***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Intermittent claudication is the primary symptom of peripheral arterial disease , affecting between 1 and 3 million Americans . Symptomatic improvement can be achieved by endovascular revascularization , but such procedures are invasive , expensive , and may be associated with procedural adverse events . Medical treatment options , including claudication medications and supervised exercise training , are also known to be effective , albeit also with associated limitations . The CLEVER ( Claudication : Exercise Vs . Endoluminal Revascularization ) study , funded by the Heart , Lung , and Blood Institute of the National Institutes of Health , is a prospect i ve , multicenter , r and omized , controlled clinical trial evaluating the relative efficacy , safety , and health economic impact of four treatment strategies for people with aortoiliac peripheral arterial disease and claudication . The treatment arms are : ( 1 ) optimal medical care ( claudication pharmacotherapy ) ; ( 2 ) primary stent placement ; ( 3 ) supervised exercise rehabilitation ; and ( 4 ) combined stenting with supervised exercise rehabilitation . The CLEVER study is a 5-year r and omized , controlled clinical trial to be conducted at approximately 25 centers in the United States that will monitor 252 patients and their responses to treatment during an 18-month follow-up period . The primary end point is change in maximum walking duration on a grade d treadmill test . Secondary end points include the change at 18 months in maximum walking duration from baseline , comparisons of free-living daily activity levels assessed by pedometer , health-related quality of life , and cost-effectiveness . Other analyses include the effect of these treatment strategies on anthropomorphic and physiologic variables , including body mass index , waist circumference , blood pressure , pulse pressure , and resting pulse as well as biochemical markers of cardiovascular health , including fasting lipids , fibrinogen , C-reactive protein , and hemoglobin A 1c values Background —We determined whether statin use ( versus nonuse ) is associated with superior lower-extremity functioning independently of cholesterol levels and other confounders in patients with and without peripheral arterial disease . Methods and Results — Participants included 392 men and women with an ankle brachial index ( ABI ) < 0.90 and 249 with ABI 0.90 to 1.50 . Functional outcomes included 6-minute walk distance and 4-meter walking velocity . A summary performance score combined performance in walking speed , st and ing balance , and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 ( 12=best ) . Adjusting for age , sex , ABI , comorbidities , education level , medical insurance status , cholesterol , and other confounders , participants taking statins  had better 6-minute walk performance ( 1276 versus 1218 feet , P = 0.045 ) , faster walking velocity ( 0.93 versus 0.89 m/s , P = 0.006 ) , and a higher summary performance score ( 10.2 versus 9.4 , P < 0.001 ) than participants not taking statins . Positive associations were attenuated slightly after additional adjustment for C-reactive protein level but remained statistically significant for walking velocity and the summary performance score . We did not find significant associations between lower-extremity functioning and  aspirin , ACE inhibitors , vasodilators , or & bgr;-blockers . Conclusions —Statin use is associated with superior leg functioning compared with no statin use , independent of cholesterol levels and other potential confounders . These data suggest that non – cholesterol-lowering properties of statins may favorably influence functioning in persons with and without peripheral arterial disease Simvastatin significantly increased treadmill exercise time until onset of intermittent claudication from baseline by 54 seconds ( a 24 % increase , p < 0.0001 ) at 6 months after treatment and by 95 seconds ( a 42 % increase , p < 0.0001 ) at 1 year after treatment . At 6 months and 1 year after treatment with placebo , treadmill exercise time until onset of intermittent claudication was not significantly different from baseline exercise time Background —Cholesterol modification reduces cardiovascular events in patients with atherosclerosis , including those with peripheral arterial disease . The purpose of this study was to determine whether cholesterol lowering with atorvastatin improves walking performance in patients with intermittent claudication . Methods and Results —This r and omized , double-blind , parallel- design study included 354 persons with claudication attributable to peripheral arterial disease . Patients were treated with placebo , atorvastatin ( 10 mg per day ) , or atorvastatin ( 80 mg per day ) for 12 months . The outcome measures included change in treadmill exercise time and patient-reported measures of physical activity and quality of life based on question naires . Maximal walking time after 12 months of treatment with atorvastatin did not change significantly . However , there was improvement in pain-free walking time after 12 months of treatment for the 80-mg ( P = 0.025 ) group compared with placebo . A physical activity question naire demonstrated improvement in ambulatory ability for the 10- and 80-mg groups ( P = 0.011 ) , whereas 2 quality of life instruments , the Walking Impairment Question naire and Short Form 36 Question naire , did not show significant change . Conclusions —Atorvastatin improves pain-free walking distance and community-based physical activity in patients with intermittent claudication . When treated with atorvastatin , patients with peripheral arterial disease may experience improvement in symptoms to complement the anticipated reduction in cardiovascular events reported in other studies of statins Background — Cardiovascular-related morbidity and mortality in patients with peripheral arterial obstructive disease remain high . We performed an international , multicenter , r and omized , 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 r and omized 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 infa rct ion , 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-r and omized patients than in placebo-r and omized 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-r and omized patients and decreased by 3.6 % in placebo-r and omized 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 BACKGROUND Changes in blood rheology have been described in diabetes mellitus .  Buflomedil , a vasoactive substance with hemorheological properties , has been widely used in the treatment of intermittent claudication . The aim of this study was to evaluate the effect of buflomedil on clinical and hemorheological parameters in subjects with type 2 diabetes and intermittent claudication . METHODS Forty patients were r and omly assigned to oral buflomedil or matching placebo for six months in a double-blind manner . Initial and absolute walking distances were assessed by a st and ard treadmill testing protocol . Erythrocyte deformability was estimated with a whole blood filtration technique . ADP- and collagen-induced platelet aggregation was assessed with an aggregation profiler . beta-thromboglobulin and platelet factor-4 were measured with radioimmunoassays . All tests were performed at baseline and after three and six months of treatment . RESULTS A significant increase in the mean initial ( 71 % ) and absolute ( 68 % ) walking distance was achieved only in the buflomedil group . ADP- and collagen-induced platelet aggregation was significantly reduced in the buflomedil group , while no significant changes in erythrocyte deformability , beta-thromboglobulin and platelet factor-4 levels were noticed . However , beta-thromboglobulin levels increased significantly in the placebo group . CONCLUSIONS These findings suggest the therapeutic efficacy of buflomedil in diabetic subjects with intermittent claudication . The inhibition of platelet aggregation and the influence on platelet activity exerted by the drug could play an important role in its clinical effect and may be of value in the treatment of such patients The efficacy , safety , and cost of pentoxifylline ( PXF ) in long-range ( > 400 m interval ) intermittent claudication was studied comparing PXF and placebo in a 12-month study . A st and ardized treadmill test was performed at inclusion and at 6 and 12 months . A training plan based on walking was associated with the control of risk factor levels . Of the 194 included patients , 135 completed the study : 75 in the PXF group and 60 in the placebo group . There were 59 dropouts ( due to low compliance ) . The authors observed a 148 % increase in total walking distance ( TWD ) at 6 months with PXF ( vs 110 % with placebo ; p<0.05 ) ; at 12 months , the increase was 170 % with PXF ( vs 131 % with placebo ; p<0.02 ) . There was a 38 % difference at 6 months and 39 % at 12 months in favor of PXF .  Treatment was well tolerated . In conclusion , PXF  improved walking distance significantly better than placebo This study compared the safety and efficacy of cilostazol and clopidogrel after coronary stenting . Patients ( n = 689 ) who underwent successful stenting were r and omly assigned to receive cilostazol ( group 1 , n = 344 , 612 lesions ) or clopidogrel ( group 2 , n = 345 , 628 lesions ) . The incidence of subacute stent thrombosis or major adverse cardiac events , including death , myocardial infa rct ion , and target lesion revascularization within 30 days ( 2.6 % in group 1 vs 2.0 % in group 2 , p = 0.61 ) and side effects that required cessation of study drug ( 0.6 % each ) did not differ statistically between groups . These results indicate that cilostazol is as safe and effective as clopidogrel in preventing thrombotic complications after stenting The efficacy , safety , and cost of pentoxifylline ( PXF ) in the treatment of severe intermittent claudication were studied comparing PXF and placebo in a r and omized 40-week study . A treadmill test was performed at inclusion and at the end of weeks 20 and 40 . A progressive training plan and the control of risk factors ( with antiplatelet treatment ) were used in both groups . Of the 200 included patients , 178 completed the study : 88 in the PXF group and 90 in the placebo group . There were 22 dropouts . The two groups were comparable for age , sex distribution , and for the presence of risk factors and smoking . There was a significant increase in pain-free walking distance ( PFWD ) in both groups . The absolute and percent increase in PFWD was significantly greater in the PXF group ( p<0.05 ) . At 20 weeks , the increase was 360.5 % in the PXF vs 252 % in the placebo group . At 40 weeks , the increase was 386 % in the PXF and 369 % in the placebo group ( p<0.02 ) . Total walking distance ( TWD ) increased at 20 weeks ( up to 254 % ) and up to 329 % at 40 weeks . In the placebo groups the increase was 158 % at 20 weeks and 183 % at 40 weeks . The excess increase produced by PXF treatment was 30 % at 20 weeks and 38 % at 40 weeks ( p<0.02 ) . Unwanted effects treatment was well tolerated . No serious drug-related side effects were observed . In summary , between-group analysis favors PXF considering walking distance and costs . Results indicate good efficacy and tolerability The Statin Safety Assessment Conference of the National Lipid Association ( NLA ) , reported in this supplement to The American Journal of Cardiology , provides a comprehensive evaluation of old and new experience on adverse events associated with the 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase in 
    Output:
    
Oral naftidrofuryl and cilostazol have an acceptable safety profile as well as sustained evidence ( documented by Cochrane analyses ) of increased walking capacity .
In contrast , buflomedil and pentoxifylline have limited and /or doubtful evidence to increase walking capacity .
Moreover , there were safety concerns about the narrow therapeutic range of buflomedil .
Most other " vasoactive " drugs were either inappropriately or insufficiently tested or showed no significant if not negative effects on IC . "
Vasoactive " drugs are no substitutes for lifestyle or exercise therapy but are adjuvant treatment to the well-appreciated triad of cardiovascular prevention ( antiplatelet agents , statins and ACE-inhibitors ) , of which statins in their own right have documented cl aims to significantly increase walking capacity .