Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease: The COMPASS Trial. Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) Ankle-brachial index and the incidence of cardiovascular events in the Mediterranean low cardiovascular risk population ARTPER cohort Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial. High-dose atorvastatin in peripheral arterial disease (PAD): effect on endothelial function, intima-media-thickness and local progression of PAD. An open randomized controlled pilot trial. Effect of niacin, warfarin, and antioxidant therapy on coagulation parameters in patients with peripheral arterial disease in the Arterial Disease Multiple Intervention Trial (ADMIT). Ticagrelor for Prevention of Ischemic Events After Myocardial Infarction in Patients With Peripheral Artery Disease. Presentations of major peripheral arterial disease and risk of major outcomes in patients with type 2 diabetes: results from the ADVANCE-ON study Secondary prevention of atherosclerosis through chlamydia pneumoniae eradication (SPACE Trial): a randomised clinical trial in patients with peripheral arterial disease. Mortality and Vascular Morbidity in Older Adults With Asymptomatic Versus Symptomatic Peripheral Artery Disease Nitroglycerin-mediated vasodilatation of the brachial artery may predict long-term cardiovascular events irrespective of the presence of atherosclerotic disease. Effects of a Home-Based Walking Intervention on Mobility and Quality of Life in People With Diabetes and Peripheral Arterial Disease Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. Can long-term antibiotic treatment prevent progression of peripheral arterial occlusive disease? A large, randomized, double-blinded, placebo-controlled trial. The influence of a long term exercise program on lower limb movement variability and walking performance in patients with peripheral arterial disease. Ten Year Mortality in Different Peripheral Arterial Disease Stages: A Population Based Observational Study on Outcome. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Women and cardiovascular risk. Effect of xuezhikang on cardiovascular events and mortality in elderly patients with a history of myocardial infarction: a subgroup analysis of elderly subjects from the China Coronary Secondary Prevention Study. Asymmetric dimethylarginine correlates with measures of disease severity, major adverse cardiovascular events and all-cause mortality in patients with peripheral arterial disease Variants of Toll-Like Receptor 4 Modify the Efficacy of Statin Therapy and the Risk of Cardiovascular Events Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. C-reactive protein in peripheral arterial disease: relation to severity of the disease and to future cardiovascular events.
BACKGROUND Patients with lower extremity peripheral artery disease ( PAD ) are at increased risk of major adverse cardiovascular events ( MACE ) and major adverse limb events ( MALE ) . There is limited information on the prognosis of patients who experience MALE . OBJECTIVES Among participants with lower extremity PAD , this study investigated : 1 ) if hospitalizations , MACE , amputations , and deaths are higher after the first episode of MALE compared with patients with PAD who do not experience MALE ; and 2 ) the impact of treatment with low-dose rivaroxaban and aspirin compared with aspirin alone on the incidence of MALE , peripheral vascular interventions , and all peripheral vascular outcomes over a median follow-up of 21 months . METHODS We analyzed outcomes in 6,391 patients with lower extremity PAD who were enrolled in the COMPASS ( Cardiovascular Outcomes for People Using Anticoagulation Strategies ) trial . COMPASS was a r and omized , double-blind placebo-controlled study of low-dose rivaroxaban and aspirin combination or rivaroxaban alone compared with aspirin alone . MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation . RESULTS A total of 128 patients experienced an incident of MALE . After MALE , the 1-year cumulative risk of a subsequent hospitalization was 61.5 % ; for vascular amputations , it was 20.5 % ; for death , it was 8.3 % ; and for MACE , it was 3.7 % . The MALE index event significantly increased the risk of experiencing subsequent hospitalizations ( hazard ratio [ HR ] : 7.21 ; p < 0.0001 ) , subsequent amputations ( HR : 197.5 ; p < 0.0001 ) , and death ( HR : 3.23 ; p < 0.001 ) . Compared with aspirin alone , the combination of rivaroxaban 2.5 mg twice daily and aspirin lowered the incidence of MALE by 43 % ( p = 0.01 ) , total vascular amputations by 58 % ( p = 0.01 ) , peripheral vascular interventions by 24 % ( p = 0.03 ) , and all peripheral vascular outcomes by 24 % ( p = 0.02 ) . CONCLUSIONS Among individuals with lower extremity PAD , the development of MALE is associated with a poor prognosis , making prevention of this condition of utmost importance . The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowered the incidence of MALE and the related complications , and this combination should be considered as an important therapy for patients with PAD . ( Cardiovascular Outcomes for People Using Anticoagulation Strategies [ COMPASS ] ; NCT01776424 ) Background : The PCSK9 ( proprotein convertase subtilisin/kexin type 9 ) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial ( Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk ) . We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease ( PAD ) as well as the effect on major adverse limb events . Methods : FOURIER was a r and omized trial of evolocumab versus placebo  in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years . Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of < 0.85 , or if they had a prior peripheral vascular procedure . The primary end point was a composite of cardiovascular death , myocardial infa rct ion , stroke , hospital admission for unstable angina , or coronary revascularization . The key secondary end point was a composite of cardiovascular death , myocardial infa rct ion , or stroke . An additional outcome of interest was major adverse limb events defined as acute limb ischemia , major amputation , or urgent peripheral revascularization for ischemia . Results : Three thous and six hundred forty-two patients ( 13.2 % ) had PAD ( 1505 with no prior myocardial infa rct ion or stroke ) . Evolocumab significantly reduced the primary end point consistently in patients with PAD ( hazard ratio [ HR ] 0.79 ; 95 % confidence interval [ CI ] , 0.66–0.94 ; P=0.0098 ) and without PAD ( HR 0.86 ; 95 % CI , 0.80–0.93 ; P=0.0003 ; Pinteraction=0.40 ) . For the key secondary end point , the HRs were 0.73 ( 0.59–0.91 ; P=0.0040 ) for those with PAD and 0.81 ( 0.73–0.90 ; P<0.0001 ) for those without PAD ( Pinteraction=0.41 ) . Because of their higher risk , patients with PAD had larger absolute risk reductions for the primary end point ( 3.5 % with PAD , 1.6 % without PAD ) and the key secondary end point ( 3.5 % with PAD , 1.4 % without PAD ) . Evolocumab reduced the risk of major adverse limb events in all patients ( HR , 0.58 ; 95 % CI , 0.38–0.88 ; P=0.0093 ) with consistent effects in those with and without known PAD . There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events ( P=0.026 for the beta coefficient ) that extended down to < 10 mg/dL. Conclusions : Patients with PAD are at high risk of cardiovascular events , and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions . Moreover , lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events . Clinical Trial Registration : URL : https://www . clinical trials.gov . Unique identifier : NCT01764633 Background Peripheral arterial disease ( PAD ) of the lower limbs is a cardiovascular disease highly prevalent particularly in the asymptomatic form . Its prevalence starts to be a concern in low coronary risk countries like Spain . Few studies have analyzed the relationship between ankle-brachial index ( ABI ) and cardiovascular morbi-mortality in low cardiovascular risk countries like Spain where we observe significant low incidence of ischemic heart diseases together with high prevalence of cardiovascular risk factors . The objective of this study is to determine the relationship between pathological ABI and incidence of cardiovascular events ( coronary disease , cerebrovascular disease , symptomatic aneurism of abdominal aorta , vascular surgery ) and death in the > 49 year population -based cohort in Spain ( ARTPER ) . Methods  Baseline ABI  was measured in 3,786 r and omly selected patients from 28 Primary Health Centers in Barcelona , distributed as : ABI<0.9 peripheral arterial disease ( PAD ) , ABI ≥1.4 arterial calcification ( AC ) , ABI 0.9 - 1.4 healthy ; and followed during 4 years . Results 3,307 subjects were included after excluding those with previous vascular events . Subjects with abnormal ABI were older with higher proportion of men , smokers and diabetics . 260 people presented cardiovascular events ( incidence 2,117/100,000 person-years ) and 124 died from any cause ( incidence 978/100,000 person-years ) . PAD had two-fold greater risk of coronary disease ( adjusted hazard ratio ( HR ) = 2.0 , 95 % confidence interval ( CI ) 1.3 - 3.2 ) and increased risk of vascular surgery ( HR = 5.6 , 95%CI 2.8 - 11.5 ) and mortality ( HR = 1.8 , 95%CI 1.4 - 2.5 ) . AC increased twice risk of cerebrovascular events ( HR = 1.9 , 95%CI 1.0 - 3.5 ) with no relationship with ischemic heart disease . Conclusions PAD increases coronary disease risk and AC cerebrovascular disease risk in low cardiovascular risk Mediterranean population . ABI could be a useful tool to detect patients at risk in Primary Health Care BACKGROUND Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke , data in peripheral artery disease ( PAD ) are less compelling . Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD , whereas clopidogrel monotherapy may be more effective in PAD . Ticagrelor , a potent , reversibly binding P2Y12 receptor antagonist , is beneficial in patients with acute coronary syndrome and prior myocardial infa rct ion . The EUCLID trial is design ed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events . STUDY DESIGN EUCLID is a r and omized , double-blind , parallel-group , multinational clinical trial design ed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD . Subjects with established PAD will be r and omized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily . The primary end point is a composite of cardiovascular death , myocardial infa rct ion , or ischemic stroke . Other end points address limb events including acute leg ischemia , need for revascularization , disease progression by ankle-brachial index , and quality of life . The primary safety objective is Thrombolysis in Myocardial Infa rct ion-defined major bleeding .  Recruitment began in December 2012 and was completed in March 2014 ; 13,887 patients were r and omized . The trial will continue until at least 1,364 adjudicated primary end points occur . CONCLUSIONS The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel , given as antiplatelet monotherapy , will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD Beneficial effects of aggressive lipid-lowering with high-dose atorvastatin ( 80 mg/day ) have been demonstrated in patients with coronary and cerebrovascular disease . The impact of such a therapy in patients with peripheral arterial disease ( PAD ) is less known so far . Here we studied the effects of high-dose atorvastatin on brachial artery endothelial function , common carotid intima-media thickness ( IMT ) and local progression of PAD in these patients . One hundred of 500 patients screened with documented PAD were r and omly assigned to receive 80 mg of atorvastatin daily for six months or to continue on conventional medical treatment .  Ninety-six percent of patients in the control group were on st and ard statin treatment . High resolution B-mode ultrasonography was used to study brachial artery flow-mediated dilation ( FMD ) , IMT and ankle-brachial index ( ABI ) at baseline and at six months . FMD and IMT at baseline and at six months were 4.1 ( 0.06 - 8.6 ) versus 5.0 ( 0.76 vs. 8.1 ) % , p = 0.96 , and 0.76 ( 0.66 - 0.82 ) versus 0.73 ( 0.63 - 0.81 ) mm , p = 0.41 , respectively , in the atorvastatin group , and 2.66 ( -1.9 - 6.9 ) versus 3.65 (0.0 - 8.6)% , p = 0.02 , and 0.78 ( 0.71 - 0.90 ) versus 0.77 ( 0.70 - 0.90 ) mm , p = 0.48 , in the control group . ABI at baseline and at six months was not different in either group . LDL cholesterol was reduced from 2.53 ( 2.21 - 3.28 ) to 1.86 ( 1.38 - 2.29 ) mM ( p < 0.0001 ) in the atorvastatin group , whereas levels remained stable in the control group [ 2.38 ( 1.94 - 3.16 ) vs. 2.33 ( 1.82 - 2.84 ) mM , p = 0.61 ] . Major adverse cardiovascular events occurred in 2.1 % in the atorvastatin group and 1.9 % in the control group ( p = 0.61 ) . In conclusion , in this pilot trial aggressive lipid-lowering with 80 mg of atorvastatin daily for six months had no effect on brachial artery FMD in patients with PAD . IMT and ABI were also similar in patients with and without high-dose atorvastatin at six months BACKGROUND Patients with peripheral arterial disease ( PAD ) have high rates of cardiovascular morbidity and mortality , including that caused by associated coronary heart disease and cerebrovascular disease . Previous studies have shown that coagulation parameters are altered in PAD and that altered coagulation may play a critical role in the susceptibility to cardiovascular complications in PAD . It is therefore important to assess the effect of secondary prevention measures on coagulation in patients with PAD . The Arterial Disease Multiple Intervention Trial ( ADMIT ) , a multicenter , r and omized , placebo-controlled trial , was conducted to determine the feasibility of a combined lipid-modifying , antioxidant , and antithrombotic treatment regimen in patients with PAD . The objective of this study was to assess the effect of the ADMIT interventions on coagulation . METHODS ADMIT participants were r and omly assigned to low-dose warfarin , niacin , and antioxidant vitamin cocktail or corresponding placebos in a 2 x 2 x 2 factorial design . Specialized coagulation studies were performed in a subset of 80 ADMIT participants at baseline and after 12 months of treatment . RESULTS Low-dose warfarin ( 1 to 4 mg/d ) result ed in a significant decrease in factor VIIc ( P < .001 ) and in plasma F1.2 ( P = .001 ) . Unexpectedly , niacin treatment also result ed in significant decrease in both fibrinogen ( 48 mg/dL ; P < .001 ) and F1.2 ( P = .04 ) . von Willebr and factor increased after antioxidant vitamin treatment ( P = .04 ) . CONCLUSIONS A regimen of low-dose warfarin effectively modifies coagulation in patients with PAD . Niacin also favorably modifies fibrinogen and plasma F1.2 . Niacin , in addition to its lipid effects , modifies abnormal coagulation factors that accompany PAD BACKGROUND Peripheral artery disease ( PAD ) is associated with heightened ischemic and bleeding risk in patients with prior myocardial infa rct ion ( MI ) . OBJECTIVES This study evaluated the efficacy and safety of ticagrelor on major cardiovascular ( CV ) events and major adverse limb events in patients with PAD and a prior MI . METHODS PEGASUS-TIMI 54 ( Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infa rct ion 54 ) r and omized 21,162 patients with prior MI ( 1 to 3 years ) to ticagrelor 90 mg twice daily , ticagrelor 60 mg twice daily , or placebo  , all on a background of low-dose aspirin . History of PAD was obtained at baseline . Occurrences of major adverse cardiovascular events ( MACE ) ( defined as CV death , MI , or stroke ) and major adverse limb events ( MALE ) ( defined as acute limb ischemia or peripheral revascularization for ischemia ) were recorded in follow-up . RESULTS A total of 1,143 patients ( 5 % ) had known PAD . In the placebo arm , those with PAD ( n = 404 ) had higher rates of MACE at 3 years than those without ( n = 6,663 ; 19.3 % vs. 8.4 % ; p < 0.001 ) , which persisted after adjusting for baseline differences ( adjusted hazard ratio : 1.60 ; 95 % confidence interval : 1.20 to 2.13 ; p = 0.0013 ) , and higher rates of acute limb ischemia ( 1.0 % vs. 0.1 % ) and peripheral revascularization procedures ( 9.15 % vs. 0.46 % ) . Whereas the relative risk reduction in MACE with ticagrelor was consistent , regardless of PAD , patients with PAD had a greater absolute risk reduction of 4.1 % ( number needed to treat : 25 ) due to their higher absolute risk . The absolute excess of TIMI major bleeding was 0.12 % ( number needed to harm : 834 ) . The 60-mg dose had particularly favorable outcomes for CV and all-cause mortality . Ticagrelor ( pooled doses ) reduced the risk of MALE ( hazard ratio : 0.65 ; 95 % confidence interval : 0.44 to 0.95 ; p = 0.026 ) . CONCLUSIONS Among stable patients with prior MI , those with concomitant PAD have heightened ischemic risk . In these patients , ticagrelor reduced MACE , with a large absolute risk reduction , and MALE . ( Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [ PEGASUS-TIMI 54 ] ; NCT01225562 ) Background Peripheral arterial disease ( PAD ) is known to be associated with high cardiovascular risk , but the individual impact of PAD presentations on risk of macrovascular and microvascular events has not been reliably compared in patients with type 2 diabetes . We aim ed to evaluate the impact of major PAD , and its different presentations , on the 10-year risk of death , major macrovascular events , and major clinical microvascular events in these patients . Methods Participants in the action in diabetes and vascular disease :  PreterAx and DiamicroN modified-release controlled evaluation ( ADVANCE ) trial and the ADVANCE-ON post-trial study were followed for a median of 5.0 ( in-trial ) , 5.4 ( post-trial ) , and 9.9 ( overall ) years . Major PAD at baseline was subdivided into lower-extremity chronic ulceration or amputation secondary to vascular disease and history of peripheral revascularization by angioplasty or surgery . Results Among 11,140 participants , 516 ( 4.6 % ) had major PAD at baseline : 300 ( 2.7 % ) had  lower-extremity  ulceration or amputation alone , 190 ( 1.7 % ) had peripheral revascularization alone , and 26 ( 0.2 % ) had both presentations . All-cause mortality , major macrovascular events , and major clinical microvascular events occurred in 2265 ( 20.3 % ) , 2166 ( 19.4 % ) , and 807 ( 7.2 % ) participants , respectively . Compared to those without PAD , patients with major PAD had increased rates of all-cause mortality ( HR 1.35 , 95 % CI 1.15–1.60 , p = 0.0004 ) , and major macrovascular events ( 1.47 [ 1.23–1.75 ] , p < 0.0001 ) , after multiple adjustments for region of origin , cardiovascular risk factors and treatments , peripheral neuropathy markers , and r and omized treatments . We have also observed a trend toward an association of baseline PAD with risk of major clinical microvascular events [ 1.31 ( 0.96–1.78 ) , p = 0.09 ] . These associations were comparable for patients with a lower-extremity ulceration or amputation and for those with a history of peripheral revascularization . Furthermore , the risk of retinal photocoagulation or blindness , but not renal events , increased in patients with lower-extremity ulceration or amputation [ 1.53 ( 1.01–2.30 ) , p = 0.04 ] . Conclusions Lower-extremity ulceration or amputation , and peripheral revascularization both increased the risks of death and cardiovascular events , but only lower-extremity ulceration or amputation increased the risk of severe retinopathy in patients with type 2 diabetes .  Screening for major PAD and its management remain crucial for cardiovascular prevention in patients with type 2 diabetes ( Clinical Trials.gov number , NCT00949286 ) BACKGROUND Sero-epidemiological and experimental studies suggest that Chlamydia pneumoniae infections play an important role in the development of atherosclerosis . Clinical trials have shown contradictory results regarding the efficacy of antibiotics to prevent atherosclerosis-related complications in patients with coronary artery disease . Our aim was to study the effect of a short course of azithromycin on the incidence of cardiovascular events and peripheral vascular function in patients with stable peripheral arterial disease ( PAD ) . PATIENTS AND METHODS Five hundred and nine PAD- patients were r and omised to receive either a 3-day course of azithromycin ( 500 mg daily ) or placebo , with 2 years of follow-up . C. pneumoniae serology was determined at baseline . Clinical endpoints were death , coronary events ( myocardial infa rct ion , unstable angina , and /or coronary revascularization procedures ) , cerebral events ( stroke , TIA , and /or carotid endarterectomy ) and peripheral arterial complications ( increased PAD-symptoms with decreased ankle-brachial index ( ABPI , 0.1-point decrease after 12 months ) , and /or peripheral revascularization procedures ) . RESULTS Five hundred and nine patients ( 160 women ) with an atherosclerotic risk factor profile were r and omised , 257 patients to azithromycin and 252 to placebo .  Four hundred and forty nine patients ( 88 % ) had intermittent claudication and 60 ( 12 % ) had critical limb ischemia . By 24-month follow up , 182 patients ( 36 % ) developed 252 complications ( 45 deaths , 34 coronary events , 34 cerebral events and 139 peripheral arterial complications ) . C. pneumoniae IgA-titres were associated with the development of cardiovascular events . Nevertheless , the number of complications ( 131 in the azithromycin group vs. 121 in the placebo group ) and the number of patients that developed complications ( 98 ( 38 % ) in the azithromycin vs. 84 ( 33 % ) in the placebo group ) was comparable in both treatment groups . Life table analysis showed no effect of azithromycin on survival or ABPI . CONCLUSION A short-term course of azithromycin offers no benefits for survival or ankle pressure in PAD- patients Background — Our aim was to assess the mortality and vascular morbidity risk of elderly individuals with asymptomatic versus symptomatic peripheral artery disease ( PAD ) in the primary care setting . Methods and Results — This prospect i ve cohort study included 6880 representative unselected patients ≥65 years of age with monitored follow-up over 5 years . According to physician diagnosis , 5392 patients had no PAD , 836 had asymptomatic PAD ( ankle brachial index < 0.9 without symptoms ) , and 593 had symptomatic PAD ( lower-extremity peripheral revascularization , amputation as  a  result  of PAD , or intermittent claudication symptoms regardless of ankle brachial index ) . The risk of symptomatic compared with asymptomatic PAD patients was significantly increased for the composite of all-cause death or severe vascular event ( myocardial infa rct ion , coronary revascularization , stroke , carotid revascularization , or lower-extremity peripheral vascular events ; hazard ratio , 1.48 ; 95 % confidence interval , 1.21 to 1.80 ) but not for all-cause death alone ( hazard ratio , 1.13 ; 95 % confidence interval , 0.89 to 1.43 ) , all-cause death/myocardial infa rct ion/stroke ( excluding lower-extremity peripheral vascular events and any revascularizations ; hazard ratio , 1.18 ; 95 % confidence interval , 0.92 to 1.52 ) , cardiovascular events alone ( hazard ratio , 1.20 ; 95 % confidence interval , 0.89 to 1.60 ) , or cerebrovascular events alone ( hazard ratio , 1.33 ; 95 % confidence interval , 0.80 to 2.20 ) . Lower ankle brachial index categories were associated with increased risk . PAD was a strong factor for the prediction of the composite end point in an adjusted model . Conclusions — Asymptomatic PAD diagnosed through routine screening in the offices of primary care physicians carries a high mortality and /or vascular event risk . Notably , the risk of mortality was similar in symptomatic and asymptomatic patients with PAD and was significantly higher than in those without PAD . In the primary care setting , the diagnosis of PAD has important prognostic value AIM Nitroglycerin-mediated vasodilatation ( NMD ) provides insight into the NTG-induced bioactivity of smooth muscle . It is plausible that in dysfunctional smooth muscle cells , the response to nitroglycerin may become blunted . The relationship between impaired brachial artery NMD and subsequent cardiovascular events is not well established . METHODS We examined brachial artery flow-mediated dilatation ( FMD ) and NMD using ultrasound in 93 subjects ( 71±7 years , including 26 with peripheral artery disease ( PAD ) , 37 with aortic aneurysms , 10 with PAD complicated with aneurysms , and 20 without evident arterial disease ) . Brachial artery responses to hyperemia and nitroglycerin were measured every minute after cuff deflation and nitroglycerin administration . Time courses of vasodilatation were assessed and maximal FMD and NMD were measured . RESULTS The time courses in response to NTG were sigmoidal and maximal diameter reached 7.2±1.6 minutes after NTG was administered sublingually . The mean FMD was 2.3±2.0 % and the mean NMD was 17.6±7.1 % . Subjects were prospect ively followed for an average of 47±13 months . Eighteen subjects had an event during follow-up ; events included myocardial infa rct ion ( five ) , unstable angina pectoris ( four ) , stroke ( two ) , aortic dissection ( one ) , ruptured aortic aneurysm ( three ) , symptomatic abdominal aortic aneurysm ( two ) , and lower limb ischemia requiring revascularization ( one ) . NMD and FMD were significantly lower in subjects with events than in those without an event . In a Cox proportional-hazards model , lower FMD as well as lower NMD independently predicted future cardiovascular events . CONCLUSION Brachial artery nitroglycerin-mediated vasodilatation may add information to conventional risk stratification OBJECTIVE Determine the efficacy of a home-based walking intervention to improve walking ability and quality of life in people with diabetes and peripheral arterial disease ( PAD ) . RESEARCH DESIGN AND METHODS We conducted a r and omized , controlled , single-blind trial within university-affiliated clinics in our local community . We r and omized 145 participants ( 45 women ) with diabetes and PAD to our intervention — a 6-month behavioral intervention targeting levels of readiness to engage in routine walking for exercise — versus attention control . Our primary outcome was 6-month change in maximal treadmill walking distance . Secondary outcomes included 3-month change in maximal walking distance , lower limb function ( i.e. , walking impairment scores ) , quality of life ( Medical Outcomes Short Form Survey ) , exercise behaviors , depressive symptoms , and self-efficacy at 3 and 6 months . RESULTS The mean age of participants was 66.5 ( SD 10.1 ) years . Intervention and control groups did not differ significantly in 6-month change in maximal treadmill walking distance ( average [ SE ] 24.5 [ 19.6 ] meters vs. 39.2 [ 19.6 ] meters ; P = 0.60 ) . Among secondary outcomes , for the intervention and control groups , respectively , average walking speed scores increased by 5.7 [ 2.2 ] units and decreased by 1.9 [ 2.8 ] units ( P = 0.03 ) ; the mental health quality of life subscale score increased by 3.2 [ 1.5 ] and decreased by 2.4 [ 1.5 ] units ( P = 0.01 ) . CONCLUSIONS A home-based walking intervention did not improve walking distance but did improve walking speed and quality of life in people with diabetes and PAD . Clinicians should consider recommending home-based walking therapy for such patients OBJECTIVES The Heart Protection Study ( HPS ) provides an opportunity to assess directly the effects of cholesterol-lowering therapy on major vascular events ( defined as myocardial infa rct ion , coronary death , stroke , or revascularization ) in patients with peripheral arterial disease ( PAD ) . In addition , the effects on peripheral vascular events ( ie , non-coronary revascularization , aneurysm repairs , major amputations or PAD deaths ) can be assessed . METHODS 6748 UK adults with PAD and 13,788 other high-risk participants were r and omly allocated to receive 40 mg simvastatin daily or matching placebo , yielding an average LDL cholesterol difference of 1.0 mmol/L ( 39 mg/dL ) during a mean of 5 years . RESULTS For participants with PAD , allocation to simvastatin was associated with a highly significant 22 % ( 95 % CI 15 - 29 ) relative reduction in the rate of first major vascular event following r and omisation ( 895 [ 26.4 % ] simvastatin-allocated vs 1101 [ 32.7 % ] placebo-allocated ; P < .0001 ) , which was similar to that seen among the other high-risk participants . The absolute reduction in first major vascular event was 63 ( SE 11 ) per 1000 patients with PAD and 50 ( SE 7 ) per 1000 without pre-existing PAD . Overall , among all participants , there was a 16 % ( 5 - 25 ) relative reduction in the rate of first peripheral vascular event following r and omisation ( 479 [ 4.7 % ] simvastatin vs 561 [ 5.5 % ] placebo ) , largely irrespective of baseline LDL cholesterol and other factors . This effect chiefly reflects a 20 % ( 8 - 31 ) relative reduction in non-coronary revascularization procedures ( 334 [ 3.3 % ] vs 415 [ 4.0 % ] ; P = .002 ) . CONCLUSION HPS demonstrates the benefits of cholesterol-lowering statin therapy in patients with PAD , regardless of their presenting cholesterol levels and other presenting features . Allocation to 40 mg simvastatin daily reduces the rate of first major vascular events by about one-quarter , and that of peripheral vascular events by about one-sixth , with large absolute benefits seen in participants with PAD because of their high vascular risk . Consequently , statin therapy should be considered routinely for all patients with PAD PURPOSE The purpose was to investigate in a large , r and omized , double-blinded , placebo-controlled trial , whether antibiotic treatment can prevent progression of peripheral arterial disease ( PAD ) . MATERIAL AND METHODS Five hundred and seven patients were included ; all patients had an established diagnosis of PAD . Their mean age was 66 years ( 36 - 85 ) , and 59 % were males . Patients were r and omized to Roxithromycin 300 mg daily for 28 days .  Baseline investigations were ankle blood pressure , ankle-brachial blood pressure index ( ABPI ) , walking distance , C. pneumoniae serology , cholesterol and medical history . Follow-up was performed every 6 months . Primary events were defined as death , peripheral revascularization and major lower limb amputation . Secondary events were thrombosis , stroke , transient cerebral ischaemic attack and myocardial infa rct ion . Change in ABPI was also investigated . Data were analyzed mainly by Cox regression and linear regression . RESULTS Included patients with PAD were r and omized . Two patients withdrew . Of the remaining , 248 received roxithromycin  and 257  placebo . In the treatment group 55 % were seropositive and 53 % in the placebo group . Mean follow-up was 2.1 years ( range 0.06 - 5.1 years ) . In the placebo group , 26 died and 80 primary events occurred in total . In the treatment group , 28 died and 74 primary events were observed . The hazard ratio of death was 1.13 ( 95 % CI : 0.68 ; 1.90 ) , and of primary events 0.92 ( 95 % CI : 0.67 ; 1.26 ) . Also on secondary events and ABPI changes , no significant differences were found . CONCLUSION Long-term treatment with roxithromycin is ineffective in preventing death , amputation , peripheral revascularization , myocardial infa rct ion , stroke , transient cerebral ischaemic attack , thrombosis and decline in ABPI in patients with an established diagnosis of PAD The purpose of this study was to examine the effects of a 12month exercise program on lower limb movement variability in patients with peripheral arterial disease ( PAD ) . Participants ( n=21 ) with an appropriate history of PAD and intermittent claudication ( IC ) volunteered for this study and were r and omly allocated to either a control group ( CPAD-IC ) ( n=11 ) , which received normal medical therapy and a treatment group ( TPAD-IC ) ( n=10 ) , which received normal medical therapy treatment and a 12month supervised exercise program . All participants underwent 2D joint angular kinematic analysis during normal walking to assess lower limb movement variability and walking speed . Between-group differences were analyzed via mixed measures ANOVA . The 12month supervised exercise program made no significant impact on the lower limb movement variability or walking speed of the TPAD-IC group as determined by either intralimb joint coordination or single joint analysis techniques . Long term supervised exercise programs do not appear to influence the lower limb movement variability of PAD-IC patients OBJECTIVE The aim was to determine long-term mortality rates and the underlying cause of death for subjects with different peripheral arterial disease ( PAD ) stages in a population based setting . METHODS A r and omly selected population sample of 5080 subjects was enrolled in the study in 2004 - 2005 . Participants completed health state question naires and underwent ankle brachial index ( ABI ) measurements for classification into PAD severity stages and reference subjects . A follow-up was conducted by the end of 2015 using data from Swedish governmental national registers for cause of death , which was then compared with PAD stage determined at baseline in 2005 . RESULTS The 10 year all cause mortality was 27 % for reference cases , 56 % for asymptomatic PAD ( APAD ) , 63 % for intermittent claudication ( IC ) , and 75 % for severe limb ischaemia ( SLI ) . Among all PAD subjects , cardiovascular ( CV ) causes were the most common main cause of death ( 45 % ) and a CV event was present as either the main or one of the three most common contributing causes of death in 64 % of the cases . The age adjusted hazard ratios for a main cause of death by a CV event were 1.9 ( 95 % CI 1.5 - 2.3 ) for APAD , 2.6 ( 95 % CI 2.1 - 3.4 ) for IC , and 3.5 ( 95 % CI 2.3 - 5.2 ) for SLI . CONCLUSION PAD subjects , including the APAD subjects , are still at high risk of CV death . The mortality risks are more than doubled in symptomatic PAD patients compared with reference subjects and increase by severity of PAD stage . Awareness and improved risk reduction management of PAD are still warranted AIMS Patients with diabetes are at excessive risk of mortality and cardiovascular morbidity . Previous studies suggest that aspirin may be less effective in diabetic patients . In this multi-centre , r and omized , double blind trial picotamide , a dual inhibitor of thromboxane A2 synthase and receptor , was compared with aspirin for the prevention of mortality and major cardiovascular events in diabetics with peripheral arterial disease ( PAD ) . METHODS AND RESULTS A total of 1209 adults aged 40 - 75 years with type 2 diabetes and PAD were r and omized to receive picotamide ( 600 mg bid ) or aspirin ( 320 mg od ) for 24 months . The cumulative incidence of the 2 years overall mortality was significantly lower amongst patients who received picotamide ( 3.0 % ) than in those who received aspirin ( 5.5 % ) with a relative risk ratio for picotamide versus aspirin of 0.55 ( 95 % CI : 0.31 - 0.98 % ) . Events were reported in 43 patients ( 7.1 % ) on picotamide and 53 ( 8.7 % ) on aspirin . The combined endpoint of mortality and morbidity had a slightly lower incidence in the picotamide group but this difference did not reach statistical significance . CONCLUSION Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated PAD Cardiovascular disease mortality rates have decreased in men during the past 20 years , but have steadily increased in women . In the United States , > 500,000 women die of coronary artery disease ( CAD ) every year . Although many factors can influence an individual 's risk for CAD , some factors are unique to women , including reproductive status . Menopause is associated with significant elevations in serum cholesterol levels and a 3-fold increase in the risk of CAD . It has been suggested that these changes result from a reduction in the level of estrogen . However , recent data from prospect i ve clinical trials have not found any evidence that hormone replacement therapy protects against cardiovascular disease . On the other h and , several studies have shown that , in women , lipid lowering with statin therapy can reduce coronary events . On the strength of these findings , the Beyond Endorsed Lipid Lowering with Electron-Beam Computed Tomography Scanning ( BELLES ) trial-a 1-year , multicenter , r and omized , double-blind , parallel-group study -has been specifically design ed to determine the benefits of aggressive statin therapy on the progression of atherosclerosis in postmenopausal women OBJECTIVES To evaluate whether lipid-lowering therapy with xuezhikang reduces the risk of coronary events and total mortality in patients with coronary heart disease ( CHD ) aged 65 and older . DESIGN Subgroup analysis of the China Coronary Secondary Prevention Study , a r and omized , double-blind , placebo-controlled , clinical trial . SETTING Sixty-six hospitals in China . PARTICIPANTS A total of 1,445 patients , aged 65 to 75 , were chosen from 4,780 patients with a history of myocardial infa rct ion . INTERVENTION The patients were r and omized to the xuezhikang ( n=735 ) or the placebo ( n=710 ) group and followed for a mean of 4 years . MEASUREMENTS The primary endpoint was recurrent coronary events ; the secondary endpoint was all-cause mortality and other clinical events , including adverse effects . RESULTS Elderly patients were at greater risk for coronary events , death from coronary events , all-cause mortality , and malignancies than younger patients .  Xuezhikang therapy reduced the incidence of coronary events 36.9 % ( P=.001 ) , death from coronary heart disease 31.0 % ( P=.04 ) , all-cause mortality 31.9 % ( P=.01 ) , stroke 44.1 % ( P=.04 ) , the need for a percutaneous coronary intervention or coronary artery bypass graft 48.6 % ( P=.07 ) , and malignancies 51.4 % ( P=.03 ) . Based on the treatment of elderly patients with xuezhikang for an average of 4 years , the number needed to treat ( NNT ) to prevent one coronary event , one coronary death , and one mortality due to all causes was estimated to be 18 , 33 , and 23 , respectively . In a like manner , the estimated NNT to prevent one coronary event , one coronary death , and one mortality due to all causes in younger patients was 23 , 82 , and 51 , respectively . There was not a significantly greater number of adverse effects in the xuezhikang group than in the placebo group . CONCLUSION This is the first study demonstrating that treatment with xuezhikang capsules is safe and effective for the secondary prevention of CHD in older Chinese people Peripheral arterial disease ( PAD ) is associated with major cardiovascular morbidity and mortality . Abnormalities in nitric oxide metabolism due to excess of the NO synthase inhibitor asymmetric dimethylarginine ( ADMA ) may be pathogenic in PAD . We explored the association between ADMA levels and markers of atherosclerosis , function , and prognosis .  A total of 133 patients with symptomatic PAD were enrolled .  Ankle — brachial index ( ABI ) , walking time , vascular function measures ( arterial compliance and flow-mediated vasodilatation ) and plasma ADMA level  were assessed for each patient at baseline . ADMA correlated inversely with ABI ( r = —0.238 , p = 0.003 ) and walking time ( r = —0.255 , p = 0.001 ) , independent of other vascular risk factors . We followed up 125 ( 94 % ) of our 133 initial subjects with baseline measurements ( mean 35 months ) . Subjects with ADMA levels in the highest quartile ( > 0.84 μmol/l ) showed a significantly greater occurrence of a major adverse cardiovascular event ( MACE ) compared to those with ADMA levels in the lower three quartiles ( p = 0.001 ) . Cox proportional-hazards regression analysis revealed that ADMA was a significant predictor of MACE , independent of other risk factors including age , sex , blood pressure , smoking history , diabetes and ABI ( hazard ratio = 5.1 , p < 0.001 ) . Measures of vascular function , such as compliance , flow-mediated vasodilatation ( FMVD ) and blood pressure , as well as markers of PAD severity , including ABI and walking time , were not predictive . In conclusion , circulating levels of ADMA correlate independently with measures of disease severity and major adverse cardiovascular events . Agents that target this pathway may be useful for this patient population . Clinical Trial Registration — URL : http:// www . clinical trials.gov . Unique identifier : Background —Atherosclerosis is increasingly considered to be a chronic inflammatory process . We examined whether genetic variants of the toll-like receptor 4 ( TLR4 ) , which are correlated with impaired innate immunity and with progression of carotid atherosclerosis , are also associated with coronary atherosclerosis and predict the risk of cardiovascular events . Methods and Results —Two polymorphisms of the TLR4 gene ( Asp299Gly and Thr399Ile ) were determined in 655 men with angiographically documented coronary atherosclerosis . All patients participated in a prospect i ve cholesterol-lowering trial evaluating the effect on coronary artery disease and were r and omly assigned to either pravastatin or placebo for 2 years . There were no significant differences between genetically defined subgroups with respect to baseline risk factors , treatment , or in-trial changes of lipid , lipoprotein , or angiographic measurements . Genotype was not associated with progression of atherosclerosis . In the pravastatin group , 299Gly carriers had a lower risk of cardiovascular events during follow-up than noncarriers ( 2.0 % versus 11.5 % , P = 0.045 ) . Among noncarriers , pravastatin reduced the risk of cardiovascular events from 18.1 % to 11.5 % ( P = 0.03 ) , whereas among 299Gly carriers this risk was strikingly reduced from 29.6 % to 2.0 % ( P = 0.0002 , P = 0.025 for interaction ) . Conclusions —Among symptomatic men with documented coronary artery disease , the TLR4 Asp299Gly polymorphism was associated with the risk of cardiovascular events . This variant also modified the efficacy of pravastatin  in preventing cardiovascular events , such that carriers of the variant allele had significantly more benefit from pravastatin treatment BACKGROUND AND METHODS The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography . Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter , documented coronary artery disease , and a family history of vascular disease , 120 completed the 2 1/2-year double-blind study , which included arteriography at base line and after treatment . Patients were given dietary counseling and were r and omly assigned to one of three treatments : lovastatin ( 20 mg twice a day ) and colestipol ( 10 g three times a day ) ; niacin ( 1 g four times a day ) and colestipol ( 10 g three times a day ) ; or conventional therapy with placebo ( or colestipol if the low-density lipoprotein [ LDL ] cholesterol level was elevated ) . RESULTS The levels of LDL and high-density lipoprotein ( HDL ) cholesterol changed only slightly in the conventional-therapy group ( mean changes , -7 and + 5 percent , respectively ) , but more substantially among patients treated with lovastatin and colestipol ( -46 and + 15 percent ) or niacin and colestipol ( -32 and + 43 percent ) . In the conventional-therapy group , 46 percent of the patients had definite lesion progression ( and no regression ) in at least one of nine proximal coronary segments ; regression was the only change in 11 percent . By comparison , progression ( as the only change ) was less frequent among patients who received lovastatin and colestipol ( 21 percent ) and those who received niacin and colestipol ( 25 percent ) , and regression was more frequent ( lovastatin and colestipol , 32 percent ; niacin and colestipol , 39 percent ; P less than 0.005 ) . Multivariate analysis indicated that a reduction in the level of apolipoprotein B ( or LDL cholesterol ) and in systolic blood pressure , and an increase in HDL cholesterol correlated independently with regression of coronary lesions . Clinical events ( death , myocardial infa rct ion , or revascularization for worsening symptoms ) occurred in 10 of 52 patients assigned to conventional therapy , as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol ( relative risk of an event during intensive treatment , 0.27 ; 95 percent confidence interval , 0.10 to 0.77 ) . CONCLUSIONS In men with coronary artery disease who were at high risk for cardiovascular events , intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions , increased the frequency of regression , and reduced the incidence of cardiovascular events BACKGROUND Serum C-reactive protein ( CRP ) has proven to be an independent marker of the extent of atherosclerosis in patients with coronary , cerebrovascular , and peripheral arterial disease . In this prospect i ve observational study , we wanted to assess the relationship between serum CRP and extent of disease transversely and longitudinally in time , as well as future cardiovascular complications in patients with peripheral arterial disease ( PAD ) . Hypothesizing that CRP not only is a marker of but also actively participates in atherogenesis , we explored the possibility of CRP production by femoral atherosclerotic plaques . METHODS  Serum CRP  was measured as highly sensitive ( hsCRP ) in 387 patients with PAD attending the vascular clinic of a university and 2 affiliated teaching hospitals .  Serum hsCRP  was related to the ankle-brachial pressure index ( ABPI ) as an indication of severity of disease at inclusion and at 12 months ' follow-up and to future events ( death and coronary , cerebral , and peripheral arterial events ) . In femoral plaques , the production of CRP was analyzed with reverse transcription-polymerase chain reaction , and CRP plaque localization was assessed with immunostaining on serial tissue sections with antibodies toward CRP , smooth muscle cells , T cells , and macrophages . RESULTS The hsCRP ( average + /- SD ) was 3.26 + /- 2.41 mg/L. Serum hsCRP showed a correlation with baseline and 12-month follow-up ABPI ( Spearman rank correlation ; P < .05 for both correlations ) . When the patients were divided into three equally sized groups according to baseline serum hsCRP , the ABPI at baseline and at 12 months decreased significantly from the low- to the high-hsCRP group ( baseline ABPI : 0.70 , 0.65 , and 0.57 , P < .01 ; 12-month follow-up ABPI : 0.78 , 0.70 , and 0.65 , P < .01 ) . These associations persisted after correction for conventional risk factors . Furthermore , serum hsCRP was related to the combined end point " death and /or any cardiovascular event " ( log-rank test ; P = .04 ) during a median 24-month follow-up period . Reverse transcription-polymerase chain reaction analysis showed CRP production in 4 of 14 femoral plaques . CRP was detected in all femoral plaques , but not in healthy brachial arteries . Immunoreactivity for CRP was observed in smooth muscle cells , macrophages , and T cells . CONCLUSIONS Serum hsCRP was related to the severity of PAD , showing a relation to future hemodynamic function and cardiovascular events in PAD patients . In addition to coronary plaques , aneurysmal aortas , and failed venous coronary bypasses , femoral plaques also produce CRP , thus illustrating that the production of CRP may represent a universal response to vascular injury and suggesting that vascular CRP may contribute to plaque development
Lipid-lowering therapy is effective in reducing cardiovascular mortality and morbidity in people with PAD .
It may also improve local symptoms .
Until further evidence on the relative effectiveness of different lipid-lowering agents is available , use of a statin in people with PAD and a blood cholesterol level > /=3.5 mmol/litre is most indicated
BACKGROUND Lipid-lowering therapy is recommended for secondary prevention in people with coronary artery disease .
It may also reduce cardiovascular events and /or local disease progression in people with lower limb peripheral arterial disease ( PAD ) .
OBJECTIVES To assess the effects of lipid-lowering therapy on all-cause mortality , cardiovascular events and local disease progression in patients with PAD of the lower limb .