Becker have received consultant fees from Cephalon France. The other authors report no conflicts.
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References |
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1. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B, for the American Association for Vascular Surgery; Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease; American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; Vascular Disease Foundation. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation. 2006; 113: e463–e654.
2. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, for the TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007; 45 (suppl S): S5–67.[CrossRef][Medline] [Order article via Infotrieve]
3. Ouriel K. Peripheral arterial disease. Lancet. 2000; 358: 1257–1264.[CrossRef]
4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996; 348: 1329–1339.[CrossRef][Medline] [Order article via Infotrieve]
5. Steg PG, Bhatt DL, Wilson PW, D’Agostino R Sr, Ohman EM, Rother J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, Pencina MJ, Goto S, for the REACH Registry Investigators. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007; 297: 1197–1206.
6. Regensteiner JG, Hiatt WR. Current medical therapies for patients with peripheral arterial disease: a critical review. Am J Med. 2002; 112: 49–57.[CrossRef][Medline] [Order article via Infotrieve]
7. Ryckewaert JJ, Maurel A, Marguerie G. In vitro studies of the effect of buflomedil on platelet responsiveness. Haemostasis. 1990; 20: 181–191.[Medline] [Order article via Infotrieve]
8. Boisseau MR, Pruvost A, Renard M, Closse C, Belloc F, Seigneur M, Maurel A. Effect of buflomedil on the neutrophil-endothelial cell interaction under inflammatory and hypoxia conditions. Haemostasis. 1996; 26 (suppl 4): 182–188.[Medline] [Order article via Infotrieve]
9. Menger MD, Steiner D, Pelikan S, Messmer K. Buflomedil hydrochloride attenuates tourniquet-induced microvascular reperfusion injury in striated muscle. Int J Microcirc Clin Exp. 1994; 14: 296–302.[Medline] [Order article via Infotrieve]
10. Holzer K, Thiel M, Kreimeier U, Moritz S, Messmer K. Buflomedil hydrochloride reduces systemic activation of polymorphonuclear leukocytes during hyperdynamic endotoxemia. Shock. 1998; 10: 335–342.[Medline] [Order article via Infotrieve]
11. De Backer TL, Vander Stichele RH, Bogaert MG. Buflomedil for intermittent claudication. Cochrane Database Syst Rev. 2001; 1: CD000988.[Medline] [Order article via Infotrieve]
12. Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial disease. JAMA. 2006; 295: 547–553.
13. Heart Outcome Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145–153.
14. 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: 71–86.
15. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005; 366: 1267–1278.[CrossRef][Medline] [Order article via Infotrieve]
16. Dubourg A, Scamuffa RF. An experimental overview of a new vasoactive drug: buflomedil HCl. Angiology. 1981; 32: 663–675.
17. Platania A, Sciuto V, De Martino Rosaroll G. Vasoactive effects of buflomedil assessed by fluorescein angiography. Curr Med Res Opin. 1987; 10: 457–467.[Medline] [Order article via Infotrieve]
18. Meade TW, for the British Medical Research Council General Practice Research Framework and participating vascular clinics. Design and intermediate results of the Lower Extremity Arterial Disease Event Reduction (LEADER) trial of bezafibrate in men with lower extremity arterial disease. Curr Control Trials Cardiovasc Med. 2001; 2: 195–204.[CrossRef][Medline] [Order article via Infotrieve]
19. Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ. 2002; 325: 1139–1144.
20. Mohler ER 3rd, Hiatt WR, Olin JW, Wade M, Jeffs R, Hirsch AT. Treatment of intermittent claudication with beraprost sodium, an orally active prostaglandin I2 analogue: a double-blinded, randomized, controlled trial. J Am Coll Cardiol. 2003; 41: 1679–1686.
21. Mohler ER 3rd, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation. 2003; 108: 1481–1486.
22. Committee for Proprietary Medicinal Products (CPMP). Note for Guidance on Clinical Investigation of Medicinal Products for the Treatment of Peripheral Arterial Occlusive Disease. London, UK: European Agency for the Evaluation of Medicinal Products; 2002. CPMP/EWP/714/98 rev 1.
23. Lievre M, Morand S, Besse B, Fiessinger JN, Boissel JP. Oral Beraprost sodium, a prostaglandin I(2) analogue, for intermittent claudication: a double-blind, randomized, multicenter controlled trial: Beraprost et Claudication Intermittente (BERCI) Research Group. Circulation. 2000; 102: 426–431.
24. Aronow WS, Nayak D, Woodworth S, Ahn C. Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment. Am J Cardiol. 2003; 92: 711–712.[CrossRef][Medline] [Order article via Infotrieve]
25. WAVE Investigators. The effects of oral anticoagulants in patients with peripheral arterial disease: rationale, design, and baseline characteristics of the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, including a meta-analysis of trials. Am Heart J. 2006; 151: 1–9.[CrossRef][Medline] [Order article via Infotrieve]
26. Doobay AV, Anand SS. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systematic review. Arterioscler Thromb Vasc Biol. 2005; 25: 1463–1469.
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Circulation 2008 117: 711-713.
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  T. L. De Backer, R. H. Vander Stichele, and L. M. Van Bortel 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, September 2, 2008; 118(10): e151 - e151. [Full Text] [PDF]
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