Lipoprotein (a) and development of intermittent claudication and major cardiovascular events in men and women: the Edinburgh Artery Study. Long term prognosis in patients with peripheral arterial disease treated with antiplatelet agents. Oral Buflomedil in the Prevention of Cardiovascular Events in Patients With Peripheral Arterial Obstructive Disease: A Randomized, Placebo-Controlled, 4-Year Study Mortality and Vascular Morbidity in Older Adults With Asymptomatic Versus Symptomatic Peripheral Artery Disease Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. The fate of patients with intermittent claudication in the 21st century revisited – results from the CAVASIC Study Ten Year Mortality in Different Peripheral Arterial Disease Stages: A Population Based Observational Study on Outcome. Serum concentrations of L-arginine and L-homoarginine in male patients with intermittent claudication: a cross-sectional and prospective investigation in the CAVASIC Study. Treatment of intermittent claudication with beraprost sodium, an orally active prostaglandin I2 analogue: a double-blinded, randomized, controlled trial. Secondary prevention of atherosclerosis through chlamydia pneumoniae eradication (SPACE Trial): a randomised clinical trial in patients with peripheral arterial disease. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. 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) Ticagrelor for Prevention of Ischemic Events After Myocardial Infarction in Patients With Peripheral Artery Disease. Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial. A prospective investigation of elevated lipoprotein (a) detected by electrophoresis and cardiovascular disease in women. The Framingham Heart Study. Impact of exercise training on inflammation and platelet activation in patients with intermittent claudication. Extended Duration Dual Antiplatelet Therapy After Coronary Stenting Among Patients With Peripheral Arterial Disease: A Subanalysis of the Dual Antiplatelet Therapy Study. Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial. Cholesterol Reduction With Atorvastatin Improves Walking Distance in Patients With Peripheral Arterial Disease Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: five-year follow-up of the Hoorn Study. Cellular Aging Reflected by Leukocyte Telomere Length Predicts Advanced Atherosclerosis and Cardiovascular Disease Risk Peripheral Arterial Occlusive Disease: Prognostic Value of Signs, Symptoms, and the Ankle-Brachial Pressure Index
Lipoprotein ( a ) may be an important risk factor for atherosclerosis . It is widely accepted that  lipoprotein ( a ) levels are raised in patients with coronary heart disease , but there is some doubt about the causality of the relationship . In addition , little is known about the relationship between lipoprotein ( a ) and either stroke or peripheral arterial disease , nor about the role of lipoprotein ( a ) in women . Subjects aged 55 - 74 years ( n=1592 ) were selected at r and om from 11 general practice s in Edinburgh , Scotl and and followed up for 5 years . The incidences of myocardial infa rct ion , intermittent claudication and stroke were 13.4 , 9.4 and 3.7 % , respectively . Raised lipoprotein ( a ) levels at baseline were associated with an increased risk ( 95 % confidence interval ) of myocardial infa rct ion RR 1.15 ( 1.00 , 1.32 ) , intermittent claudication RR 1.32 ( 1.10 , 1.57 ) but not significantly for stroke RR 1.24 ( 0.93 , 1.64 ) . This increased risk persisted for intermittent claudication after adjustment for baseline cardiovascular disease and other risk factors RR 1.20 ( 1.00 , 1.43 ) , but for myocardial infa rct ion became non-significant RR 1.06 ( 0.91 , 1.23 ) . The risk of disease associated with raised lipoprotein ( a ) was slightly higher in women than in men , especially for intermittent claudication ( men RR 1.09 ( 0.87 , 1.36 ) compared to women RR 1.37 ( 1.01 , 1.87 ) ) . In conclusion , we found that lipoprotein ( a ) was an independent predictor of cardiovascular events in both sexes . The association between lipoprotein ( a ) and cardiovascular events may have been stronger in women than in men , and for peripheral arterial disease than myocardial infa rct ion and stroke OBJECTIVE To determine the fatal and non-fatal cardiovascular event rate in patients with intermittent claudication treated with antiplatelet agents .  METHODS AND DESIGN Patients with PAD-II stage Fontaine ( n=223 ) and sex and age matched controls ( n=446 ) were followed up from 1974 to 1998 . All patients were treated with antiplatelet agents ( aspirin , 325 mg once daily or ticlopidine , 250 mg twice daily ) and for risk factors , if present . The end points were death for any cause ( vascular event , cancer , and others ) and non-fatal vascular events ( myocardial infa rct ion , ischemic/hemorrhagic stroke , and leg amputation ) . RESULTS PAD patients had a significantly higher mortality rate than controls ( 3.99 vs. 2.53 deaths for 100 patients per year , respectively ) , cancer ( mostly lung , stomach and colon ) and vascular mortality accounted for such difference . The incidence of non-fatal vascular events was three times higher in patients than in controls ( 1.7 vs. 0.56 , 100 patients per year , respectively , p<0.05 ) even considering amputation separately ( 0.28 vs. 0.00 , 100 patients per year , p<0.05 ) . No difference between patients treated with aspirin or ticlopidine could be found in both end points . CONCLUSIONS Vascular mortality and morbidity , despite the use of antiplatelet agents , are still higher than sex and age matched controls ; however , the commonest cause of death is cancer 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 — 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 BACKGROUND Intermittent claudication is associated with a poor prognosis , but less is known of the risks associated with asymptomatic peripheral arterial disease . The aims of this study were to determine the incidence and natural history of claudication , and the incidence of cardiovascular events in symptomatic and asymptomatic peripheral arterial disease . METHODS In 1988 , 1592 subjects aged 55 - 74 years were selected r and omly from the age-sex register of 10 general practice s in Edinburgh , Scotl and . The presence of peripheral arterial disease was determined by the World Health Organization question naire on intermittent claudication , the ankle brachial pressure index and a reactive hyperaemia test . This cohort was followed prospect ively over 5 years for subsequent cardiovascular events and death . RESULTS One hundred and sixteen new cases of claudication were identified ( incidence density 15.5 per 1000 person-years ) . Of those with claudication at baseline , 28.8 % and still had pain after 5 years , 8.2 % underwent  vascular surgery or amputation , and 1.4 % developed leg ulceration .  Claudicants had a significantly increased risk of developing angina compared with normals ( RR : 2.31 , 95 % CI : 1.04 - 5.10 ) , and asymptomatic subjects had a slightly increased risk of myocardial infa rct ion and stroke . Deaths from cardiovascular disease were more likely in both claudicants ( RR : 2.67 , 95 % CI : 1.34 - 5.29 ) and subjects with major ( RR : 2.08 , 95 % CI : 1.13 - 3.83 ) or minor asymptomatic disease ( RR : 1.74 , 95 % CI : 1.09 - 2.76 ) . Subjects with major asymptomatic disease also had an increased risk of non-cardiovascular death ( RR : 2.19 , 95 % CI : 1.33 - 3.59 ) , and therefore had the highest overall risk of death ( RR : 2.44 , 95 % CI : 1.59 - 3.74 ) . CONCLUSIONS Subjects with asymptomatic peripheral arterial disease appear to have the same increased risk of cardiovascular events and death found in claudicants Patients with intermittent claudication carry a high risk for cardiovascular complications . The TransAtlantic Inter-Society Consensus ( TASC ) Group estimated a five-year overall mortality of 30 % for these patients , the majority dying from cardiovascular causes . We investigated whether this evaluation is still applicable in nowadays patients . We therefore prospect ively followed 255 male patients with intermittent claudication from the CAVASIC Study during 7 years for overall mortality , vascular morbidity and mortality and local PAD outcomes . Overall mortality reached 16.1 % ( n = 41 ) . Most patients died from cancer ( n = 20 ) . Half of patients ( n = 22 ; 8.6 % ) died within the first five years . Incident cardiovascular events were observed among 70 patients ( 27.5 % ) , 54 ( 21.2 % ) during the first five years . Vascular mortality was low with 5.1 % ( n = 13 ) for the entire and 3.1 % for the first five years of follow-up . Prevalent coronary artery disease did not increase the risk to die from all or vascular causes . PAD symptoms remained stable or improved in the majority of patients ( 67 % ) . In summary , compared to TASC , the proportion of cardiovascular events did not markedly decrease over the last two decades . Vascular mortality , however , was low among our population . This indicates that nowadays patients more often survive cardiovascular events and a major number dies from cancer 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 BACKGROUND High serum concentrations of l-arginine and l-homoarginine increase nitric oxide ( NO ) availability and thereby improve endothelial function . Information about the association of these markers with peripheral arterial disease ( PAD ) and related outcomes is sparse . METHODS l-arginine , its metabolites and l-homoarginine were analyzed in the CAVASIC Study including 232 male patients diagnosed with intermittent claudication and 246 age- and diabetes-matched controls . After the baseline investigation PAD patients were prospect ively followed ( median 7 years ) . The association of these markers with symptomatic PAD at baseline , incident cardiovascular events and all-cause mortality was assessed . RESULTS At baseline each increase of ln-l-homoarginine and l-arginine by one st and ard deviation was associated with symptomatic PAD : OR=0.75 , 95%CI 0.59 - 0.96 , P=0.02 and OR=1.36 , 95%CI 1.07 - 1.73 , P=0.01 , respectively ( both models adjusted for ln-CRP , GFR , HDL cholesterol , and current smoking ) . Only l-arginine remained significant after additional adjustment for ln-NT-proBNP and hs-cTnT : OR=1.49 , P=0.002 . In the Cox regression analysis elevated ln-l-homoarginine significantly reduced the risk to die ( n=38 ) even independent from ln-NT-proBNP and hs-cTnT : HR=0.59 , 95%CI 0.41 - 0.84 , P=0.004 . l-arginine was significantly predicting incident cardiovascular events ( n=65 ) : HR=1.68 , 95%CI 1.35 - 2.10 , P < 0.001 . CONCLUSIONS This study in male patients with intermittent claudication and age- and diabetes-matched controls showed an association of l-homoarginine and l-arginine with PAD . During follow-up , l-arginine was associated with incident cardiovascular events probably due to its primary role in NO metabolism and impact on endothelial integrity . l-homoarginine was related to all-cause mortality implying a broader role in metabolic processes besides endothelial function OBJECTIVES In the current study , we hypothesized that beraprost would : 1 ) improve treadmill exercise performance and quality of life ; and 2 ) decrease rates of ischemic events in patients with intermittent claudication . BACKGROUND Previous trials with beraprost sodium , an orally active prostagl and in I(2 ) analogue , in the treatment of claudication in patients with peripheral arterial disease ( PAD ) have been inconsistent . METHODS Patients with intermittent claudication ( n = 897 ) were r and omized to receive either 40 microg three times a day of beraprost with meals ( n = 385 ) or placebo ( n = 377 ) in a double-blinded manner for one year . The primary efficacy parameter was treadmill-measured maximum walking distance , as assessed at three and six months after r and omization . Secondary efficacy parameters included treadmill-measured pain-free walking distance and change in quality of life . RESULTS There was no significant improvement in maximum walking distance in the beraprost group ( 16.7 % ) as compared with the placebo group ( 14.6 % , p = NS ) . Administration of beraprost did not improve the pain-free walking distance ( p = NS between treatment groups ) , and there was no improvement in the quality -of-life measures between the treatment groups . The incidence of critical cardiovascular events was 7.3 % in the beraprost group and 11.4 % in the placebo group ( p = NS ) . There was a significant reduction in the combination of cardiovascular death and myocardial infa rct ion in the beraprost group ( p = 0.01 ) . CONCLUSIONS Despite previous investigations suggesting efficacy , these results indicate that beraprost is not an effective treatment to improve symptoms of intermittent claudication in patients with PAD . The potential benefit of beraprost on critical cardiovascular events would require confirmation in a larger prospect i ve investigation 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 Atherosclerotic peripheral arterial disease is associated with an increased risk of myocardial infa rct ion , stroke , and death from cardiovascular causes . Antiplatelet drugs reduce this risk , but the role of oral anticoagulant agents in the prevention of cardiovascular complications in patients with peripheral arterial disease is unclear . METHODS We assigned patients with peripheral arterial disease to combination therapy with an antiplatelet agent and an oral anticoagulant agent ( target international normalized ratio [ INR ] , 2.0 to 3.0 ) or to antiplatelet therapy alone . The first co primary outcome was myocardial infa rct ion , stroke , or death from cardiovascular causes ; the second co primary outcome was myocardial infa rct ion , stroke , severe ischemia of the peripheral or coronary arteries leading to urgent intervention , or death from cardiovascular causes . RESULTS A total of 2161 patients were r and omly assigned to therapy . The mean follow-up time was 35 months . Myocardial infa rct ion , stroke , or death from cardiovascular causes occurred in 132 of 1080 patients receiving combination therapy ( 12.2 % ) and in 144 of 1081 patients receiving antiplatelet therapy alone ( 13.3 % ) ( relative risk , 0.92 ; 95 % confidence interval [ CI ] , 0.73 to 1.16 ; P=0.48 ) . Myocardial infa rct ion , stroke , severe ischemia , or death from cardiovascular causes occurred in 172 patients receiving combination therapy ( 15.9 % ) as compared with 188 patients receiving antiplatelet therapy alone ( 17.4 % ) ( relative risk , 0.91 ; 95 % CI , 0.74 to 1.12 ; P=0.37 ) . Life-threatening bleeding occurred in 43 patients receiving combination therapy ( 4.0 % ) as compared with 13 patients receiving antiplatelet therapy alone ( 1.2 % ) ( relative risk , 3.41 ; 95 % CI , 1.84 to 6.35 ; P<0.001 ) . CONCLUSIONS In patients with peripheral arterial disease , the combination of an oral anticoagulant and antiplatelet therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with an increase in life-threatening bleeding . ( Clinical Trials.gov number , NCT00125671 [ Clinical Trials.gov ] . ) 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 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 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 BACKGROUND Sinking prebeta lipoprotein is a putative marker for elevated levels of lipoprotein ( a ) . Although prospect i ve data suggest that increased plasma lipoprotein ( a ) is an independent risk factor for coronary heart disease in men , no prospect i ve studies are available in women . METHODS AND RESULTS From 1968 through 1975 , sinking prebeta lipoprotein  was determined by paper electrophoresis in 3103 women Framingham Heart Study participants who were free of prevalent cardiovascular disease . A  sinking prebeta lipoprotein b and was detectable in 434 of the women ( 14 % ) studied . The median follow-up interval was approximately 12 years . Incident cardiovascular disease was associated with b and presence using a proportional hazards model that included age , smoking , body mass index , systolic blood pressure , glucose intolerance , low- and high-density lipoprotein cholesterol , and ECG left ventricular hypertrophy . Multivariable adjusted relative risk estimates ( with 95 % confidence intervals ) for outcomes in the b and present versus absent groups were as follows : myocardial infa rct ion ( 82 events ) , 2.37 ( 1.48 to 3.81 ) ; intermittent claudication ( 62 events ) , 1.94 ( 1.07 to 3.50 ) ; cerebrovascular disease ( 83 events ) , 1.88 ( 1.12 to 3.15 ) ; total coronary heart disease ( 174 events ) , 1.61 ( 1.13 to 2.29 ) ; and total cardiovascular disease ( 305 events ) , 1.44 ( 1.09 to 1.91 ) . A subset analysis indicated that b and presence was 50.9 % sensitive and 95.4 % specific for detecting plasma lipoprotein ( a ) levels of > 30 mg/dL , the threshold value linked to increased cardiovascular disease risk in men . CONCLUSIONS Sinking prebeta lipoprotein was a valid surrogate for elevated lipoprotein ( a ) levels in Framingham Heart Study women . B and presence and , equivalently , elevated plasma lipoprotein ( a ) , was a strong , independent predictor of myocardial infa rct ion , intermittent claudication , and cerebrovascular disease . Confirmation of these findings in other longitudinal studies of women is needed BACKGROUND Serum markers of inflammation and platelet activation are related to cardiovascular risk . Cardiovascular risk reduction is a major treatment goal in patients with peripheral arterial disease ( PAD ) . Although current guidelines recommend supervised exercise training ( SET ) for PAD patients with intermittent claudication , its contribution to risk reduction remains unclear . Aim of the present study was to assess the impact of SET on inflammation and platelet activation as surrogates for cardiovascular risk . METHODS Fifty-three patients with intermittent claudication were r and omly assigned to SET on top of best medical treatment ( BMT ) for 6 months ( SET-group ) or to BMT only ( BMT-group ) . High sensitivity C-reactive protein ( hs-CRP ) , interleukin-6 ( IL-6 ) and fibrinogen as well as soluble P-selectin ( sP-sel ) , prothrombin fragment 1 + 2 ( F1.2 ) and monocyte-platelet aggregates ( MPA ) were determined at study entry , after 3 , 6 and 12 months . RESULTS While clinical improvement , reflected by an increase of walking capacity , was observed upon SET , no lasting changes of markers of inflammation and platelet activation were found within the SET-group during the training period . Compared to the BMT-group no improvements of these markers were observed in response to training at any time point ( all p > 0.05 ) . CONCLUSION Regular SET added no further anti-inflammatory effect and had no effect on platelet activation when provided on top of BMT in PAD patients with intermittent claudication OBJECTIVES This study sought to determine whether patients with peripheral arterial disease ( PAD ) experience different reductions in ischemic event and increases in bleeding events with extended duration dual antiplatelet therapy versus those without PAD . BACKGROUND Patients with PAD have increased ischemic and bleeding risks after coronary stenting . METHODS The DAPT ( Dual Antiplatelet Therapy ) study r and omized 11,648 patients free from ischemic and bleeding events 12 months after coronary stenting to continued thienopyridine plus aspirin therapy for an additional 18 months versus aspirin therapy alone . The effects of continued thienopyridine on myocardial infa rct ion ( MI ) or stent thrombosis , major adverse cardiovascular and cerebrovascular events ( death , MI , or stroke ) and bleeding ( GUSTO [ Global Utilization of t-PA and Streptokinase for Occluded Coronary Arteries ] moderate or severe ) were assessed among those with versus without PAD . RESULTS Among 11,648 r and omized patients , 649 ( 5.57 % ) had PAD . Between 12 and 30 months , r and omized patients with PAD had higher rates of MI/stent thrombosis ( 6.03 % vs. 2.92 % ; p < 0.001 ) , major adverse cardiovascular and cerebrovascular events ( 11.65 % vs. 4.62 % ; p < 0.001 ) , and bleeding ( 4.86 % vs. 1.74 % ; p < 0.001 ) . Continued thienopyridine versus placebo was associated with consistent treatment effects for MI/stent thrombosis ( with PAD , HR : 0.63 ; 95 % CI : 0.32 to 1.22 ; without PAD , HR : 0.53 ; 95 % CI : 0.42 , 0.66 ; interaction p = 0.631 ) , major adverse cardiovascular and cerebrovascular events ( with PAD , HR : 1.06 ; 95 % CI : 0.67 to 1.67 ; without PAD , HR : 0.70 ; 95 % CI : 0.59 to 0.84 ; interaction p = 0.103 ) , and bleeding ( with PAD , HR , 1.82 ; 95 % CI : 0.87 to 3.83 ; without PAD , HR : 1.66 ; 95 % CI : 1.23 to 2.24 ; interaction p = 0.811 ) . CONCLUSIONS Among patients undergoing coronary stenting , those with PAD have more ischemic and bleeding events versus those without PAD . Extended duration dual antiplatelet therapy is associated with consistent ischemic benefit and bleeding harm among patients with and without PAD CONTEXT Accumulation of iron in excess of physiologic requirements has been implicated in risk of cardiovascular disease because of increased iron-catalyzed free radical-mediated oxidative stress . OBJECTIVE To test the hypothesis that reducing body iron stores through phlebotomy will influence clinical outcomes in a cohort of patients with symptomatic peripheral arterial disease ( PAD ) . DESIGN , SETTING , AND PATIENTS Multicenter , r and omized , controlled , single-blinded clinical trial based on the Iron ( Fe ) and Atherosclerosis Study ( FeAST ) ( VA Cooperative Study # 410 ) and conducted between May 1 , 1999 , and April 30 , 2005 , within the Department of Veterans Affairs Cooperative Studies Program and enrolling 1277 patients with symptomatic but stable PAD . Those with conditions likely to cause acute-phase increase of the ferritin level or with a diagnosis of visceral malignancy within the preceding 5 years were excluded . Analysis was by intent-to-treat . INTERVENTION Patients were assigned to a control group  ( n = 641 ) or to a group undergoing reduction of iron stores by phlebotomy with removal of defined volumes of blood at 6-month intervals ( avoiding iron deficiency ) ( n = 636 ) , stratified by hospital , age , and baseline smoking status , diagnosis of diabetes mellitus , ratio of high-density to low-density lipoprotein cholesterol level , and ferritin level . MAIN OUTCOME MEASURES The primary end point was all-cause mortality ; the secondary end point was death plus nonfatal myocardial infa rct ion and stroke . RESULTS There were no significant differences between treatment groups for the primary or secondary study end points . All-cause deaths occurred in 148 patients ( 23 % ) in the control group and in 125 ( 20 % ) in the iron-reduction group ( hazard ratio ( HR ) , 0.85 ; 95 % confidence interval ( CI ) , 0.67 - 1.08 ; P = .17 ) . Death plus nonfatal myocardial infa rct ion and stroke occurred in 205 patients ( 32 % ) in the control group and in 180 ( 28 % ) in the iron-reduction group ( HR , 0.88 ; 95 % CI , 0.72 - 1.07 ; P = .20 ) . CONCLUSION Reduction of body iron stores in patients with symptomatic PAD did not significantly decrease all-cause mortality or death plus nonfatal myocardial infa rct ion and stroke . TRIAL REGISTRATION Clinical trials.gov Identifier : NCT00032357 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 The Swedish Ticlopidine Multicentre Study ( STIMS ) was a double-blind placebo-controlled trial design ed to determine whether ticlopidine , a platelet antiaggregatory agent , reduces the incidence of myocardial infa rct ion , stroke and transitory ischaemic attacks in patients with intermittent claudication . A total of 687 patients was monitored for a minimum of 5 years or until an end-point was reached . The number of end points ( 99 vs. 89 ) , analysed according to the intention-to-treat principle , was 11.4 % lower in the ticlopidine group ( P = 0.24 ) . The mortality rate was 29.1 % lower in the ticlopidine group ( 64 vs. 89 , P = 0.015 ) ; this observation could be accounted for by a reduced mortality from ischaemic heart disease . On-treatment analysis showed there to be significantly fewer end points in the ticlopidine group ( 47 vs. 76 , P = 0.017 ) . Diarrhoea was the most common side-effect . Reversible leucopenia or thrombocytopenia was reported in seven patients on ticlopidine . It is concluded that the high morbidity and mortality from cardio- and cerebrovascular disease in patients with intermittent claudication can be reduced by long-term treatment with ticlopidine Microalbuminuria ( MA ) is associated with increased  cardiovascular and all-cause mortality .  It has been proposed that MA reflects generalized atherosclerosis and may thus predict mortality . To investigate this hypothesis , we studied the associations between , on the one h and , MA and peripheral arterial disease ( PAD ) , a generally accepted marker of generalized atherosclerosis , and , on the other h and , cardiovascular and all-cause mortality in an age- , sex- , and glucose tolerance-stratified sample ( n=631 ) of a population -based cohort aged 50 to 75 years followed prospect ively for 5 years . At baseline , the  albumin-to-creatinine ratio ( ACR ) was measured in an overnight spot urine sample ; MA was defined as ACR > 2.0 mg/mmol . PAD was defined as an ankle-brachial pressure index below 0.90 and /or a history of a peripheral arterial bypass or amputation . After 5 years of follow-up , 58 subjects had died ( 24 of cardiovascular causes ) . Both MA and PAD were associated with a 4-fold increase in cardiovascular mortality . After adjusting for age , sex , diabetes mellitus , hypertension , levels of total and HDL-cholesterol and triglyceride , body mass index , smoking habits , and preexistent ischemic heart disease , the relative risks ( RR ) ( 95 % confidence intervals ) were 3.2 ( 1.3 to 8.1 ) for MA and 2.4 ( 0.9 to 6.1 ) for PAD . When both MA and PAD were included in the multivariate analysis , the RRs were 2.9 ( 1.1 to 7.3 ) for MA and 2.0 ( 0.7 to 5.7 ) for PAD . MA and PAD were both associated with an about 2-fold increase in all-cause mortality . The RRs of all-cause mortality associated with MA and PAD were about 4 times higher among hypertensive than among normotensive subjects . We conclude that both MA and PAD are associated with an increased risk of cardiovascular mortality . MA and PAD are mutually independent risk indicators . The associations of MA and PAD with all-cause mortality are somewhat weaker . They are more pronounced in the presence of hypertension than in its absence . These data suggest that MA affects mortality risk through a mechanism different from generalized atherosclerosis Objective —To determine the association between  leukocyte telomere length ( TL ) and atherosclerosis and its clinical sequelae stroke and myocardial infa rct ion . Methods and Results —Within the scope of the prospect i ve population -based Bruneck Study ,  leukocyte TL  was measured by quantitative polymerase chain reaction in 800 women and men aged 45 to 84 years ( in 1995 ) . The manifestation of cardiovascular disease ( CVD ) ( 1995–2005 ) and the progression of atherosclerosis ( 1995–2000 ) were carefully assessed . The TL was shorter in men than in women ( age-adjusted mean [ 95 % CI ] , 1.41 [ 1.33 to 1.49 ] versus 1.55 [ 1.47 to 1.62 ] ; P=0.02 ) and inversely correlated to age ( r=−0.22 , P<0.001 ) and family history of CVD ( P=0.03 ) . Participants with CVD events during follow-up ( n=88 ) had significantly shorter telomeres ( age- and sex-adjusted mean [ 95 % CI ] , 1.25 [ 1.08 to 1.42 ] versus 1.51 [ 1.45 to 1.57 ] ; P<0.001 ) . In multivariable Cox models , baseline TL emerged as a significant and independent risk predictor for the composite CVD end point and its individual components ( myocardial infa rct ion and stroke ) ; however , this was not the case for de novo stable angina and intermittent claudication . Subjects in the top and bottom TL tertile group differed in their CVD risk by a factor of 2.72 ( 95 % CI , 1.41 to 5.28 ) , which is the risk ratio attributable to a 13.9-year difference in chronological age . Remarkably , in our atherosclerosis progression model , TL was strongly associated with advanced , but not early , atherogenesis . All findings were consistent in women and men . Conclusion —Our findings indicate a differential role of telomere shortening in the various stages of atherosclerosis , with preferential involvement in advanced vessel pathology and acute vascular syndromes Objectives . To determine whether different levels of the ankle-brachial pressure index ( ABPI ) are associated with an increased risk for progressive limbischemia , nonfatal and fatal cardiovascular events . To investigate the prognostic value of signs and symptoms associated with peripheral arterial occlusive disease ( PAOD ) . Design . Prospect i ve follow-up study . Setting . Eighteen general practice centers in the Netherl and s. Participants . Three thous and six hundred forty-nine participants ( 53 % female ) with a mean age of 59 years ( range : 40 - 78 years ) . Main outcome measures . Progressive limbischemia , cardiovascular morbidity and mortality . Results . At baseline , 458 participants had PAOD , defined as an ABPI < 0.95 . Among these , 148 ( 32.2 % ) had an ABPI < 0.70 . Cox proportional hazards models showed that after a mean follow-up period of 7.2 years , PAOD patients with an ABPI < 0.70 were at higher risk for cardiovascular death , compared with participants with a moderately reduced ABPI ( < 0.95 - 0.70 ) : HR 2.3 versus 1.2 . Older age , complaints of intermittent claudication , abnormal pedal pulses , elevated blood pressure , and coexisting cardiovascular disease at baseline were also significant independent prognostic factors for one or more of the adverse outcome events in these patients . Conclusion . The ABPI is inversely associated with cardiovascular mortality  in PAOD patients . A low ABPI is an independent predictor for cardiovascular mortality in PAOD patients
Antiplatelet agents have a beneficial effect in reducing all cause mortality and fatal cardiovascular events in patients with IC .
BACKGROUND Peripheral arterial disease ( PAD ) is common and is a marker of systemic atherosclerosis .
Patients with symptoms of intermittent claudication ( IC ) are at increased risk of cardiovascular events ( myocardial infa rct ion ( MI ) and stroke ) and of both cardiovascular and all cause mortality .
OBJECTIVES To determine the effectiveness of antiplatelet agents in reducing mortality ( all cause and cardiovascular ) and cardiovascular events in patients with intermittent claudication .