今日の臨床サポート

下肢末梢動脈疾患(LEAD)

著者: 中村正人 東邦大学 循環器内科

監修: 代田浩之 順天堂大学大学院医学研究科循環器内科学

著者校正済:2022/09/14
現在監修レビュー中
参考ガイドライン:
  1. 日本循環器学会日本血管外科学会:2022年改訂版末梢動脈疾患ガイドライン
  1. 欧州心臓病学会(ESC)、欧州血管外科学会(ESVS)合同: Peripheral Arterial Diseases(末梢動脈疾患)の診断と治療に関するガイドライン(2018年2月)
  1. 米国心臓協会(AHA)/米国心臓病学会(ACC):2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary
  1. 米国血管外科学会(SVS),欧州血管外科学会(ESVS),および世界血管外科学会連合(WFVS):Global vascular guidelines on the management of chronic limb-threatening ischemia(2019年)
患者向け説明資料

概要・推奨   

  1. 下肢末梢動脈疾患(LEAD)症例はpolyvascular diseaseが高率であり、アテローム血栓症として考えるべきである(JG)。
  1. LEADは急性下肢虚血と慢性下肢虚血に大別される(改訂JG)。
  1. 慢性下肢虚血は無症候性と症候性に分けられ、症候性は間歇性跛行と包括的高度慢性下肢虚血(CLTI)に分けられる(JG)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
中村正人 : 講演料(テルモ(株)),研究費・助成金など(ニプロ(株),アボットメディカルジャパン(株)),企業などが提供する寄付講座(ボストン・サイエンティフィックジャパン(株))[2022年]
監修:代田浩之 : 講演料(ノバルティスファーマ,バイエル薬品),研究費・助成金など(フィリップスジャパン,東邦ホールディングス,旭化成,インターリハ,富士フイルム,グローリー),奨学(奨励)寄付など(バイエル薬品,エーザイ),企業などが提供する寄付講座(フィリップスジャパン,レスメド,フクダ電子,パラマウントベッド)[2022年]

改訂のポイント:
  1. 旧ガイドラインからACC/AHAガイドライン2016へ加筆
  1. 旧ガイドラインからESCガイドライン2017を加筆
  1. 旧ガイドラインからJCS2022年改訂版末梢動脈疾患ガイドラインを加筆

病態・疫学・診察

疾患情報  
  1. 末梢動脈疾患(peripheral arterial disease、PAD)とは厳密には冠動脈以外の血管の閉塞性疾患のことであり、下肢の閉塞性動脈硬化症はLEAD(Lower extremity arterial disease)と呼ばれる。
 
 
  1. 下肢虚血は急性下肢虚血と慢性下肢虚血に分類される。
  1. LEADは閉塞性動脈硬化症(arteriosclerosis obliterans、ASO)、Buerger病など多彩な疾患を含む概念である。
  1. 1970年頃まではBuerger病がLEADの半数を占めたが、近年では、Buerger病の頻度が減少し、食生活、生活スタイルの変化に伴いASOが増加、95%を占めている。このためASOがLEADの主体となっておりLEADとASOは同義語として用いられるようになっている。
 
LEADとは

LEADの95%以上を閉塞性動脈硬化症(ASO)が占めることから、欧米同様LEADをASOと同義に用いることが多い。

出典

img1:  著者提供
 
 
 
  1. PADの発症頻度は1~3%で、加齢に伴い有意に増加し、喫煙者、糖尿病歴を持つ患者で高率に合併する。70歳以上では2~5%、糖尿病では5~10%とされる。また、男性は女性に比し2倍のリスクを有する。
  1. 受動喫煙によっても曝露量依存性にLEAD発症リスクが高まる。
  1. ASOのリスク因子として、喫煙、糖尿病はオッズ比が3~4倍、高血圧は1.5~2倍である。一方、冠動脈疾患と異なり脂質異常の寄与度は高血圧、糖尿病よりも小さい。
  1. 冠動脈疾患の13~19%、脳血管障害の18.8%、透析例の15~24%の頻度で足関節上腕血圧比(ABI)<0.9の症例を認めたという報告がある。
  1. LEADは無症候性と有症候性に分けられ、無症候例(無症候性虚血肢)が最も多く、その頻度は有症候例の2~5倍である。
  1. 症状として、間歇性跛行、血管雑音、脈拍の欠損を認める。有症候例の主訴の70%は間歇性跛行である。
  1. 間歇性跛行とは、歩行運動などの運動負荷によって疼痛や違和感などが出現し、運動停止で症状が軽快消失する状態を指す。
  1. 包括的高度慢性下肢虚血(chronic limb-threatening ischemia、CLTI)とは、下肢虚血、組織欠損、神経障害、感染などの肢切断リスクを持ち、治療介入が必要な下肢病変を総称する概念である。
  1. 重症下肢虚血(CLI)は、より包括的に治療介入が必要な下肢の創傷としてCLTIと呼称されるようになった。
  1. 糖尿病性潰瘍または2週間以上以上継続する下肢潰瘍、下腿、または足部の壊疽、血行動態WIfI Grade3以上の虚血を有する下肢潰瘍、安静時疼痛がCLTIに該当する。跛行の病歴なく発症する症例が40%程度を占める。
  1. 静脈性潰瘍、外傷、急性動脈閉塞(発症後2週間以内)や非動脈硬化性慢性動脈疾患(血管炎、Buerger病など)によるものは除外される。
  1. CLTIの中で慢性虚血による安静時疼痛(2週間以上)、または潰瘍、壊死を伴った状態は、血行再建なしでは組織の維持や疼痛の除去が困難であり、疼痛コントロールにはオピオイドを必要とする。
 
  1. LEAD症例はpolyvascular diseaseが高率であり、アテローム血栓症として考えるべきである。
  1. ABI<0.9例はABI1.0~1.5の症例に比し、心筋梗塞の既往、狭心症、心不全歴が2倍高率であると報告されており[1][2]、REACH registryではLEAD症例の60%に脳血管障害、心血管障害を合併する[3]。このように多血管領域に疾患を合併する症例をpolyvascular diseaseと称するが、BARI registryによると、LEADを合併した心血管疾患は非合併例に比し4.9倍死亡リスクが高く[4]、冠動脈形成術を施行した8つの多施設臨床試験1万9,867例のメタ解析でも、LEAD合併例は1年後の死亡、心筋梗塞リスクは2倍高いことが示されている[5]。このように複数の血管疾患を有するPolyvascular disease症例の予後は不良である[6]。そのため、厳重なリスク管理が求められる[7]
 
問診・診察のポイント  
  1. LEADのハイリスク例や下肢の機能低下を有する症例に対しては末梢動脈の触診などLEADを考慮した診察を行う。

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文献 

A B Newman, D S Siscovick, T A Manolio, J Polak, L P Fried, N O Borhani, S K Wolfson
Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group.
Circulation. 1993 Sep;88(3):837-45.
Abstract/Text BACKGROUND: Peripheral arterial disease measured noninvasively by the ankle-arm index (AAI) is common in older adults, largely asymptomatic, and associated with clinically manifest cardiovascular disease (CVD). The criteria for an abnormal AAI have varied in previous studies. To determine whether there is an inverse dose-response relation between the AAI and clinical CVD, subclinical disease, and risk factors, we examined the relation of the AAI to cardiovascular risk factors, other noninvasive measures of subclinical atherosclerosis using carotid ultrasound, echocardiography and electrocardiography, and clinical CVD.
METHODS AND RESULTS: The AAI was measured in 5084 participants > or = 65 years old at the baseline examination of the Cardiovascular Health Study. All subjects had detailed assessment of prevalent CVD, measures of cardiovascular risk factors, and noninvasive measures of disease. Participants were stratified by baseline clinical CVD status and AAI (< 0.8, > or = 0.8 to < 0.9, > or = 0.9 to < 1.0, > or = 1.0 to < 1.5). Analyses tested for a dose-response relation of the AAI with clinical CVD, risk factors, and subclinical disease. The cumulative frequency of a low AAI was 7.4% of participants < 0.8, 12.4% < 0.9, and 23.6% < 1.0. participants with an AAI < 0.8 were more than twice as likely as those with an AAI of 1.0 to 1.5 to have a history of myocardial infarction, angina, congestive heart failure, stroke, or transient ischemic attack (all P < .01). In participants free of clinical CVD at baseline, the AAI was inversely related to history of hypertension, history of diabetes, and smoking, as well as systolic blood pressure, serum creatinine, fasting glucose, fasting insulin, measures of pulmonary function, and fibrinogen level (all P < .01). Risk factor associations with the AAI were similar in men and women free of CVD except for serum total and low-density lipoprotein cholesterol, which were inversely associated with AAI level only in women. Risk factors associated with an AAI of < 1.0 in multivariate analysis included smoking (odds ratio [OR], 2.55), history of diabetes (OR, 3.84), increasing age (OR, 1.54), and nonwhite race (OR, 2.36). In the 3372 participants free of clinical CVD, other noninvasive measures of subclinical CVD, including carotid stenosis by duplex scanning, segmental wall motion abnormalities by echocardiogram, and major ECG abnormalities were inversely related to the AAI (all P < .01).
CONCLUSIONS: There was an inverse dose-response relation of the AAI with CVD risk factors and subclinical and clinical CVD among older adults. The lower the AAI, the greater the increase in CVD risk; however, even those with modest, asymptomatic reductions in the AAI (0.8 to 1.0) appear to be at increased risk of CVD.

PMID 8353913
Z J Zheng, A R Sharrett, L E Chambless, W D Rosamond, F J Nieto, D S Sheps, A Dobs, G W Evans, G Heiss
Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study.
Atherosclerosis. 1997 May;131(1):115-25.
Abstract/Text The resting ankle-brachial index (ABI) is a non-invasive method to assess the patency of the lower extremity arterial system and to screen for the presence of peripheral occlusive arterial disease. To determine how the ABI is associated with clinical coronary heart disease (CHD), stroke, preclinical carotid plaque and far wall intimal-medial thickness (IMT) of the carotid and popliteal arteries, we conducted analyses in 15 106 middle-aged adults from the baseline examination (1987-1989) of the Atherosclerosis Risk in Communities (ARIC) Study. The prevalence of clinical CHD, stroke/transient ischemic attack (TIA) and preclinical carotid plaque increased with decreasing ABI levels, particularly at those of < 0.90. Individuals with ABI < 0.90 were twice as likely to have prevalent CHD as those with ABI > 0.90 (age-adjusted odds ratio (OR) ranging from 2.2 (95% CI: 1.0-5.1) in African-American men to 3.3 (95% CI: 2.1-5.0) in white men). Men with ABI < 0.90 were more than four times as likely to have stroke/TIA as those with ABI > 0.90 (age-adjusted OR: 4.2 (95% CI: 1.8-9.5) in African-American men and 4.9 (95% CI: 2.6-9.0) in white men). In women the association was weaker and not statistically significant. Among those free of clinical cardiovascular disease, individuals with ABI < or = 0.90 had statistically significantly higher prevalence of preclinical carotid plaque compared to those with ABI > 0.90 (age-adjusted ORs ranging from 1.5 (95% CI: 1.0-1.9) in white women to 2.6 (95% CI: 1.0-6.6) in african-american men). The ABI was also inversely associated with far wall IMT of the carotid arteries (in both men and women) and the popliteal arteries (in men only). The associations of ABI with clinical CHD, stroke, preclinical carotid plaque and IMT of the carotid and popliteal arteries were attenuated and often not statistically significant after further adjustment for LDL cholesterol, cigarette smoking, hypertension and diabetes. These data demonstrate that low ABI levels, particularly those of < 0.90, are indicative of generalized atherosclerosis.

PMID 9180252
Deepak L Bhatt, P Gabriel Steg, E Magnus Ohman, Alan T Hirsch, Yasuo Ikeda, Jean-Louis Mas, Shinya Goto, Chiau-Suong Liau, Alain J Richard, Joachim Röther, Peter W F Wilson, REACH Registry Investigators
International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis.
JAMA. 2006 Jan 11;295(2):180-9. doi: 10.1001/jama.295.2.180.
Abstract/Text CONTEXT: Atherothrombosis is the leading cause of cardiovascular morbidity and mortality around the globe. To date, no single international database has characterized the atherosclerosis risk factor profile or treatment intensity of individuals with atherothrombosis.
OBJECTIVE: To determine whether atherosclerosis risk factor prevalence and treatment would demonstrate comparable patterns in many countries around the world.
DESIGN, SETTING, AND PARTICIPANTS: The Reduction of Atherothrombosis for Continued Health (REACH) Registry collected data on atherosclerosis risk factors and treatment. A total of 67,888 patients aged 45 years or older from 5473 physician practices in 44 countries had either established arterial disease (coronary artery disease [CAD], n = 40,258; cerebrovascular disease, n = 18,843; peripheral arterial disease, n = 8273) or 3 or more risk factors for atherothrombosis (n = 12,389) between 2003 and 2004.
MAIN OUTCOME MEASURES: Baseline prevalence of atherosclerosis risk factors, medication use, and degree of risk factor control.
RESULTS: Atherothrombotic patients throughout the world had similar risk factor profiles: a high proportion with hypertension (81.8%), hypercholesterolemia (72.4%), and diabetes (44.3%). The prevalence of overweight (39.8%), obesity (26.6%), and morbid obesity (3.6%) were similar in most geographic locales, but was highest in North America (overweight: 37.1%, obese: 36.5%, and morbidly obese: 5.8%; P<.001 vs other regions). Patients were generally undertreated with statins (69.4% overall; range: 56.4% for cerebrovascular disease to 76.2% for CAD), antiplatelet agents (78.6% overall; range: 53.9% for > or =3 risk factors to 85.6% for CAD), and other evidence-based risk reduction therapies. Current tobacco use in patients with established vascular disease was substantial (14.4%). Undertreated hypertension (50.0% with elevated blood pressure at baseline), undiagnosed hyperglycemia (4.9%), and impaired fasting glucose (36.5% in those not known to be diabetic) were common. Among those with symptomatic atherothrombosis, 15.9% had symptomatic polyvascular disease.
CONCLUSION: This large, international, contemporary database shows that classic cardiovascular risk factors are consistent and common but are largely undertreated and undercontrolled in many regions of the world.

PMID 16403930
K A Burek, K Sutton-Tyrrell, M M Brooks, B Naydeck, N Keller, M A Sellers, G Roubin, R Jandová, C S Rihal
Prognostic importance of lower extremity arterial disease in patients undergoing coronary revascularization in the Bypass Angioplasty Revascularization Investigation (BARI).
J Am Coll Cardiol. 1999 Sep;34(3):716-21.
Abstract/Text OBJECTIVES: The purpose of this study was to evaluate the prevalence and prognostic importance of lower extremity arterial disease (LEAD) in patients with multivessel coronary artery disease.
BACKGROUND: The presence of clinically evident LEAD increases the risk of death in patients with known coronary artery disease. Because studies have lacked noninvasive measures of subclinical LEAD, the true prognostic importance of lower extremity atherosclerosis in this population has probably been underestimated.
METHODS: Ankle blood pressures were measured in 405 consecutive patients with angiographically documented multivessel coronary disease from seven Bypass Angioplasty Revascularization Investigation (BARI) sites and a parallel study site within 3 years of enrollment. Lower extremity arterial disease was defined as an ankle/arm systolic blood pressure ratio of 0.90 or less.
RESULTS: Among patients studied, 69 (17%) had LEAD. These patients were more likely to be current smokers, treated for diabetes, older and present with unstable angina compared with patients without LEAD. Among patients who underwent coronary arterial bypass grafting, major complications occurred in 2.8% of those without LEAD compared with 20.7% of those with LEAD (p = 0.002). Five-year mortality rates were similar for symptomatic LEAD (14%) and asymptomatic LEAD (14%). Patients without LEAD had a 3% mortality. After adjusting for baseline differences, the relative risk of death was 4.9 times greater for patients with LEAD compared with those without (95% confidence interval [CI]: 1.8, 13.4, p < 0.01).
CONCLUSIONS: Patients with LEAD have a significantly higher risk of death than patients without LEAD, regardless of the presence of symptoms. An abnormal ankle/arm index is a strong predictor of mortality and can be used to further stratify risk among patients with multivessel coronary artery disease.

PMID 10483952
Jacqueline Saw, Deepak L Bhatt, David J Moliterno, Sorin J Brener, Steven R Steinhubl, A Michael Lincoff, James E Tcheng, Robert A Harrington, Maarten Simoons, TingFei Hu, Mobeen A Sheikh, Dean J Kereiakes, Eric J Topol
The influence of peripheral arterial disease on outcomes: a pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials.
J Am Coll Cardiol. 2006 Oct 17;48(8):1567-72. doi: 10.1016/j.jacc.2006.03.067. Epub 2006 Sep 26.
Abstract/Text OBJECTIVES: We aimed to evaluate clinical outcomes among peripheral arterial disease (PAD) patients following percutaneous coronary intervention (PCI).
BACKGROUND: A significant proportion of patients with coronary artery disease undergoing PCI have concomitant PAD, which may be associated with worse outcomes.
METHODS: We performed a pooled analysis of 8 randomized PCI trials. We included multicenter PCI trials that compared antiplatelet therapies (EPIC, EPILOG, EPISTENT, RAPPORT, CAPTURE, IMPACT-II, TARGET, and CREDO) and had baseline PAD status recorded. Multivariable analyses were performed with stepwise logistic regression for 7- and 30-day outcomes and Cox regression for 6-month and 1-year events.
RESULTS: In our pooled analysis of 19,867 patients undergoing PCI, 1,602 (8.1%) were previously diagnosed with PAD. Patients with PAD had higher incidences of 7-day death (1.0% vs. 0.4%; p < 0.001) or myocardial infarction (MI) (6.8% vs. 5.6%; p = 0.047), 30-day death (1.7% vs. 0.7%; p < 0.001) or MI (7.4% vs. 6.1%; p = 0.05), 6-month death (4.2% vs. 1.5%; p < 0.001) or MI (9.1%, vs. 7.7%; p = 0.048), and 1-year death (5.0% vs. 2.1%; p < 0.001). There was a trend toward higher major bleeding risk with PAD (4.8% vs. 3.9%; p = 0.06). With multivariable analyses, PAD remains a significant predictor of mortality at 30 days (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.03 to 2.70; p = 0.039), 6 months (HR 1.76, 95% CI 1.31 to 2.37; p < 0.001), and 1 year (HR 1.46, 95% CI 1.08 to 1.96; p = 0.013).
CONCLUSIONS: The presence of PAD is associated with higher rates of post-PCI death and MI, and is an independent predictor of short- and long-term mortality.

PMID 17045889
Deepak L Bhatt, Kim A Eagle, E Magnus Ohman, Alan T Hirsch, Shinya Goto, Elizabeth M Mahoney, Peter W F Wilson, Mark J Alberts, Ralph D'Agostino, Chiau-Suong Liau, Jean-Louis Mas, Joachim Röther, Sidney C Smith, Geneviève Salette, Charles F Contant, Joseph M Massaro, Ph Gabriel Steg, REACH Registry Investigators
Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis.
JAMA. 2010 Sep 22;304(12):1350-7. doi: 10.1001/jama.2010.1322. Epub 2010 Aug 30.
Abstract/Text CONTEXT: Clinicians and trialists have difficulty with identifying which patients are highest risk for cardiovascular events. Prior ischemic events, polyvascular disease, and diabetes mellitus have all been identified as predictors of ischemic events, but their comparative contributions to future risk remain unclear.
OBJECTIVE: To categorize the risk of cardiovascular events in stable outpatients with various initial manifestations of atherothrombosis using simple clinical descriptors.
DESIGN, SETTING, AND PATIENTS: Outpatients with coronary artery disease, cerebrovascular disease, or peripheral arterial disease or with multiple risk factors for atherothrombosis were enrolled in the global Reduction of Atherothrombosis for Continued Health (REACH) Registry and were followed up for as long as 4 years. Patients from 3647 centers in 29 countries were enrolled between 2003 and 2004 and followed up until 2008. Final database lock was in April 2009.
MAIN OUTCOME MEASURES: Rates of cardiovascular death, myocardial infarction, and stroke.
RESULTS: A total of 45,227 patients with baseline data were included in this 4-year analysis. During the follow-up period, a total of 5481 patients experienced at least 1 event, including 2315 with cardiovascular death, 1228 with myocardial infarction, 1898 with stroke, and 40 with both a myocardial infarction and stroke on the same day. Among patients with atherothrombosis, those with a prior history of ischemic events at baseline (n = 21,890) had the highest rate of subsequent ischemic events (18.3%; 95% confidence interval [CI], 17.4%-19.1%); patients with stable coronary, cerebrovascular, or peripheral artery disease (n = 15,264) had a lower risk (12.2%; 95% CI, 11.4%-12.9%); and patients without established atherothrombosis but with risk factors only (n = 8073) had the lowest risk (9.1%; 95% CI, 8.3%-9.9%) (P < .001 for all comparisons). In addition, in multivariable modeling, the presence of diabetes (hazard ratio [HR], 1.44; 95% CI, 1.36-1.53; P < .001), an ischemic event in the previous year (HR, 1.71; 95% CI, 1.57-1.85; P < .001), and polyvascular disease (HR, 1.99; 95% CI, 1.78-2.24; P < .001) each were associated with a significantly higher risk of the primary end point.
CONCLUSION: Clinical descriptors can assist clinicians in identifying high-risk patients within the broad range of risk for outpatients with atherothrombosis.

PMID 20805624
Ph Gabriel Steg, Deepak L Bhatt, Peter W F Wilson, Ralph D'Agostino, E Magnus Ohman, Joachim Röther, Chiau-Suong Liau, Alan T Hirsch, Jean-Louis Mas, Yasuo Ikeda, Michael J Pencina, Shinya Goto, REACH Registry Investigators
One-year cardiovascular event rates in outpatients with atherothrombosis.
JAMA. 2007 Mar 21;297(11):1197-206. doi: 10.1001/jama.297.11.1197.
Abstract/Text CONTEXT: Few data document current cardiovascular (CV) event rates in stable patients with atherothrombosis in a community setting. Differential event rates for patients with documented coronary artery disease (CAD), cerebrovascular disease (CVD), or peripheral arterial disease (PAD) or those at risk of these diseases have not been previously evaluated in a single international cohort.
OBJECTIVE: To establish contemporary, international, 1-year CV event rates in outpatients with established arterial disease or with multiple risk factors for atherothrombosis.
DESIGN, SETTING, AND PARTICIPANTS: The Reduction of Atherothrombosis for Continued Health (REACH) Registry is an international, prospective cohort of 68 236 patients with either established atherosclerotic arterial disease (CAD, PAD, CVD; n = 55 814) or at least 3 risk factors for atherothrombosis (n = 12 422), who were enrolled from 5587 physician practices in 44 countries in 2003-2004.
MAIN OUTCOME MEASURES: Rates of CV death, myocardial infarction (MI), and stroke.
RESULTS: As of July 2006, 1-year outcomes were available for 95.22% (n = 64 977) of participants. Cardiovascular death, MI, or stroke rates were 4.24% overall: 4.69% for those with established atherosclerotic arterial disease vs 2.15% for patients with multiple risk factors only. Among patients with established disease, CV death, MI, or stroke rates were 4.52% for patients with CAD, 6.47% for patients with CVD, and 5.35% for patients with PAD. The incidences of the end point of CV death, MI, or stroke or of hospitalization for atherothrombotic event(s) were 15.20% for CAD, 14.53% for CVD, and 21.14% for PAD patients with established disease. These event rates increased with the number of symptomatic arterial disease locations, ranging from 5.31% for patients with risk factors only to 12.58% for patients with 1, 21.14% for patients with 2, and 26.27% for patients with 3 symptomatic arterial disease locations (P<.001 for trend).
CONCLUSIONS: In this large, contemporary, international study, outpatients with established atherosclerotic arterial disease, or at risk of atherothrombosis, experienced relatively high annual CV event rates. Multiple disease locations increased the 1-year risk of CV events.

PMID 17374814
A T Hirsch, M H Criqui, D Treat-Jacobson, J G Regensteiner, M A Creager, J W Olin, S H Krook, D B Hunninghake, A J Comerota, M E Walsh, M M McDermott, W R Hiatt
Peripheral arterial disease detection, awareness, and treatment in primary care.
JAMA. 2001 Sep 19;286(11):1317-24.
Abstract/Text CONTEXT: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis that is common and is associated with an increased risk of death and ischemic events, yet may be underdiagnosed in primary care practice.
OBJECTIVE: To assess the feasibility of detecting PAD in primary care clinics, patient and physician awareness of PAD, and intensity of risk factor treatment and use of antiplatelet therapies in primary care clinics.
DESIGN AND SETTING: The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, a multicenter, cross-sectional study conducted at 27 sites in 25 cities and 350 primary care practices throughout the United States in June-October 1999.
PATIENTS: A total of 6979 patients aged 70 years or older or aged 50 through 69 years with history of cigarette smoking or diabetes were evaluated by history and by measurement of the ankle-brachial index (ABI). PAD was considered present if the ABI was 0.90 or less, if it was documented in the medical record, or if there was a history of limb revascularization. Cardiovascular disease (CVD) was defined as a history of atherosclerotic coronary, cerebral, or abdominal aortic aneurysmal disease.
MAIN OUTCOME MEASURES: Frequency of detection of PAD; physician and patient awareness of PAD diagnosis; treatment intensity in PAD patients compared with treatment of other forms of CVD and with patients without clinical evidence of atherosclerosis.
RESULTS: PAD was detected in 1865 patients (29%); 825 of these (44%) had PAD only, without evidence of CVD. Overall, 13% had PAD only, 16% had PAD and CVD, 24% had CVD only, and 47% had neither PAD nor CVD (the reference group). There were 457 patients (55%) with newly diagnosed PAD only and 366 (35%) with PAD and CVD who were newly diagnosed during the survey. Eighty-three percent of patients with prior PAD were aware of their diagnosis, but only 49% of physicians were aware of this diagnosis. Among patients with PAD, classic claudication was distinctly uncommon (11%). Patients with PAD had similar atherosclerosis risk factor profiles compared with those who had CVD. Smoking behavior was more frequently treated in patients with new (53%) and prior PAD (51%) only than in those with CVD only (35%; P <.001). Hypertension was treated less frequently in new (84%) and prior PAD (88%) only vs CVD only (95%; P <.001) and hyperlipidemia was treated less frequently in new (44%) and prior PAD (56%) only vs CVD only (73%, P<.001). Antiplatelet medications were prescribed less often in patients with new (33%) and prior PAD (54%) only vs CVD only (71%, P<.001). Treatment intensity for diabetes and use of hormone replacement therapy in women were similar across all groups.
CONCLUSIONS: Prevalence of PAD in primary care practices is high, yet physician awareness of the PAD diagnosis is relatively low. A simple ABI measurement identified a large number of patients with previously unrecognized PAD. Atherosclerosis risk factors were very prevalent in PAD patients, but these patients received less intensive treatment for lipid disorders and hypertension and were prescribed antiplatelet therapy less frequently than were patients with CVD. These results demonstrate that underdiagnosis of PAD in primary care practice may be a barrier to effective secondary prevention of the high ischemic cardiovascular risk associated with PAD.

PMID 11560536
J I Weitz, J Byrne, G P Clagett, M E Farkouh, J M Porter, D L Sackett, D E Strandness, L M Taylor
Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review.
Circulation. 1996 Dec 1;94(11):3026-49.
Abstract/Text
PMID 8941154
M M McDermott, S Mehta, P Greenland
Exertional leg symptoms other than intermittent claudication are common in peripheral arterial disease.
Arch Intern Med. 1999 Feb 22;159(4):387-92.
Abstract/Text BACKGROUND: Epidemiological data show that most community-dwelling men and women with lower-extremity peripheral arterial disease (PAD) do not have typical symptoms of intermittent claudication. We compared the prevalence of intermittent claudication, leg symptoms other than intermittent claudication, and absence of exertional leg symptoms between patients with PAD identified from a blood flow laboratory (group 1), patients with PAD in a general medicine practice (group 2), and control patients without PAD (group 3).
METHODS: Numbers of participants in groups 1, 2, and 3 were 137, 26, and 105, respectively. Patients with previously diagnosed PAD were excluded from groups 2 and 3. All participants underwent ankle-brachial index measurement and were administered the San Diego claudication questionnaire to assess leg symptoms.
RESULTS: Within groups 1, 2, and 3, prevalences of intermittent claudication were 28.5% (n = 39), 3.8% (n = 1), and 3.8% (n= 4), respectively. Prevalences of exertional leg symptoms other than intermittent claudication were 56.2% (n= 77), 42.3% (n= 11), and 19.0% (n = 20), respectively. Absence of exertional leg symptoms was reported by 15.3% (n= 21), 53.8% (n= 14), and 77.1% (n=81), respectively. Among patients with PAD, older age, male sex, diabetes mellitus, and group 2 vs group 1 status were associated independently with absence of exertional leg symptoms in multivariable regression analysis. Lower ankle-brachial index levels and group 1 vs group 2 status were associated with intermittent claudication.
CONCLUSIONS: Clinical manifestations of PAD are diverse, particularly among patients identified by ankle-brachial index screening. Exertional leg symptoms other than intermittent claudication are common in PAD. Patients with PAD who are older, male, diabetic, or identified with ankle-brachial index screening in a primary care setting are more likely to have asymptomatic PAD.

PMID 10030313
M M McDermott, P Greenland, K Liu, J M Guralnik, M H Criqui, N C Dolan, C Chan, L Celic, W H Pearce, J R Schneider, L Sharma, E Clark, D Gibson, G J Martin
Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment.
JAMA. 2001 Oct 3;286(13):1599-606.
Abstract/Text CONTEXT: Persons with lower-extremity peripheral arterial disease (PAD) are often asymptomatic or have leg symptoms other than intermittent claudication (IC).
OBJECTIVE: To identify clinical characteristics and functional limitations associated with a broad range of leg symptoms identified among patients with PAD.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of 460 men and women with PAD and 130 without PAD, who were identified consecutively, conducted between October 1998 and January 2000 at 3 Chicago-area medical centers.
MAIN OUTCOME MEASURES: Ankle-brachial index score of less than 0.90; scores from 6-minute walk, accelerometer-measured physical activity over 7 days, repeated chair raises, standing balance (full tandem stand), 4-m walking velocity, San Diego claudication questionnaire, Geriatric Depression Score Short-Form, and the Walking Impairment Questionnaire.
RESULTS: All groups with PAD had poorer functioning than participants without PAD. The following values are for patients without IC vs those with IC. Participants in the group with leg pain on exertion and rest (n = 88) had a higher (poorer) score for neuropathy (5.6 vs 3.5; P<.001), prevalence of diabetes mellitus (48.9% vs 26.7%; P<.001), and spinal stenosis (20.8% vs 7.2%; P =.002). The atypical exertional leg pain/carry on group (exertional leg pain other than IC associated with walking through leg pain [n = 41]) and the atypical exertional leg pain/stop group (exertional leg pain other than IC that causes one to stop walking [n = 90]) had better functioning than the IC group. The group without exertional leg pain/inactive (no exertional leg pain in individual who walks CONCLUSIONS: There is a wide range of leg symptoms in persons with PAD beyond that of classic IC. Comorbid disease may contribute to these symptoms in PAD. Functional impairments are found in every PAD symptom group, and the degree of functional limitation varies depending on the type of leg symptom.

PMID 11585483
Uwe Zeymer, Klaus G Parhofer, David Pittrow, Christiane Binz, Markus Schwertfeger, Tobias Limbourg, Joachim Röther
Risk factor profile, management and prognosis of patients with peripheral arterial disease with or without coronary artery disease: results of the prospective German REACH registry cohort.
Clin Res Cardiol. 2009 Apr;98(4):249-56. doi: 10.1007/s00392-009-0754-1. Epub 2009 Feb 16.
Abstract/Text AIMS: Peripheral arterial disease (PAD) and coronary artery disease (CAD) are manifestations of the same underlying condition, atherothrombosis. We compared patients with PAD only with those having PAD and concomitant documented CAD in terms of characteristics, risk factors, treatment and prognosis.
METHODS AND RESULTS: This is a subgroup analysis of the German cohort of the Reduction of Atherothrombosis for Continued Health (REACH) Registry. It includes 483 patients with PAD only, and 479 patients with PAD plus CAD. Patients with concomitant cerebrovascular disease were excluded. Symptomatic PAD was defined as intermittent claudication (IC), confirmed by ankle brachial index <0.9, or PAD-related intervention. Patients in the total cohort were predominantly elderly (mean age 67.3 +/- 8.9 years), males (72.3%), current or previous smokers (80.18%), and had often abdominal obesity (49.6%). Atherosclerotic risk factors and comorbidities were highly prevalent. Patients with PAD + CAD compared to those with PAD only were significantly more intensively treated with regards to antihrombotic agents (97.1% vs. 88.8%), statins (80.2% vs. 51.6%), or ACE inhibitors/ARB (75.6% vs. 61.1%). After two-year follow-up, no significant differences between subgroups were noted for total mortality (4.6% vs. 5.5%), cardiovascular mortality (3.7% vs. 3.9%), non-fatal myocardial infarction (1.9% vs. 2.7%) but for non-fatal stroke (4.4% vs. 2.0%, P < 0.05).
CONCLUSION: Peripheral arterial disease patients carry a high burden of risk factors and co-morbidities, and are at high risk of death and cardiovascular events. If documented CAD is absent, PAD patients are undertreated. Thus, in PAD patients, secondary cardiovascular prevention with stringent treatment of risk factors to the same extent as in CAD patients is mandatory, in line with current guidelines.

PMID 19221687
Gijs M J M Welten, Olaf Schouten, Sanne E Hoeks, Michel Chonchol, Radosav Vidakovic, Ron T van Domburg, Jeroen J Bax, Marc R H M van Sambeek, Don Poldermans
Long-term prognosis of patients with peripheral arterial disease: a comparison in patients with coronary artery disease.
J Am Coll Cardiol. 2008 Apr 22;51(16):1588-96. doi: 10.1016/j.jacc.2007.11.077.
Abstract/Text OBJECTIVES: This study was designed to compare the long-term outcomes of patients with peripheral arterial disease (PAD) with a risk factor matched population of coronary artery disease (CAD) patients, but without PAD.
BACKGROUND: The PAD is considered to be a risk factor for adverse late outcome.
METHODS: A total of 2,730 PAD patients undergoing vascular surgery were categorized into groups: 1) carotid endarterectomy (n = 560); 2) elective abdominal aortic surgery (AAA) (n = 923); 3) acute AAA surgery (r-AAA) (n = 200), and 4) lower limb reconstruction procedures (n = 1,047). All patients were matched using the propensity score, with 2,730 CAD patients who underwent coronary angioplasty. Survival status of all patients was obtained. In addition, the cause of death and complications after surgery in PAD patients were noted. The Kaplan-Meier method was used to compare survival between the matched PAD and CAD population and the different operation groups. Prognostic risk factors and perioperative complications were identified with the Cox proportional hazards regression model.
RESULTS: The PAD patients had a worse long-term prognosis (hazard ratio 2.40, 95% confidence interval 2.18 to 2.65) and received less medication (beta-blockers, statins, angiotensin-converting enzyme inhibitors, aspirin, nitrates, and calcium antagonists) than CAD patients did (p < 0.001). Cerebro-cardiovascular complications were the major cause of long-term death (46%). Importantly, no significant difference in long-term survival was observed between the AAA and lower limb reconstruction groups (log rank p = 0.70). After vascular surgery, perioperative cardiac complications were associated with long-term cardiac death, and noncardiac complications were associated with all-cause death.
CONCLUSIONS: Long-term prognosis of vascular surgery patients is significantly worse than for patients with CAD. The vascular surgery patients receive less cardiac medication than CAD patients do, and cerebro-cardiovascular events are the major cause of late death.

PMID 18420103
R B McLafferty, G L Dunnington, M A Mattos, S J Markwell, D E Ramsey, J P Henretta, L A Karch, K J Hodgson, D S Sumner
Factors affecting the diagnosis of peripheral vascular disease before vascular surgery referral.
J Vasc Surg. 2000 May;31(5):870-9. doi: 10.1067/mva.2000.106422.
Abstract/Text OBJECTIVE: Many new patients evaluated by vascular surgeons are referred by internal medicine physicians (IMPs). Objectives shared by vascular surgeons and IMPs include early identification of peripheral arterial disease (PAD), improved referral relationships, and reduction of health care costs. The approach to PAD by IMPs and identification of deficiencies that might contribute to suboptimal care form the basis for this report.
METHODS: An anonymous survey was mailed to all IMPs (n = 843) in the central and southern parts of Illinois. Questions concerned IMP demographics, approach to diagnostic testing, referral patterns, perception of adequacy of education of PAD, and how often parts of the history and physical examination for PAD would be performed on the initial office visit of a hypothetical 65-year-old male with hypertension (each answer measured as 0%-25%, 25%-50%, 50%-75%, and 75%-100% of the time completed).
RESULTS: There was a response from 360 IMPs: 230 IMPs (27.3%) returned the questionnaire, and 130 IMPs (15.4%) declined to participate. Practice locations for IMPs returning the questionnaire included rural (36%), suburban (22%), and urban (40%). Practice types included academic (7%), solo private (29%), group private (53%), and other (14%). A history of cardiac disease was obtained most of the time by 92% of IMPs (75%-100% answer category). Histories for pulmonary disease, diabetes mellitus, stroke, and smoking were obtained most of the time with similar frequencies (85%, 86%, 73%, and 96%, respectively). In contrast, only 37% obtained a history for claudication, and 26% obtained a history for foot ulceration 75% to 100% of the time (P <.05, all comparisons). Examination of the heart (95%) and lungs (96%) occurred most of the time (75%-100% answer category) compared with each part of the pulse examination (range, 34%-60%; P <.05, all comparisons) and aortic aneurysm palpation (39%; P <.05). If pedal pulses were absent, examination by IMPs with Doppler scan and ankle-arm indices were mostly distributed in the 0% to 25% answer category (79% and 79%, respectively). After suspecting PAD, most IMPs obtained diagnostic tests first compared with specialist referral: carotid disease (91% vs 9%), aortic aneurysm (91% vs 9%), and lower extremity PAD (86% vs 14%). Initial referral patterns were made to vascular surgeons (49%), general surgeons (33%), cardiothoracic surgeons (13%), cardiologists (4%), and radiologists (1%). Most IMPs believed medical school (70%) and residency (73%) provided adequate training for PAD diagnosis.
CONCLUSIONS: Deficiencies may exist in the identification of PAD by IMPs that could adversely affect diagnosis, time to referral, health care costs, and ultimately, patient outcome. Improvements in medical school education and IMP training in the diagnosis of PAD are needed.

PMID 10805876
L Norgren, W R Hiatt, J A Dormandy, M R Nehler, K A Harris, F G R Fowkes, TASC II Working Group, Kevin Bell, Joseph Caporusso, Isabelle Durand-Zaleski, Kimihiro Komori, Johannes Lammer, Christos Liapis, Salvatore Novo, Mahmood Razavi, Johns Robbs, Nicholaas Schaper, Hiroshi Shigematsu, Marc Sapoval, Christopher White, John White, Denis Clement, Mark Creager, Michael Jaff, Emile Mohler, Robert B Rutherford, Peter Sheehan, Henrik Sillesen, Kenneth Rosenfield
Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
Eur J Vasc Endovasc Surg. 2007;33 Suppl 1:S1-75. doi: 10.1016/j.ejvs.2006.09.024. Epub 2006 Nov 29.
Abstract/Text
PMID 17140820
Abstract/Text In cardiovascular surveys, the WHO questionnaire on intermittent claudication has traditionally been used as a measure of atherosclerotic peripheral arterial disease of the lower limbs. But the questionnaire is of limited value because atherosclerotic disease is frequently asymptomatic. Research on the validity and reliability of the questionnaire and the simpler non-invasive tests of peripheral arterial disease are reviewed. These tests include measurement of the ankle-brachial systolic pressure ratio, a treadmill exercise test, a reactive hyperaemia test, and assessment of toe-pulse reappearance time. The performance of these non-invasive tests is such that they should be used, in conjunction with the intermittent claudication questionnaire, in epidemiological studies of atherosclerotic peripheral arterial disease of the lower limbs.

PMID 3042648
Osamu Iida, Mitsuyoshi Takahara, Yoshimitsu Soga, Akio Kodama, Hiroto Terashi, Nobuyoshi Azuma, SPINACH Investigators
Three-Year Outcomes of Surgical Versus Endovascular Revascularization for Critical Limb Ischemia: The SPINACH Study (Surgical Reconstruction Versus Peripheral Intervention in Patients With Critical Limb Ischemia).
Circ Cardiovasc Interv. 2017 Dec;10(12). doi: 10.1161/CIRCINTERVENTIONS.117.005531.
Abstract/Text BACKGROUND: The aim of this study was to compare clinical outcomes between surgical reconstruction and endovascular therapy (EVT) for critical limb ischemia (CLI) in today's real-world settings.
METHODS AND RESULTS: This multicenter, prospective, observational study registered and followed 548 Japanese CLI patients. The registration was in advance of revascularization; 197 patients were scheduled to receive surgical reconstruction, and the remaining 351 were scheduled to receive EVT. The primary end point was 3-year amputation-free survival, compared between the 2 treatments in an intention-to-treat manner, using propensity score matching. Interaction analysis was additionally performed to explore which subgroups had better outcomes with surgical reconstruction or EVT. After propensity score matching, the 3-year amputation-free survival was not significantly different between the 2 groups (52% [95% confidence interval, 43%-60%] and 52% [95% confidence interval, 44-60%]; P=0.26). Subsequent interaction analysis identified (1) Wound, Ischemia, and foot Infection (WIfI) classification W-3, (2) fI-2/3, (3) history of ipsilateral minor amputation, (4) history of revascularization after CLI onset, and (5) bilateral CLI as the factors more favorable for surgical reconstruction, whereas (1) diabetes mellitus, (2) renal failure, (3) anemia, (4) history of nonadherence to cardiovascular risk management, and (5) contralateral major amputation were as those less favorable for surgical reconstruction.
CONCLUSIONS: The 3-year amputation-free survival was not different between surgical reconstruction and EVT in the overall CLI population. The subsequent interaction analysis suggested that there would be a subgroup more suited for surgical reconstruction and another benefiting more from EVT.
CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN000007050.

Copyright © 2017 The Authors.
PMID 29246911
Alan T Hirsch, Ziv J Haskal, Norman R Hertzer, Curtis W Bakal, Mark A Creager, Jonathan L Halperin, Loren F Hiratzka, William R C Murphy, Jeffrey W Olin, Jules B Puschett, Kenneth A Rosenfield, David Sacks, James C Stanley, Lloyd M Taylor, Christopher J White, John White, Rodney A White, Elliott M Antman, Sidney C Smith, Cynthia D Adams, Jeffrey L Anderson, David P Faxon, Valentin Fuster, Raymond J Gibbons, Jonathan L Halperin, Loren F Hiratzka, Sharon A Hunt, Alice K Jacobs, Rick Nishimura, Joseph P Ornato, Richard L Page, Barbara Riegel, American Association for Vascular Surgery, Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, ACC/AHA Task Force on Practice Guidelines, American Association of Cardiovascular and Pulmonary Rehabilitation, National Heart, Lung, and Blood Institute, Society for Vascular Nursing, TransAtlantic Inter-Society Consensus, Vascular Disease Foundation
ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.
J Am Coll Cardiol. 2006 Mar 21;47(6):1239-312. doi: 10.1016/j.jacc.2005.10.009.
Abstract/Text
PMID 16545667
Curt Diehm, Jens Rainer Allenberg, David Pittrow, Matthias Mahn, Gerhart Tepohl, Roman L Haberl, Harald Darius, Ina Burghaus, Hans Joachim Trampisch, German Epidemiological Trial on Ankle Brachial Index Study Group
Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease.
Circulation. 2009 Nov 24;120(21):2053-61. doi: 10.1161/CIRCULATIONAHA.109.865600. Epub 2009 Nov 9.
Abstract/Text 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 prospective cohort study included 6880 representative unselected patients >or=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 infarction, 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 infarction/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.

PMID 19901192
A B Newman, K Sutton-Tyrrell, M T Vogt, L H Kuller
Morbidity and mortality in hypertensive adults with a low ankle/arm blood pressure index.
JAMA. 1993 Jul 28;270(4):487-9.
Abstract/Text OBJECTIVE: To evaluate the relationship between the ankle/arm blood pressure index (AAI, the ratio of ankle to arm systolic blood pressure, a measure of peripheral arterial disease) and short-term cardiovascular morbidity and mortality in older adults with systolic hypertension.
DESIGN: Prospective cohort study, 1- to 2-year follow-up (mean, 16 months).
SETTING: Eleven of 16 field centers from the Systolic Hypertension in the Elderly Program.
PARTICIPANTS: 1537 older men and women with systolic hypertension.
MAIN OUTCOME MEASURES: All-cause mortality, coronary heart disease (CHD) mortality, cardiovascular disease (CVD) mortality, and CHD and CVD morbidity and mortality.
RESULTS: The AAI was measured at the 1989-1990 clinic examination and was 0.9 or less in 25.5% of 1537 participants. A low AAI was associated with most major CHD and CVD risk factors. In those with a low AAI (< or = 0.9) compared with those with an AAI of more than 0.9, age- and sex-adjusted relative risks for mortality end points at follow-up were as follows: total mortality, 3.8 (95% confidence interval [CI], 2.1 to 6.9); CHD mortality, 3.24 (95% CI, 1.4 to 7.5); and CVD mortality, 3.7 (95% CI, 1.8 to 7.7). For CVD morbidity and mortality, the age- and sex-adjusted relative risk was 2.5 (95% CI, 1.5 to 4.3). After adjustment for baseline CVD and other cardiovascular risk factors, the relative risk for total mortality was 4.1 (95% CI, 2.0 to 8.3) and for CVD morbidity and mortality, 2.4 (95% CI, 1.3 to 4.4). Results were similar when participants with clinical CVD at baseline were excluded.
CONCLUSION: A low AAI appears to be an important predictor of morbidity and mortality among older adults with systolic hypertension.

PMID 8147959
Abstract/Text Non-invasive measurements, especially segmental pressure ratios and flow measurements, are useful for gauging the severity of peripheral arterial disease (PAD). Although the incidence of PAD is similar for men and women, men are more likely to have severe disease, while women usually have more moderate or asymptomatic disease. Published reports confirm the clinical impression that patients with PAD are more likely to have both coronary artery disease and cerebrovascular disease than those without PAD. However, the degree of overlap is a function of the sensitivity of the diagnostic assessments for the three conditions. A San Diego population study found that the incidence of PAD may be underestimated, with many patients being asymptomatic. Based on blood flow measurements, the study found that 11.9% of the study population had large vessel PAD. Morbidity from both coronary heart disease and stroke was increased in people with PAD, who were 2.5 times more likely to present with morbidity from cardiovascular disease (CVD) than those who did not have PAD. Several studies have now confirmed the strong predictive value of PAD for subsequent CVD mortality and that the risk of CVD mortality increases with the severity of PAD.

PMID 9892517
M H Criqui, R D Langer, A Fronek, H S Feigelson, M R Klauber, T J McCann, D Browner
Mortality over a period of 10 years in patients with peripheral arterial disease.
N Engl J Med. 1992 Feb 6;326(6):381-6. doi: 10.1056/NEJM199202063260605.
Abstract/Text BACKGROUND: Previous investigators have observed a doubling of the mortality rate among patients with intermittent claudication, and we have reported a fourfold increase in the overall mortality rate among subjects with large-vessel peripheral arterial disease, as diagnosed by noninvasive testing. In this study, we investigated the association of large-vessel peripheral arterial disease with rates of mortality from all cardiovascular diseases and from coronary heart disease.
METHODS: We examined 565 men and women (average age, 66 years) for the presence of large-vessel peripheral arterial disease by means of two noninvasive techniques--measurement of segmental blood pressure and determination of flow velocity by Doppler ultrasound. We identified 67 subjects with the disease (11.9 percent), whom we followed prospectively for 10 years.
RESULTS: Twenty-one of the 34 men (61.8 percent) and 11 of the 33 women (33.3 percent) with large-vessel peripheral arterial disease died during follow-up, as compared with 31 of the 183 men (16.9 percent) and 26 of the 225 women (11.6 percent) without evidence of peripheral arterial disease. After multivariate adjustment for age, sex, and other risk factors for cardiovascular disease, the relative risk of dying among subjects with large-vessel peripheral arterial disease as compared with those with no evidence of such disease was 3.1 (95 percent confidence interval, 1.9 to 4.9) for deaths from all causes, 5.9 (95 percent confidence interval, 3.0 to 11.4) for all deaths from cardiovascular disease, and 6.6 (95 percent confidence interval, 2.9 to 14.9) for deaths from coronary heart disease. The relative risk of death from causes other than cardiovascular disease was not significantly increased among the subjects with large-vessel peripheral arterial disease. After the exclusion of subjects who had a history of cardiovascular disease at base line, the relative risks among those with large-vessel peripheral arterial disease remained significantly elevated. Additional analyses revealed a 15-fold increase in rates of mortality due to cardiovascular disease and coronary heart disease among subjects with large-vessel peripheral arterial disease that was both severe and symptomatic.
CONCLUSIONS: Patients with large-vessel peripheral arterial disease have a high risk of death from cardiovascular causes.

PMID 1729621
J Ostergren, P Sleight, G Dagenais, K Danisa, J Bosch, Yi Qilong, S Yusuf, HOPE study investigators
Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease.
Eur Heart J. 2004 Jan;25(1):17-24.
Abstract/Text AIMS: The aim of this study was to assess the prognostic importance of peripheral arterial disease (PAD) as evaluated by ankle blood pressure index (ABI), and the impact of ramipril on the prevention of major cardiovascular events in PAD patients included in the Heart Outcomes Prevention Evaluation (HOPE) study.
METHODS AND RESULTS: Patients were randomized to treatment with ramipril or placebo and followed for 4.5 years. Ankle brachial blood pressure index was measured, mainly by digital palpation of the foot pulse, at baseline in 8986 patients. The ABI was subnormal (< or =0.9) in 3099 patients and normal in 5887 patients. A low ABI was a strong predictor of morbidity and mortality during the follow-up even in patients with no clinical symptoms of PAD (n=6769). This was so for the primary outcome of the study; ABI>0.9:13.1%, 0.6-0.9: 18.2% and <0.6: 18.0% (P<0.0001) and for mortality from all causes: in those with a normal ABI it was 8.5%, in those with ABI >0.6-0.9, 12.4% and 14.2% in those with an ABI lower than 0.6 (P<0.0001). Ramipril reduced the risk of clinical outcomes in those with a clinical history of PAD as well as in the patients with subclinical PAD.
CONCLUSIONS: The ABI even if measured simply by palpation of the foot arteries is a strong predictor for future cardiovascular events and for all-cause mortality. Ramipril prevented major cardiovascular events in patients with clinical as well as subclinical PAD.

PMID 14683738
P Cacoub, J-P Cambou, S Kownator, J-P Belliard, J-P Beregi, A Branchereau, P Carpentier, P Léger, F Luizy, D Maïza, E Mihci, M-A Herrmann, P Priollet
Prevalence of peripheral arterial disease in high-risk patients using ankle-brachial index in general practice: a cross-sectional study.
Int J Clin Pract. 2009 Jan;63(1):63-70. doi: 10.1111/j.1742-1241.2008.01953.x.
Abstract/Text AIMS: The deleterious nature of peripheral arterial disease (PAD) is compounded by a status of underdiagnosed and undertreated disease. We evaluated the prevalence and predictive factors of PAD in high-risk patients using the ankle-brachial index (ABI).
METHODS: The ABI was measured by general practitioners in France (May 2005-February 2006) in 5679 adults aged 55 years or older and considered at high risk. The primary outcome was prevalence of PAD (ABI strictly below 0.90).
RESULTS: In all, 21.3% patients had signs or symptoms suggestive of PAD, 42.1% had previous history of atherothrombotic disease and 36.6% had two or more cardiovascular risk factors. Prevalence of PAD was 27.8% overall, ranging from 10.4% in patients with cardiovascular risk factors only to approximately 38% in each other subgroup. Prevalence differed depending on the localization of atherothrombotic events: it was 57.1-75.0% in patients with past history of symptomatic PAD; 24.6-31.1% in those who had experienced cerebrovascular and/or coronary events. Regarding the classical cardiovascular risk factors, PAD was more frequent when smoking and hypercholesterolemia history were reported. PAD prevalence was also higher in patients with history of abdominal aortic aneurysm, renal hypertension or atherothrombotic event. Intermittent claudication, lack of one pulse in the lower limbs, smoking, diabetes and renovascular hypertension were the main factors predictive of low ABI.
CONCLUSIONS: Given the elevated prevalence of PAD in high-risk patients and easiness of diagnosis using ABI in primary care, undoubtedly better awareness would help preserve individual cardiovascular health and achieve public health goals.

PMID 19125994
M McKenna, S Wolfson, L Kuller
The ratio of ankle and arm arterial pressure as an independent predictor of mortality.
Atherosclerosis. 1991 Apr;87(2-3):119-28.
Abstract/Text We carefully ascertained deaths for a cohort of 744 patients who had undergone noninvasive testing for lower extremity peripheral arterial disease (PAD) in a university affiliated, community hospital. Using a ratio of the ankle and brachial blood pressures (ABI) of less than 0.85 as the criteria, the relative risk (RR) for total mortality associated with PAD was 2.36 (95% CL = 1.60, 3.48) after adjusting for baseline covariates in a proportional hazards model. There was a strong trend for increasing risk with decreasing ABI (P less than 0.0001). Specific causes of death for which survival was directly related to the magnitude of ABI were myocardial infarctions, and deaths other than vascular disease and cancer. There was no relationship between ABI and the risk of mortality from cancer. The mortality experience of those with normal ABI was very similar to that of the general U.S. population (age adjusted RR = 1.14, 95% CL = 0.78, 1.61), whereas the risk for those with an ABI less than 0.4 was markedly elevated in comparison to the U.S. population (RR = 4.49, 95% CL = 3.52, 5.64). Our results suggest that the relatively technically simple measure of the ratio of ankle to brachial blood pressures, if low, carries a very poor prognosis and should prompt investigation and treatment of atherosclerotic disease in other vascular systems.

PMID 1854359
Ankle Brachial Index Collaboration, F G R Fowkes, G D Murray, I Butcher, C L Heald, R J Lee, L E Chambless, A R Folsom, A T Hirsch, M Dramaix, G deBacker, J-C Wautrecht, M Kornitzer, A B Newman, M Cushman, K Sutton-Tyrrell, F G R Fowkes, A J Lee, J F Price, R B d'Agostino, J M Murabito, P E Norman, K Jamrozik, J D Curb, K H Masaki, B L Rodríguez, J M Dekker, L M Bouter, R J Heine, G Nijpels, C D A Stehouwer, L Ferrucci, M M McDermott, H E Stoffers, J D Hooi, J A Knottnerus, M Ogren, B Hedblad, J C Witteman, M M B Breteler, M G M Hunink, A Hofman, M H Criqui, R D Langer, A Fronek, W R Hiatt, R Hamman, H E Resnick, J Guralnik, M M McDermott
Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.
JAMA. 2008 Jul 9;300(2):197-208. doi: 10.1001/jama.300.2.197.
Abstract/Text CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction.
OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction.
DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.
STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality.
DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease.
RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women.
CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

PMID 18612117
M T Vogt, J A Cauley, A B Newman, L H Kuller, S B Hulley
Decreased ankle/arm blood pressure index and mortality in elderly women.
JAMA. 1993 Jul 28;270(4):465-9.
Abstract/Text OBJECTIVE: To evaluate the relationship of the ankle/arm blood pressure index to short-term mortality in women 65 years of age or older.
DESIGN: Prospective cohort study with average follow-up of 4.3 years.
SETTING: Rural community near Pittsburgh, Pa.
PARTICIPANTS: A total of 1492 white women 65 years of age or older, living in the community and ambulatory without the help of another person.
OUTCOME MEASURES: All-cause and cause-specific mortality.
RESULTS: The ankle/arm index (the systolic pressure in the posterior tibial artery divided by that in the brachial artery) was measured in 1986 through 1988 and found to be 0.9 or less in 82 (5.5%) of the women, 67 of whom reported no symptoms of claudication. Comparing women with an index of 0.9 or less with those with an index greater than 0.9, the relative risk for all-cause mortality 4 years later (after adjustment for age, smoking, and other risk factors) was 3.1 (95% confidence interval [Cl], 1.7 to 5.5); for heart disease, 3.7 (95% Cl, 1.2 to 11.6); for cardiovascular diseases, 4.0 (95% Cl, 1.3 to 8.5); for cancer, 3.3 (95% Cl, 1.3 to 8.5); and for all other causes, 1.1 (95% Cl, 0.1 to 9.2). Similar levels of risk were found after excluding women with symptoms of claudication and/or a history of cardiovascular disease at baseline.
CONCLUSIONS: Healthy, older women with an ankle/arm index of 0.9 or less are at high risk of death and therefore may be considered for aggressive therapy to modify cardiovascular risk factors.

PMID 8320785
S Yusuf, P Sleight, J Pogue, J Bosch, R Davies, G Dagenais
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
N Engl J Med. 2000 Jan 20;342(3):145-53. doi: 10.1056/NEJM200001203420301.
Abstract/Text BACKGROUND: Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure.
METHODS: A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper.
RESULTS: A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03).
CONCLUSIONS: Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

PMID 10639539
L Norgren, W R Hiatt, J A Dormandy, M R Nehler, K A Harris, F G R Fowkes, TASC II Working Group
Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
J Vasc Surg. 2007 Jan;45 Suppl S:S5-67. doi: 10.1016/j.jvs.2006.12.037.
Abstract/Text
PMID 17223489
G C Leng, A J Lee, F G Fowkes, M Whiteman, J Dunbar, E Housley, C V Ruckley
Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population.
Int J Epidemiol. 1996 Dec;25(6):1172-81.
Abstract/Text 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 randomly from the age-sex register of 10 general practices in Edinburgh, Scotland. The presence of peripheral arterial disease was determined by the World Health Organization questionnaire on intermittent claudication, the ankle brachial pressure index and a reactive hyperaemia test. This cohort was followed prospectively 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 infarction 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.

PMID 9027521
M H Criqui
Peripheral arterial disease--epidemiological aspects.
Vasc Med. 2001;6(3 Suppl):3-7.
Abstract/Text As many as 10 million people in the USA have peripheral arterial disease (PAD) with a prevalence over 10% in people aged more than 60 years old. Generally, men have a higher prevalence of PAD than women. The risk factors for PAD are similar to those for coronary artery disease (CAD) and cerebrovascular disease (CBVD), but diabetes and cigarette smoking have a particularly strong association with PAD. Patients with PAD also have CAD and CBVD as co-morbidities, although the extent of co-morbidity depends on the sensitivity of assessment. The risk of mortality is proportional to the severity of PAD, and the relative risk of all-cause mortality due to PAD is unaltered by the presence of CAD or CBVD. PAD is under-recognized and under-treated, even though it should be regarded as a severe disease leading to significant death and disability from stroke and myocardial infarction (MI). Thus, accurate diagnosis of PAD could provide an early indication of the need for intervention and help prevent future morbidity and mortality.

PMID 11789963
Alan T Hirsch, Ziv J Haskal, Norman R Hertzer, Curtis W Bakal, Mark A Creager, Jonathan L Halperin, Loren F Hiratzka, William R C Murphy, Jeffrey W Olin, Jules B Puschett, Kenneth A Rosenfield, David Sacks, James C Stanley, Lloyd M Taylor, Christopher J White, John White, Rodney A White, Elliott M Antman, Sidney C Smith, Cynthia D Adams, Jeffrey L Anderson, David P Faxon, Valentin Fuster, Raymond J Gibbons, Sharon A Hunt, Alice K Jacobs, Rick Nishimura, Joseph P Ornato, Richard L Page, Barbara Riegel, American Association for Vascular Surgery, Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, ACC/AHA Task Force on Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease, American Association of Cardiovascular and Pulmonary Rehabilitation, National Heart, Lung, and Blood Institute, Society for Vascular Nursing, TransAtlantic Inter-Society Consensus, Vascular Disease Foundation
ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.
Circulation. 2006 Mar 21;113(11):e463-654. doi: 10.1161/CIRCULATIONAHA.106.174526.
Abstract/Text
PMID 16549646
W T Meijer, D E Grobbee, M G Hunink, A Hofman, A W Hoes
Determinants of peripheral arterial disease in the elderly: the Rotterdam study.
Arch Intern Med. 2000 Oct 23;160(19):2934-8.
Abstract/Text OBJECTIVE: To examine which atherosclerotic risk factors are determinants for peripheral arterial disease (PAD), we performed a population-based study in 6450 subjects (40% men, 60% women) aged 55 years and older.
METHODS: The presence of PAD was assessed by measuring the ankle-arm systolic blood pressure index (AAI); PAD was considered present if the AAI was lower than 0.90 in either leg. In addition, a threshold AAI of 0.70 in either leg defined severe PAD.
RESULTS: Determinants strongly and independently associated with PAD were age of at least 75 years (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0-1.6), fibrinogen level (OR, 1.5; 95% CI, 1.3-1.7), cigarette smoking (OR, 2.8; 95% CI, 2.3-3.4), diabetes mellitus (OR, 2.0; 95% CI, 1.6-2.5), and systolic blood pressure (OR, 1.2; 95% CI, 1.1-1.2). An inverse relation of high-density lipoprotein cholesterol level with PAD (OR, 0.7; 95% CI, 0.5-0.8) was found. Similar results were demonstrated for severe PAD. Separate analyses for men and women did not demonstrate differences in risk factors for PAD.
CONCLUSIONS: Assessment of a wide range of atherosclerotic risk factors enabled us to quantify the relative importance of each factor as determinant for PAD. In total, 69% of the occurrence of PAD is attributable to cardiovascular risk factors measured in our study; smoking accounted for most (etiologic fraction, 18.1%). The results suggest that preventive management of PAD should be directed at systolic blood pressure, fibrinogen level, smoking, high-density lipoprotein cholesterol level, and diabetes mellitus. Arch Intern Med. 2000;160:2934-2938

PMID 11041900
A W Gardner, E T Poehlman
Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis.
JAMA. 1995 Sep 27;274(12):975-80.
Abstract/Text OBJECTIVE: To identify the components of exercise rehabilitation programs that were most effective in improving claudication pain symptoms in patients with peripheral arterial disease.
DATA SOURCES: English-language articles were identified by a computer search using Index Medicus and MEDLINE, followed by an extensive bibliography review.
STUDY SELECTION: Studies were included if they provided the mean or individual walking distances or times to the onset of claudication pain and to maximal pain during a treadmill test before and after rehabilitation.
DATA EXTRACTION: Walking distances and times and characteristics of the exercise programs were independently abstracted by two observers.
DATA SYNTHESIS: Thirty-three English-language studies were identified, of which 21 met the inclusion criteria. Overall, following a program of exercise rehabilitation, the distance (mean +/- SD) to onset of claudication pain increased 179% from 125.9 +/- 57.3 m to 351.2 +/- 188.7 m (P < .001), and the distance to maximal claudication pain increased 122% from 325.8 +/- 148.1 m to 723.3 +/- 591.5 m (P < .001). The greatest improvement in pain distances occurred with the following exercise program: duration greater than 30 minutes per session, frequency of at least three sessions per week, walking used as the mode of exercise, use of near-maximal pain during training as claudication pain end point, and program length of greater than 6 months. However, the claudication pain end point, program length, and mode of exercise were the only independent predictors (P < .001) for improvement in distances.
CONCLUSIONS: The optimal exercise program for improving claudication pain distances in patients with peripheral arterial disease uses intermittent walking to near-maximal pain during a program of at least 6 months. Such a program should be part of the standard medical care for patients with intermittent claudication.

PMID 7674529
G C Leng, B Fowler, E Ernst
Exercise for intermittent claudication.
Cochrane Database Syst Rev. 2000;(2):CD000990. doi: 10.1002/14651858.CD000990.
Abstract/Text BACKGROUND: Exercise is an inexpensive, low risk option compared with other more invasive therapies for leg pain on walking (intermittent claudication).
OBJECTIVES: The objective of this review was to determine the effects of exercise for leg pain.
SEARCH STRATEGY: The reviewers searched the Cochrane Peripheral Vascular Diseases Group trials register, Embase, reference lists of relevant articles, and contacted principal investigators of trials.
SELECTION CRITERIA: Randomised trials of exercise regimens in patients with leg pain on walking (intermittent claudication).
DATA COLLECTION AND ANALYSIS: At least two reviewers extracted and assessed data trial quality independently. The reviewers contacted investigators to obtain information or data needed for the review that could not be found in published reports.
MAIN RESULTS: Fifteen trials were identified that met the inclusion criteria, but five were subsequently excluded because of poor quality. The remaining ten trials involved a total of almost 250 male and female patients with stable leg pain. The follow-up ranged from 12 weeks to 15 months. There was also some variation in the exercise regimens used, although all recommended at least two weekly sessions of, mostly, supervised exercise. All trials used a treadmill walking test as one of the outcome measures. The overall quality of the included trials was generally good, though the trials were all small (20-49 patients). Exercise therapy significantly improved maximal walking time (minutes) (weighted mean difference 6.51, 95% confidence interval 4.36 to 8.66, fixed effect model [FE]), with an overall improvement in walking ability of approximately 150% (range 74% to 230%). Exercise produced significant improvements in walking time compared with both angioplasty at six months (weighted mean difference 3.30, 95% confidence interval 2.21 to 4.39, FE) and antiplatelet therapy (weighted mean difference 1.06, 95% confidence interval 0.15 to 1.97, FE), and did not differ significantly from surgical treatment. In one small trial, exercise was less effective than pentoxifylline (weighted mean difference -0.45, 95% confidence interval -0.66 to -0.24, FE).
REVIEWER'S CONCLUSIONS: Exercise is of significant benefit to patients with leg pain.

PMID 10796572
Richard V Milani, Carl J Lavie
The role of exercise training in peripheral arterial disease.
Vasc Med. 2007 Nov;12(4):351-8. doi: 10.1177/1358863X07083177.
Abstract/Text Peripheral arterial disease (PAD) is currently a major health problem affecting 8-12 million Americans, 15-40% of whom will have intermittent claudication that can lead to substantial impairment in their ability to carry out normal daily activities as well as perform the recommended cardiovascular exercise. Supervised exercise training is an effective tool in the treatment of claudication and is currently a recommended first-line therapy for patients with this condition. In addition to improving pain-free walking distance and quality of life, supervised exercise training can improve many cardiovascular risk factors, possibly reducing the risk for subsequent myocardial infarction, stroke, and death. This paper will review the benefits of supervised exercise training in patients with PAD.

PMID 18048473
Abstract/Text The Diabetes Control and Complications Trial (DCCT), a multicenter, randomized, controlled clinical trial, demonstrated that intensive diabetes therapy delays the onset and slows the progression of retinopathy, nephropathy, and neuropathy in patients with insulin-dependent diabetes mellitus. This study presents the effect of intensive therapy on atherosclerosis-related events and associated risk factors. Patients (n = 1,441) between the ages of 13 and 39 years with insulin-dependent diabetes mellitus were randomly assigned to conventional or intensive diabetes treatment. The patients were free of cardiovascular disease at baseline. Patients with hypertension, hypercholesterolemia, or obesity were excluded. Average length of follow-up was 6.5 years (range 3.5 to 9). The study used standardized definitions of macrovascular events, verification of such events, and central laboratories for determination of lipids and the grading of electrocardiograms. The number of combined major macrovascular events was almost twice as high in the conventionally treated group (40 events) as in the intensive-treatment group (23 events), although the differences were not statistically significant (p = 0.08). There were no differences in the cumulative incidence of hypertension. Mean total serum cholesterol, calculated low-density lipoprotein cholesterol, and triglycerides were significantly reduced in the intensive-treatment group (p < or = 0.01), as was the development of low-density lipoprotein cholesterol levels > 160 mg/dl. Weight gain was significantly increased in the intensive-treatment group (p < 0.001). There were no differences in cigarette smoking habits, consumption of alcohol, or aspirin use between treatment groups. The reduction in some, but not all, cardiovascular risk factors suggests a potential beneficial effect of intensive therapy on macrovascular disease in insulin-dependent diabetes mellitus.

PMID 7732997
Abstract/Text BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.
METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy.
FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg).
INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)

PMID 9742976
Emile R Mohler, William R Hiatt, Mark A Creager
Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease.
Circulation. 2003 Sep 23;108(12):1481-6. doi: 10.1161/01.CIR.0000090686.57897.F5. Epub 2003 Sep 2.
Abstract/Text 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 randomized, 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 questionnaires. 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 questionnaire demonstrated improvement in ambulatory ability for the 10- and 80-mg groups (P=0.011), whereas 2 quality of life instruments, the Walking Impairment Questionnaire and Short Form 36 Questionnaire, 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.

PMID 12952839
Anna A Ahimastos, Adam Lawler, Christopher M Reid, Peter A Blombery, Bronwyn A Kingwell
Brief communication: ramipril markedly improves walking ability in patients with peripheral arterial disease: a randomized trial.
Ann Intern Med. 2006 May 2;144(9):660-4.
Abstract/Text BACKGROUND: Peripheral arterial disease (PAD) affects up to 12% of adults older than 50 years of age. Conventional therapies have only modest effects in improving symptoms.
OBJECTIVE: To examine the effects of angiotensin-converting enzyme inhibition on walking ability in patients with PAD.
DESIGN: Randomized, double-blind, placebo-controlled trial initiated in March 2003 and completed in January 2005.
SETTING: The Alfred Hospital, Melbourne, Australia.
PARTICIPANTS: 40 older adults with symptomatic PAD and no history of diabetes or hypertension.
INTERVENTION: 10 mg of ramipril (n = 20) or placebo (n = 20) once daily for 24 weeks. All patients completed the trial.
MEASUREMENTS: Pain-free and maximum walking time were recorded during a standard treadmill test, and the standard Walking Impairment Questionnaire was administered.
RESULTS: After adjustment for the baseline pain-free walking time, mean pain-free walking time after ramipril treatment was 227 seconds (95% CI, 175 seconds to 278 seconds; P < 0.001) longer than that after placebo treatment. Similarly, maximum walking time improved by 451 seconds in the ramipril group (CI, 367 seconds to 536 seconds; P < 0.001) but did not change in the placebo group. Ramipril improved the Walking Impairment Questionnaire median distance score from 5% (range, 1% to 39%) to 21% (range, 12% to 58%; P < 0.001), speed score from 3% (range, 3% to 39%) to 18% (range, 8% to 50%; P < 0.001), and stair-climbing score from 17% (range, 4% to 80%) to 67% (range, 38% to 88%; P < 0.001). No adverse events were reported.
LIMITATIONS: The sample size is modest, and the strict inclusion criteria limit the applicability of the results to patients with claudication and infrainguinal disease and those without diabetes.
CONCLUSION: Ramipril improved pain-free and maximum walking time in some adults with symptomatic PAD.

PMID 16670135
Sharath Chandra Vikram Paravastu, Derick Mendonca, Anthony Da Silva
Beta blockers for peripheral arterial disease.
Cochrane Database Syst Rev. 2008 Oct 8;(4):CD005508. doi: 10.1002/14651858.CD005508.pub2. Epub 2008 Oct 8.
Abstract/Text BACKGROUND: Beta (ss) blockers are indicated for use in coronary artery disease (CAD). However, optimal therapy for people with CAD accompanied by intermittent claudication has been controversial due to the presumed peripheral haemodynamic consequences of beta blockers, leading to worsening symptoms of intermittent claudication.
OBJECTIVES: To quantify the potential harm of beta blockers on maximum walking distance, claudication distance, calf blood flow, calf vascular resistance, and skin temperature when used in patients with peripheral arterial disease (PAD).
SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases (PVD) Group searched for publications describing randomised controlled trials (RCTs) of beta blockers in PAD in their Trials Register (last searched 6 May 2008) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched The Cochrane Library 2008, Issue 2). We handsearched relevant journals and conference proceedings.
SELECTION CRITERIA: Randomised controlled trials evaluating the role of both selective (beta1) and non-selective (beta1 and beta2) beta blockers compared with placebo. We excluded trials comparing different types of beta blockers.
DATA COLLECTION AND ANALYSIS: Primary outcome measures were claudication distance in metres, and the time to claudication in minutes, and maximum walking distance in metres and minutes (as assessed by treadmill).Secondary outcome measures were calf blood flow (ml/100 ml/min), calf vascular resistance, and skin temperature (degrees C).
MAIN RESULTS: We included six RCTs fulfilling the above criteria, with a total of 119 patients. The beta blockers studied were atenolol, propranolol, pindolol, and metoprolol. None of the trials showed a statistically significant worsening effect of beta blockers on either the primary or secondary outcomes. There were no reports of any adverse events with the beta blockers studied.
AUTHORS' CONCLUSIONS: There is currently no evidence that beta blockers adversely affect walking distance in people with intermittent claudication. However, due to the lack of large published trials beta blockers should be used with caution if clinically indicated.

PMID 18843692
Abstract/Text BACKGROUND: Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate.
METHODS: CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years.
FINDINGS: 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group.
INTERPRETATION: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.

PMID 8918275
Deepak L Bhatt, Keith A A Fox, Werner Hacke, Peter B Berger, Henry R Black, William E Boden, Patrice Cacoub, Eric A Cohen, Mark A Creager, J Donald Easton, Marcus D Flather, Steven M Haffner, Christian W Hamm, Graeme J Hankey, S Claiborne Johnston, Koon-Hou Mak, Jean-Louis Mas, Gilles Montalescot, Thomas A Pearson, P Gabriel Steg, Steven R Steinhubl, Michael A Weber, Danielle M Brennan, Liz Fabry-Ribaudo, Joan Booth, Eric J Topol, CHARISMA Investigators
Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
N Engl J Med. 2006 Apr 20;354(16):1706-17. doi: 10.1056/NEJMoa060989. Epub 2006 Mar 12.
Abstract/Text BACKGROUND: Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events.
METHODS: We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes.
RESULTS: The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046).
CONCLUSIONS: In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.).

Copyright 2006 Massachusetts Medical Society.
PMID 16531616
Deepak L Bhatt, Marcus D Flather, Werner Hacke, Peter B Berger, Henry R Black, William E Boden, Patrice Cacoub, Eric A Cohen, Mark A Creager, J Donald Easton, Christian W Hamm, Graeme J Hankey, S Claiborne Johnston, Koon-Hou Mak, Jean-Louis Mas, Gilles Montalescot, Thomas A Pearson, P Gabriel Steg, Steven R Steinhubl, Michael A Weber, Liz Fabry-Ribaudo, Tingfei Hu, Eric J Topol, Keith A A Fox, CHARISMA Investigators
Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.
J Am Coll Cardiol. 2007 May 15;49(19):1982-8. doi: 10.1016/j.jacc.2007.03.025. Epub 2007 Apr 11.
Abstract/Text OBJECTIVES: The purpose of this study was to determine the possible benefit of dual antiplatelet therapy in patients with prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease (PAD).
BACKGROUND: Dual antiplatelet therapy with clopidogrel plus aspirin has been validated in the settings of acute coronary syndromes and coronary stenting. The value of this combination was recently evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, where no statistically significant benefit was found in the overall broad population of stable patients studied.
METHODS: We identified the subgroup in the CHARISMA trial who were enrolled with documented prior MI, ischemic stroke, or symptomatic PAD.
RESULTS: A total of 9,478 patients met the inclusion criteria for this analysis. The median duration of follow-up was 27.6 months. The rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel plus aspirin arm than in the placebo plus aspirin arm: 7.3% versus 8.8% (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.72 to 0.96, p = 0.01). Additionally, hospitalizations for ischemia were significantly decreased, 11.4% versus 13.2% (HR 0.86, 95% CI 0.76 to 0.96, p = 0.008). There was no significant difference in the rate of severe bleeding: 1.7% versus 1.5% (HR 1.12, 95% CI 0.81 to 1.53, p = 0.50); moderate bleeding was significantly increased: 2.0% versus 1.3% (HR 1.60, 95% CI 1.16 to 2.20, p = 0.004).
CONCLUSIONS: In this analysis of the CHARISMA trial, the large number of patients with documented prior MI, ischemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy with clopidogrel plus aspirin. Such patients may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate. (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA]; http://clinicaltrials.gov/ct/show/NCT00050817?order=1; NCT00050817).

PMID 17498584
Sonia S Anand, Salim Yusuf
Oral anticoagulants in patients with coronary artery disease.
J Am Coll Cardiol. 2003 Feb 19;41(4 Suppl S):62S-69S.
Abstract/Text Oral anticoagulants have been used in patients with vascular disease for over 40 years, yet their role in the secondary prevention of recurrent cardiovascular (CV) events remains controversial. The objectives of this systematic review are to more reliably determine the role of oral anticoagulants with and without antiplatelet therapy in patients with established coronary artery disease (CAD). Randomized trials in which oral anticoagulants were tested in CAD patients who were treated for at least three months were identified, and each trial was classified by the targeted level of intensity of anticoagulation. Data from the trials were combined using the modified Mantel-Haenszel method, and odds ratios were computed. Data from over 20,000 patients indicated that high-intensity oral anticoagulation (international normalized ratio [INR] >2.8) significantly reduced CV complications and increased bleeding compared with controls. Moderate-intensity oral anticoagulation (INR 2 to 3) also reduced CV complications compared with controls. The combination of moderate-intensity oral anticoagulation and aspirin is more effective and equally as safe as aspirin alone. Low-intensity oral anticoagulation (INR <2) in the presence of aspirin does not reduce CV complications and increases bleeding compared with aspirin alone.

PMID 12644343
Warfarin Antiplatelet Vascular Evaluation Trial Investigators, Sonia Anand, Salim Yusuf, Changchun Xie, Janice Pogue, John Eikelboom, Andrzej Budaj, Bruce Sussex, Lisheng Liu, Randy Guzman, Claudio Cina, Richard Crowell, Matyas Keltai, Gilbert Gosselin
Oral anticoagulant and antiplatelet therapy and peripheral arterial disease.
N Engl J Med. 2007 Jul 19;357(3):217-27. doi: 10.1056/NEJMoa065959.
Abstract/Text BACKGROUND: Atherosclerotic peripheral arterial disease is associated with an increased risk of myocardial infarction, 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 coprimary outcome was myocardial infarction, stroke, or death from cardiovascular causes; the second coprimary outcome was myocardial infarction, 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 randomly assigned to therapy. The mean follow-up time was 35 months. Myocardial infarction, 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 infarction, 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. (ClinicalTrials.gov number, NCT00125671 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17634457
Christian Bianchi, Valerie Montalvo, Harry W Ou, Vicki Bishop, Ahmed M Abou-Zamzam
Pharmacologic risk factor treatment of peripheral arterial disease is lacking and requires vascular surgeon participation.
Ann Vasc Surg. 2007 Mar;21(2):163-6. doi: 10.1016/j.avsg.2007.01.008.
Abstract/Text The pharmacologic treatment of the cardiovascular comorbidities in patients with peripheral arterial disease (PAD) can have a profound effect on the outcomes of these patients. Guidelines for the treatment of hypertension, hyperlipidemia, diabetes, and tobacco use have been published by the American Heart Association and American College of Cardiology (AHA/ACC). Patients with PAD are often under-treated for these conditions. We sought to evaluate the adherence to these established guidelines in all new patients presenting with PAD to a vascular surgery clinic and delineate the opportunity for vascular surgeon involvement in these treatments. Consecutive new patients with symptomatic, objectively proven PAD (ankle-brachial index < 0.9) were evaluated in a vascular surgery clinic by a staff vascular surgeon. PAD risk factors, pre-visit medications, and prior cardiovascular interventions were recorded. Patients were stratified whether they were receiving appropriate preventive pharmacotherapy and whether they were meeting AHA/ACC goals. In patients without prior cardiovascular history, screening for these conditions was performed. One hundred sixty-seven new patients were evaluated over a 1-year period. Objectively diagnosed PAD included intermittent claudication in 115 (69%) and critical limb ischemia in 52 (31%) patients. Average age was 67.8 years, and 73 patients (44%) were current smokers. At initial evaluation, only 115 (69%) patients reported antiplatelet use. Patients with a recorded diagnosis of hypertension met clinical guidelines in 39 instances (71%). Eighteen patients (20%) with diabetes mellitus had poor glycemic control (Hgb-A1C > 7.0%). Seventeen (19%) of 88 patients with a history of hyperlipidemia were not adequately treated. Vascular surgeon medical interventions resulted in 31% of patients being started on antiplatelet therapy, 29% of hypertension therapies were modified, 19% of established lipid therapy was modified, and lipid therapy was initiated in 20%. A new diagnosis of hypertension was made in 10 cases (6%) and hyperlipidemia in 13 cases (7%). Despite clear guidelines for the medical community regarding cardiovascular prevention, a large percentage of patients with symptomatic PAD presenting to the vascular surgery clinic are not receiving appropriate therapy for their comorbidities or are not meeting the established goals. Vascular surgeons have an important role in promoting vascular health through the systemic prevention of ischemic events.

PMID 17349357
Mary McGrae McDermott, Elizabeth A Hahn, Philip Greenland, David Cella, Judith K Ockene, Donna Brogan, William H Pearce, Alan T Hirsch, Kendra Hanley, Linda Odom, Shaheen Khan, Michael H Criqui, Martin S Lipsky, Stacie Hudgens
Atherosclerotic risk factor reduction in peripheral arterial diseasea: results of a national physician survey.
J Gen Intern Med. 2002 Dec;17(12):895-904.
Abstract/Text OBJECTIVE: Individuals with peripheral arterial disease (PAD) have a 3- to 6-fold increased risk of coronary heart disease and stroke compared to those without PAD. We documented physician-reported practice behavior, knowledge, and attitudes regarding atherosclerotic risk factor reduction in patients with PAD.
DESIGN: National physician survey.
PATIENTS/PARTICIPANTS: General internists (N = 406), family practitioners (N = 435), cardiologists (N = 473), and vascular surgeons (N = 264) randomly identified using the American Medical Association's physician database.
MEASUREMENTS AND MAIN RESULTS: Physicians were randomized to 1 of 3 questionnaires describing a) a 55- to 65-year-old patient with PAD; b) a 55- to 65-year-old patient with coronary artery disease (CAD), or c) a 55- to 65-year-old patient without clinically evident atherosclerosis (no disease). A mailed questionnaire was used to compare physician behavior, knowledge, and attitude regarding risk factor reduction for each patient. Rates of prescribed antiplatelet therapy were significantly lower for the patient with PAD than for the patient with CAD. Average low-density lipoprotein levels at which physicians "almost always" initiated lipid-lowering drugs were 121.6 +/- 23.5 mg/dL, 136.3 +/- 28.9 mg/dL, and 149.7 +/- 24.4 mg/dL for the CAD, PAD, and no-disease patients, respectively (P <.001). Physicians stated that antiplatelet therapy (P <.001) and cholesterol-lowering therapy (P <.001) were extremely important significantly more often for the CAD than for the PAD patient. Perceived importance of risk factor interventions was highly correlated with practice behavior. Compared to other specialties, cardiologists had lowest thresholds, whereas vascular surgeons had the highest thresholds for initiating cholesterol-lowering interventions for the patient with PAD. Cardiologists were significantly more likely to report "almost always" prescribing antiplatelet therapy for the patient with PAD than were all other physicians.
CONCLUSIONS: Deficiencies in physician knowledge and attitudes contribute to lower rates of atherosclerotic risk factor reduction for patients with PAD. Reversing these deficiencies may reduce the high rates of cardiovascular morbidity and mortality associated with PAD.

PMID 12472925
H G Beebe, D L Dawson, B S Cutler, J A Herd, D E Strandness, E B Bortey, W P Forbes
A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial.
Arch Intern Med. 1999 Sep 27;159(17):2041-50.
Abstract/Text BACKGROUND: Effective medication is limited for the relief of intermittent claudication, a common manifestation of arterial occlusive disease. Cilostazol is a potent inhibitor of platelet aggregation with vasodilation effects.
OBJECTIVE: To evaluate the safety and efficacy of cilostazol for the treatment of intermittent claudication.
METHODS: Thirty-seven outpatient vascular medicine clinics at regional tertiary and university hospitals in the United States participated in this multicenter, randomized, double-blind, placebo-controlled, parallel trial. Of the 663 screened volunteer patients with leg discomfort, a total of 516 men and women 40 years or older with a diagnosis of moderately severe chronic, stable, symptomatic intermittent claudication were randomized to receive cilostazol, 100 mg, cilostazol, 50 mg, or placebo twice a day orally for 24 weeks. Outcome measures included pain-free and maximal walking distances via treadmill testing, patient-based quality-of-life measures, global assessments by patient and physician, and cardiovascular morbidity and all-cause mortality survival analysis.
RESULTS: The clinical and statistical superiority of active treatment over placebo was evident as early as week 4, with continued improvement at all subsequent time points. After 24 weeks, patients who received cilostazol, 100 mg, twice a day had a 51% geometric mean improvement in maximal walking distance (P<.001 vs placebo); those who received cilostazol, 50 mg, twice a day had a 38% geometric mean improvement in maximal walking distance (P<.001 vs placebo). These percentages translate into an arithmetic mean increase in distance walked, from 129.7 m at baseline to 258.8 m at week 24 for the cilostazol, 100 mg, group, and from 131.5 to 198.8 m for the cilostazol, 50 mg, group. Geometric mean change for pain-free walking distance increased by 59% (P<.001) and 48% (P<.001), respectively, in the cilostazol, 100 mg, and cilostazol, 50 mg, groups. These results were corroborated by the results of subjective quality-of-life assessments, functional status, and global evaluations. Headache, abnormal stool samples or diarrhea, dizziness, and palpitations were the most commonly reported potentially drug-related adverse events and were self-limited. A total of 75 patients (14.5%) withdrew because of any adverse event, which was equally distributed between all 3 treatment groups. Similarly, there were no differences between groups in the incidence of combined cardiovascular morbidity or all-cause mortality.
CONCLUSION: Compared with placebo, long-term use of cilostazol, 100 mg or 50 mg, twice a day significantly improves walking distances in patients with intermittent claudication.

PMID 10510990
Abstract/Text BACKGROUND: Cilostazol is a new phosphodiesterase inhibitor that suppresses platelet aggregation and also acts as a direct arterial vasodilator. This prospective, randomized, placebo-controlled, parallel-group clinical trial evaluated the efficacy of cilostazol for treatment of stable, moderately severe intermittent claudication.
METHODS AND RESULTS: Study inclusion criteria included age > or =40 years, initial claudication distance (ICD) on treadmill (12.5% incline, 3.2 km/h) between 30 and 200 m, and confirmation of diagnosis of chronic lower-extremity arterial occlusive disease. After stabilization and single-blind placebo lead-in, 81 subjects (62 male, 19 female) from 3 centers were randomized unequally (2:1) to 12 weeks of treatment with cilostazol 100 mg PO BID or placebo. Primary outcome measures included ICD and maximum distance walked (absolute claudication distance, or ACD). Secondary outcome measures included ankle pressures, subjective assessments of benefit by patients and physicians, and safety. Treatment and control groups were similar with respect to age, severity of symptoms, ankle pressures, and smoking status. Statistical analyses used intention-to-treat analyses for each of 77 subjects who had > or =1 treadmill test after initiation of therapy. Comparisons between groups were based on logarithms of ratios of ICD and ACD changes from baseline using ANOVA test at last treatment visit. The estimated treatment effect showed a 35% increase in ICD (P<0.01) and a 41% increase in ACD (P<0.01). There was no significant change in resting or postexercise ankle/brachial indexes. Patients' and physicians' subjective assessments corroborated the measured improvements in walking performance observed in the cilostazol-treated group.
CONCLUSIONS: Cilostazol improved walking distances, significantly increasing ICD and ACD. The data suggest cilostazol is safe and well tolerated for the treatment of intermittent claudication.

PMID 9715861
S R Money, J A Herd, J L Isaacsohn, M Davidson, B Cutler, J Heckman, W P Forbes
Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease.
J Vasc Surg. 1998 Feb;27(2):267-74; discussion 274-5.
Abstract/Text PURPOSE: This study evaluated the effects of cilostazol on walking distances in patients with intermittent claudication (IC) caused by peripheral arterial occlusive disease.
METHODS: The study was a multicenter, randomized, double-blind, placebo-controlled trial. Two hundred thirty-nine patients with IC were randomly assigned to receive cilostazol (100 mg b.i.d.) or a placebo for 16 weeks. All patients underwent serial, variable-grade, constant-speed treadmill testing. Absolute claudication distance (ACD), assessed at the end of the 12-hour dosing interval (trough), was the primary end point. Secondary end points included ACD assessed 3 to 4 hours after dosing (peak) and initial claudication distances (trough and peak). Functional status measures, including the Medical Outcomes Scale (SF-36) and Walking Impairment Questionnaire, were used to assess subjective changes over the 16-week treatment period. Ankle-brachial indexes were calculated from Doppler-measured systolic pressures at every visit with treadmill testing.
RESULTS: Patients treated with cilostazol demonstrated significant improvements over the placebo patients in ACD at all three time points tested after baseline (weeks 8, 12, and 16). Peak treadmill testing at weeks 8 and 12 also showed significant improvement in walking distances for cilostazol-treated patients over placebo-treated patients. At week 16, patients in the cilostazol group had a 96.4-meter (47%) increase in ACD compared with 31.4 meters (12.9%) for the placebo group (p < 0.001). In the SF-36, significant improvement was observed in the physical component subscale and the composite physical component score. In the Walking Impairment Questionnaire, improvements were significant in patient reports of walking speed and specific measures of walking difficulty. Ankle-brachial indexes improved in the cilostazol group (0.64 +/- 0.02 to 0.70 +/- 0.02) compared with the placebo group (0.68 +/- 0.02 to 0.69 +/- 0.02) (p < 0.0125). The most frequent adverse events were headache, abnormal stools (e.g. loose stools), diarrhea, and dizziness.
CONCLUSIONS: Cilostazol significantly increased ACD at all measured time points and initial claudication distances at most time points. This agent may represent a new treatment option for patients with intermittent claudication.

PMID 9510281
D Eugene Strandness, Ronald L Dalman, Steve Panian, Marc S Rendell, Philip C Comp, Peter Zhang, William P Forbes
Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study.
Vasc Endovascular Surg. 2002 Mar-Apr;36(2):83-91.
Abstract/Text A multicenter, double-blind, randomized, placebo-controlled, parallel study was conducted to compare the efficacy and safety of cilostazol 100 mg and 50 mg, both administered twice daily, with that of placebo in patients with moderately severe intermittent claudication (IC) secondary to peripheral arterial disease.A total of 394 subjects 40 years of age or older with chronic, stable, symptomatic IC received cilostazol 100 mg twice daily, 50 mg twice daily, or placebo for 24 weeks. Subjects receiving cilostazol 100 mg twice daily experienced a 21% net improvement in maximal walking distance (MWD)compared with placebo subjects (p = 0.0003) and a 22% net improvement in distance walked to the onset of symptoms (PFWD) (p = 0.0015). Subjects who received cilostazol 50 mg twice daily also benefited from therapy, but not to a statistically significant degree (7% and 11% improvement in MWD and PFWD, respectively). Quality-of-life and functional status assessments corroborated these objective results. Cilostazol, in particular 100 mg twice daily, significantly improves symptoms in patients with IC.

PMID 11951094
E R Mohler, H G Beebe, S Salles-Cuhna, R Zimet, P Zhang, J Heckman, W P Forbes
Effects of cilostazol on resting ankle pressures and exercise-induced ischemia in patients with intermittent claudication.
Vasc Med. 2001;6(3):151-6.
Abstract/Text During exercise, patients with intermittent claudication (IC) have decreased limb arterial blood pressure that recovers during rest. A novel method for assessing dynamic recovery of function is measurement of the hemodynamic response after exercise. Cilostazol (Pletal), a new agent for the treatment of IC, increases walking distance and may decrease ischemic burden. The objective of this study was to assess the effect of cilostazol versus placebo on hemodynamic measurements after exercise-induced ischemia in patients with IC. Two double-blind, placebo-controlled studies with similar inclusion/exclusion criteria and duration (24 weeks) were pooled. Patients walked on a treadmill at 2.0 miles/h (3.2 km/h) on a 12.5% grade until the claudication-limited maximal walking distance (MWD) was reached. Anterior and posterior tibial pressures were measured with Doppler ultrasound at baseline and at 1, 5, and 9 min during recovery. Area under the curve (AUC), a measure of the time course of recovery of systolic pressure after exercise-induced ischemia, and ankle-brachial index (ABI) were calculated and compared using analysis of variance (ANOVA). All three treatment groups (308 patients randomized to cilostazol 100 mg bid, 303 to cilostazol 50 mg bid, and 299 to placebo) had similar baseline characteristics. Mean post-exercise AUC for cilostazol 100 mg and 50 mg bid versus placebo increased by 0.31 (p = 0.001) and 0.26 (p = 0.004), respectively. Mean resting ABI increased by 0.03 (p = 0.0039) and 0.04 (p = 0.0001) in the cilostazol 100 mg and 50 mg bid groups, respectively. In conclusion, following 24 weeks of treatment, cilostazol increased the ABI at rest and improved the recovery time of ankle pressures post-exercise.

PMID 11789969
Therese M Chapman, Karen L Goa
Cilostazol: a review of its use in intermittent claudication.
Am J Cardiovasc Drugs. 2003;3(2):117-38.
Abstract/Text UNLABELLED: Cilostazol (Pletal) is a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties. It also exhibits antiproliferative effects on smooth muscle cells and has beneficial effects on high density lipoprotein-cholesterol and triglyceride levels.Randomized, double-blind, placebo-controlled 12- to 24-week trials in >2000 patients with moderate to severe intermittent claudication demonstrated that cilostazol generally significantly increased walking distances and improved quality of life compared with placebo. Additionally, a large comparative 24-week trial showed that cilostazol 100 mg twice daily was significantly more effective than pentoxifylline 400mg three times daily (pentoxifylline was not significantly different from placebo). Cilostazol was generally well tolerated. Adverse events reported significantly more often with cilostazol than with placebo included headache, diarrhea, abnormal stools, infection, rhinitis and peripheral edema and in comparison with pentoxifylline were headache, diarrhea, abnormal stools and palpitations. Adverse events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal. Significant drug interactions are observed when cilostazol is coadministered with other agents that inhibit cytochrome P450 (CYP) 3A4 (e.g. erythromycin or diltiazem) or CYP2C19 (e.g. omeprazole). As a result, in Europe cilostazol is contraindicated in patients receiving CYP3A4 or CYP2C19 inhibitors and in the US it is recommended that dosage reduction for cilostazol be considered during coadministration of cilostazol and CYP3A4 or CYP2C19 inhibitors. Conversely, cilostazol itself does not appear to inhibit CYP3A4. Coadministration of cilostazol with aspirin or warfarin did not result in any clinically significant changes to coagulation parameters, bleeding time or platelet aggregation.
CONCLUSION: In six of eight well designed clinical trials, cilostazol was significantly more effective than placebo in increasing walking distances and improving the quality of life of patients with moderate to severe intermittent claudication. In addition, limited comparative data have shown that cilostazol has superior efficacy compared with pentoxifylline. Cilostazol is also generally well tolerated. Additional comparative trials are required to confirm these results, to determine the place of cilostazol in relation to other agents or exercise therapy and risk factor reduction alone, and to establish the effects of long-term treatment with cilostazol in patients with intermittent claudication. Cilostazol is contraindicated in several subpopulations of patients, particularly those with congestive heart failure and severe hepatic or renal impairment. Nonetheless, current data support the choice of cilostazol as a promising therapy amongst the limited options available for patients with intermittent claudication.

PMID 14727939
John R Laird, Barry T Katzen, Dierk Scheinert, Johannes Lammer, Jeffrey Carpenter, Maurice Buchbinder, Rajesh Dave, Gary Ansel, Alexandra Lansky, Ecaterina Cristea, Tyrone J Collins, Jeffrey Goldstein, Michael R Jaff, RESILIENT Investigators
Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial.
Circ Cardiovasc Interv. 2010 Jun 1;3(3):267-76. doi: 10.1161/CIRCINTERVENTIONS.109.903468. Epub 2010 May 18.
Abstract/Text BACKGROUND: Controversy still exists regarding the best endovascular treatment strategy for patients with symptomatic disease of the superficial femoral artery. There are conflicting data regarding the benefits of superficial femoral artery stenting and the role of primary stenting compared with balloon angioplasty with provisional stent implantation.
METHODS AND RESULTS: A total of 206 patients from 24 centers in the United States and Europe with obstructive lesions of the superficial femoral artery and proximal popliteal artery and intermittent claudication were randomized to implantation of nitinol stents or percutaneous transluminal angioplasty. The mean total lesion length was 71 mm for the stent group and 64 mm for the angioplasty group. Acute lesion success (<30%residual stenosis) was superior for the stent group compared with the angioplasty group (95.8% versus 83.9%; P<0.01). Twenty-nine (40.3%) patients in the angioplasty group underwent bailout stenting because of a suboptimal angiographic result or flow-limiting dissection. Bailout stenting was treated as a target lesion revascularization and loss of primary patency in the final analysis. At 12 months, freedom from target lesion revascularization was 87.3% for the stent group compared with 45.1% for the angioplasty group (P<0.0001). Duplex ultrasound-derived primary patency at 12 months was better for the stent group (81.3% versus 36.7%; P<0.0001). Through 12 months, fractures occurred in 3.1% of stents implanted. No stent fractures resulted in loss of patency or target lesion revascularization.
CONCLUSIONS: In this multicenter trial, primary implantation of a self-expanding nitinol stent for moderate-length lesions in the superficial femoral artery and proximal popliteal artery was associated with better acute angiographic results and improved patency compared with balloon angioplasty alone.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00673985.

PMID 20484101
Stephan H Duda, Marc Bosiers, Johannes Lammer, Dierk Scheinert, Thomas Zeller, Vincent Oliva, Alexander Tielbeek, John Anderson, Benjamin Wiesinger, Gunnar Tepe, Alexandra Lansky, Michael R Jaff, Catharina Mudde, Hans Tielemans, Jean-Paul Beregi
Drug-eluting and bare nitinol stents for the treatment of atherosclerotic lesions in the superficial femoral artery: long-term results from the SIROCCO trial.
J Endovasc Ther. 2006 Dec;13(6):701-10. doi: 10.1583/05-1704.1.
Abstract/Text PURPOSE: To review clinical outcomes of patients with chronic limb ischemia and TASC type C lesions treated with sirolimus-eluting versus bare SMART nitinol self-expanding stents.
METHODS: Data were obtained from a randomized, multicenter, double-blinded study conducted in 2 phases. All 93 patients had chronic limb ischemia and superficial femoral artery (SFA) occlusions or stenoses (average lesion length 8.3 cm). In total, 47 patients (31 men; mean age 66.3+/-9.1 years, range 50-84) received the sirolimus-eluting SMART stent and 46 patients (36 men; mean age 65.9 +/-10.8 years, range 38-83) received a bare SMART nitinol stent. Both groups were followed for a mean 24 months.
RESULTS: Both the sirolimus-eluting and the bare SMART stents were effective in revascularizing the diseased SFA and in sustaining freedom from restenosis. For both types of stents, improvements in ankle-brachial indices (ABI) and symptoms of claudication were maintained over 24 months (median 24-month ABI 0.96 for the sirolimus group versus 0.87 for the bare stent group, p>0.05). At 24 months, the restenosis rate in the sirolimus group was 22.9% versus 21.1% in the bare stent group (p>0.05). The cumulative in-stent restenosis rates according to duplex ultrasound were 4.7%, 9.0%, 15.6%, and 21.9%, respectively, at 6, 9, 18, and 24 months; the rates did not differ significantly between the treatment groups. The TLR rate for the sirolimus group was 6% and for the bare stent group 13%; the TVR rates were somewhat higher: 13% and 22%, respectively. Mortality rates did not differ significantly between the groups.
CONCLUSION: These data demonstrate that the sirolimus-eluting and the bare SMART stent are effective, safe, and free from restenosis in a majority of patients for up to 24 months. Because the restenosis rate in the bare stent group is unexpectedly low, no significant difference could be found between the sirolimus-eluting and the bare SMART stents.

PMID 17154704
Johannes Lammer, Marc Bosiers, Thomas Zeller, Martin Schillinger, Els Boone, Margo J Zaugg, Patrick Verta, Lei Peng, Xingyu Gao, Lewis B Schwartz
First clinical trial of nitinol self-expanding everolimus-eluting stent implantation for peripheral arterial occlusive disease.
J Vasc Surg. 2011 Aug;54(2):394-401. doi: 10.1016/j.jvs.2011.01.047. Epub 2011 Jun 12.
Abstract/Text BACKGROUND: A novel self-expanding drug-eluting stent was designed to slowly release everolimus to prevent restenosis following peripheral arterial intervention. The purpose of the first-in-human Superficial Femoral Artery Treatment with Drug-Eluting Stents (STRIDES) trial was to evaluate the safety and efficacy of this device for the treatment of symptomatic superficial femoral and proximal popliteal arterial occlusive disease.
METHODS AND RESULTS: One hundred four patients were enrolled at 11 European investigative centers in a prospective, nonrandomized, single-arm trial. The patients had severe symptomatic vascular disease, including a significant proportion of patients with critical limb ischemia (17%), diabetes (39%), and single-vessel outflow (26%). The mean lesion length was 9.0 ± 4.3 cm. Ninety-nine percent of patients were available for 12-month follow-up, including duplex imaging in 90% and arteriography in 83%. Clinical improvement, defined as a sustained decrease in Rutherford-Becker clinical category, was achieved in 80% of patients. Primary patency (freedom from ≥50% in-stent restenosis) was 94 ± 2.3% and 68 ± 4.6% at 6 and 12 months, respectively. Plain radiographic examination of 122 implanted devices at 12 months revealed no evidence for stent fracture.
CONCLUSIONS: The everolimus-eluting self-expanding nitinol stent can be successfully implanted in patients with severe peripheral arterial disease with favorable outcomes and clinical improvements observed in the majority of patients.

Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.
PMID 21658885
Michael D Dake, Gary M Ansel, Michael R Jaff, Takao Ohki, Richard R Saxon, H Bob Smouse, Thomas Zeller, Gary S Roubin, Mark W Burket, Yazan Khatib, Scott A Snyder, Anthony O Ragheb, J King White, Lindsay S Machan, Zilver PTX Investigators
Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results.
Circ Cardiovasc Interv. 2011 Oct 1;4(5):495-504. doi: 10.1161/CIRCINTERVENTIONS.111.962324. Epub 2011 Sep 27.
Abstract/Text BACKGROUND: Sustained benefits of drug-eluting stents in femoropopliteal arteries have not been demonstrated. This prospective, multinational, randomized study was designed to compare the 12-month safety and effectiveness of a polymer-free, paclitaxel-coated nitinol drug-eluting stent (DES) with percutaneous transluminal angioplasty (PTA) and provisional bare metal stent (BMS) placement in patients with femoropopliteal peripheral artery disease.
METHODS AND RESULTS: Patients were randomly assigned to primary DES implantation (n=236) or PTA (n=238). Demographics and lesion characteristics were similar between groups (eg, average lesion length, approximately 65±40 mm). One hundred twenty patients had acute PTA failure and underwent secondary random assignment to provisional DES (n=61) or BMS (n=59). Primary end points were the 12-month rates of event-free survival and patency in the primary DES and PTA groups. Compared with the PTA group, the primary DES group exhibited superior 12-month event-free survival (90.4% versus 82.6%; P=0.004) and primary patency (83.1% versus 32.8%; P<0.001), satisfying the primary hypotheses. In the secondary evaluations, (1) the primary DES group exhibited superior clinical benefit compared with the PTA group (88.3% versus 75.8%; P<0.001), (2) the provisional DES group exhibited superior primary patency (89.9% versus 73.0%; P=0.01) and superior clinical benefit (90.5% and 72.3%, P=0.009) compared with the provisional BMS group, and (3) the stent fracture rate (both DES and BMS) was 0.9% (4/457).
CONCLUSIONS: Femoropopliteal peripheral artery disease treatment with the paclitaxel-eluting stent was associated with superior 12-month outcomes compared with PTA and provisional BMS placement.

PMID 21953370
Gunnar Tepe, Thomas Zeller, Thomas Albrecht, Stephan Heller, Uwe Schwarzwälder, Jean-Paul Beregi, Claus D Claussen, Anja Oldenburg, Bruno Scheller, Ulrich Speck
Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg.
N Engl J Med. 2008 Feb 14;358(7):689-99. doi: 10.1056/NEJMoa0706356.
Abstract/Text BACKGROUND: Drug-eluting stents reduce restenosis in coronary arteries, but clinical trials have failed to prove their efficacy in peripheral arteries. We investigated the use of paclitaxel-coated angioplasty balloons and paclitaxel dissolved in the angiographic contrast medium during angioplasty of the leg.
METHODS: In a small, multicenter trial, we randomly assigned 154 patients with stenosis or occlusion of a femoropopliteal artery to treatment with standard balloon catheters coated with paclitaxel, uncoated balloons with paclitaxel dissolved in the contrast medium, or uncoated balloons without paclitaxel (control). The primary end point was late lumen loss at 6 months.
RESULTS: The mean (+/-SD) age of the patients was 68+/-8 years, 24% were smokers, and 49% had diabetes. Twenty-seven percent of the lesions were total occlusions, and 36% were restenotic lesions. The mean lesion length was 7.4+/-6.5 cm. There were no significant differences in baseline characteristics between the groups. There were no adverse events attributable to the paclitaxel-coated balloons. At 6 months, the mean late lumen loss was 1.7+/-1.8 mm in the control group, as compared with 0.4+/-1.2 mm (P<0.001) in the group treated with paclitaxel-coated balloons and 2.2+/-1.6 mm (P=0.11) in the group treated with paclitaxel in the contrast medium. The rate of revascularization of target lesions at 6 months was 20 of 54 (37%) in the control group, 2 of 48 (4%) in the group treated with paclitaxel-coated balloons (P<0.001 vs. control), and 15 of 52 (29%) in the group treated with paclitaxel in the contrast medium (P=0.41 vs. control); at 24 months, the rates increased to 28 of 54 (52%), 7 of 48 (15%), and 21 of 52 (40%), respectively.
CONCLUSIONS: Use of paclitaxel-coated angioplasty balloons during percutaneous treatment of femoropopliteal disease is associated with significant reductions in late lumen loss and target-lesion revascularization. No significant benefit is seen with the use of a paclitaxel-containing contrast medium. (ClinicalTrials.gov number, NCT00156624 [ClinicalTrials.gov].).

Copyright 2008 Massachusetts Medical Society.
PMID 18272892
D J Adam, J D Beard, T Cleveland, J Bell, A W Bradbury, J F Forbes, F G R Fowkes, I Gillepsie, C V Ruckley, G Raab, H Storkey, BASIL trial participants
Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial.
Lancet. 2005 Dec 3;366(9501):1925-34. doi: 10.1016/S0140-6736(05)67704-5.
Abstract/Text BACKGROUND: The treatment of rest pain, ulceration, and gangrene of the leg (severe limb ischaemia) remains controversial. We instigated the BASIL trial to compare the outcome of bypass surgery and balloon angioplasty in such patients.
METHODS: We randomly assigned 452 patients, who presented to 27 UK hospitals with severe limb ischaemia due to infra-inguinal disease, to receive a surgery-first (n=228) or an angioplasty-first (n=224) strategy. The primary endpoint was amputation (of trial leg) free survival. Analysis was by intention to treat. The BASIL trial is registered with the National Research Register (NRR) and as an International Standard Randomised Controlled Trial, number ISRCTN45398889.
FINDINGS: The trial ran for 5.5 years, and follow-up finished when patients reached an endpoint (amputation of trial leg above the ankle or death). Seven individuals were lost to follow-up after randomisation (three assigned angioplasty, two surgery); of these, three were lost (one angioplasty, two surgery) during the first year of follow-up. 195 (86%) of 228 patients assigned to bypass surgery and 216 (96%) of 224 to balloon angioplasty underwent an attempt at their allocated intervention at a median (IQR) of 6 (3-16) and 6 (2-20) days after randomisation, respectively. At the end of follow-up, 248 (55%) patients were alive without amputation (of trial leg), 38 (8%) alive with amputation, 36 (8%) dead after amputation, and 130 (29%) dead without amputation. After 6 months, the two strategies did not differ significantly in amputation-free survival (48 vs 60 patients; unadjusted hazard ratio 1.07, 95% CI 0.72-1.6; adjusted hazard ratio 0.73, 0.49-1.07). We saw no difference in health-related quality of life between the two strategies, but for the first year the hospital costs associated with a surgery-first strategy were about one third higher than those with an angioplasty-first strategy.
INTERPRETATION: In patients presenting with severe limb ischaemia due to infra-inguinal disease and who are suitable for surgery and angioplasty, a bypass-surgery-first and a balloon-angioplasty-first strategy are associated with broadly similar outcomes in terms of amputation-free survival, and in the short-term, surgery is more expensive than angioplasty.

PMID 16325694
Vincent L Rowe, William Lee, Fred A Weaver, David Etzioni
Patterns of treatment for peripheral arterial disease in the United States: 1996-2005.
J Vasc Surg. 2009 Apr;49(4):910-7. doi: 10.1016/j.jvs.2008.11.054.
Abstract/Text OBJECTIVE: Endovascular procedures are increasingly used in the treatment of peripheral arterial disease (PAD). Whether this new procedural approach translates to clinical outcomes equivalent or superior to open surgical revascularization is a subject of debate. We sought to analyze population-based rates of major amputations for PAD during a time period in which the use of endovascular surgical procedures increased dramatically.
METHODS: We used the 1996-2005 Nationwide Inpatient Sample (NIS) to analyze rates of amputations and vascular interventions, and also to characterize the treatment of patients admitted acutely for PAD. Vascular interventions were designated based on International Classification of Diseases (ICD) procedure codes as open bypass, endovascular intervention, or major amputation (disarticulation at ankle or higher amputation). Population-based age-adjusted incidence rates of treatment were calculated by combining procedure rates with census data.
RESULTS: Our analysis included 97,000 acute admissions for PAD, 83,000 major amputations, 77,500 endovascular procedures, and 171,000 open vascular bypass operations. Between 1996 and 2005, population-based rates of acute admissions for PAD decreased by 4.3% per year, open procedures by 6.6% per year, and major amputations by 6.4% per year, whereas endovascular procedures increased by 4.8% per year. Of patients acutely admitted for PAD, the likelihood of undergoing an amputation decreased (30.2% to 21.8%), the likelihood of undergoing an open vascular procedure decreased (34.5% to 26.3%), and the likelihood of undergoing an endovascular operation increased (12.7% to 28.3%). All of these changes were statistically significant at P < .05.
CONCLUSION: The last decade has seen a significant increase in the use of endovascular procedures and a decrease in rates of major amputation. These trends are seen both for patients admitted with acute PAD, as well as in the population in general. While our study was not designed to demonstrate a causal relationship, our findings suggest an association between increased application of endovascular technology and reduced rates of amputation in patients with PAD.

PMID 19341885
Shailja V Parikh, Shoaib Saya, Punag Divanji, Subhash Banerjee, Faith Selzer, J Dawn Abbott, Srihari S Naidu, Robert L Wilensky, David P Faxon, Alice K Jacobs, Elizabeth M Holper
Risk of death and myocardial infarction in patients with peripheral arterial disease undergoing percutaneous coronary intervention (from the National Heart, Lung and Blood Institute Dynamic Registry).
Am J Cardiol. 2011 Apr 1;107(7):959-64. doi: 10.1016/j.amjcard.2010.11.019. Epub 2011 Jan 20.
Abstract/Text Patients with peripheral arterial disease (PAD) undergoing percutaneous coronary intervention (PCI) are at high risk for adverse cardiovascular events. Trends over time in outcomes with advances in PCI and medical therapy are unknown. We evaluated 866 patients with PAD in the National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry undergoing PCI according to treatment eras: the early bare metal stent (BMS) era (wave 1, 1997 to 1998, n = 180), the BMS era (waves 2 and 3, 1999 and 2001 to 2002, n = 339), and the drug-eluting stent (DES) era (waves 4 and 5, 2004 and 2006, n = 347). We compared in-hospital and 1-year outcomes by recruitment era. In-hospital coronary artery bypass graft surgery rates were significantly lower in the later eras (3.9%, 0.9%, and 0.6% for the early BMS, BMS, and DES eras, respectively, p for trend = 0.005), and an increasing percentage of patients were discharged on aspirin, β blockers, statins, and thienopyridines (p for trend <0.001 for all comparisons). Cumulative 1-year event rates in patients with PAD in the early BMS era, BMS era, and DES era for death were 13.7%, 10.5%, and 9.8% (p for trend = 0.21), those for myocardial infarction (MI) were 9.8%, 8.8%, and 10.0% (p for trend = 0.95), and those for repeat revascularization were 26.8%, 21.0%, and 17.2% (p for trend = 0.008). The 1-year adjusted hazard ratios of adverse events in patients with PAD using the early BMS era as the reference were 0.84 for death in the BMS era (95% confidence interval [CI] 0.46 to 1.55, p = 0.58) and 1.35 in the DES era (95% CI 0.71 to 2.56, p = 0.36), 0.89 for MI in the BMS era (95% CI 0.48 to 1.66, p = 0.72) and 1.02 in the DES era (95% CI 0.55 to 1.87, p = 0.95), and 0.63 for repeat revascularization in the BMS era (95% CI 0.41 to 0.97, p = 0.04) and 0.46 in the DES era (95% CI 0.29 to 0.73, p = 0.001). In conclusion, despite significant improvements in medical therapy and a decrease in repeat revascularization over time, patients with PAD who undergo PCI have a persistent high rate of death and MI.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID 21256469

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