2011 Peripheral Artery Disease Focused Update Summary Table

Study Title	Aim of Study	Study Type	Study Size	Patient Population/Inclusion and Exclusion Criteria		Endpoints		Statistical Analysis (Results)	P (95% CI)	OR/HR/RR	Study Conclusion (as Reported in Study Article)	Other Information
				Inclusion	Exclusion	Primary	Secondary
Revascularization versus medical therapy for RAS: the ASTRAL Investigators5	To review the clinical benefit of percutaneous revascularization of the renal arteries to improve patency in atherosclerotic renovascular disease	Randomized, unblinded trial	806	Patients who had substantial anatomical atherosclerotic stenosis in ≥1 renal artery that was considered potentially suitable for endovascular revascularization and whose physician was uncertain that the patient would definitely receive a worthwhile clinical benefit from revascularization, taking into account the available evidence	Patients who required surgical revascularization or were considered to have a high likelihood of requiring revascularization within 6 mo, if they had nonatheromatous CV disease, or if they had undergone previous revascularization for RAS	Renal function, measured by the reciprocal of the serum creatinine level	Blood pressure, time to renal and major CV events, and mortality	During a 5-y period, rate of progression of renal impairment (as shown by the slope of the reciprocal of the serum creatinine level) was −0.07×10−3 L/micromole/y in the revascularization group, compared with −0.13×10−3 L/micromole/y in the medical therapy group, a difference favoring revascularization of 0.06×10−3 L/micromole/y (95% CI: −0.002 to 0.13; P=0.06). Over the same time, mean serum creatinine level was 1.6 mmol/L (95% CI: −8.4 to 5.2 [0.02 mg/dL; 95% CI:−0.10 to 0.06]) lower in the revascularization group than in the medical therapy group. There was no significance between-groups difference in systolic blood pressure; decrease in diastolic blood pressure was smaller in the revascularization group than in the medical-therapy group.	Revascularization group: P=0.88; 95% CI: 1.40; 0.67 to 1.40 Major CV events: P=0.61; 95% CI: 0.75 to 1.1 Death: P=0.46; 95% CI: 0.69 to 1.18	The 2 study groups had similar rates of renal events. Revascularization group: HR: 0.97; 95% CI: 0.67 to 1.40; P=0.88 Major CV events: HR: 0.94; 95% CI: 0.75 to 1.19; P=0.61 Death: HR: 0.90; 95% CI: 0.69 to 1.18; P=0.46	There are substantial risks but no evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease.	Power=80%, ITT analysis
ABI combined with FRS to predict CV events and mortality: a meta-analysis ABI collaboration24	To determine if ABI provides information on risk of CV events and mortality independent of FRS and can improve risk prediction	Meta-analysis	24955 men and 23339 women with 480325 person-years of follow-up. Studies included 16 population cohort studies.	Studies whose participants were derived from a general population, measured ABI at baseline, and individual followed up to detect total and CV mortality	N/A			Risk of death by ABI had a reverse J-shaped distribution with a normal (low-risk) ABI of 1.11 to 1.40. 10-y CV mortality in men with low ABI (0.90) was 18.7% (95% CI: 13.3% to 24.1%) and with normal ABI (1.11 to 1.40) was 4.4% (95% CI: 3.2% to 5.7%). Corresponding mortalities in women were 12.6% (95% CI: 6.2% to 19.0%) and 4.1% (95% CI: 2.2% to 6.1%). Low ABI (0.90) was associated with approximately twice the 10-y total mortality, CV mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of ABI in CV risk stratification using the FRS would result in reclassification of risk category and modification of treatment recommendations in ~19% of men and 36% of women.		10-y CV mortality: Men: HR: 4.2; 95% CI: 3.3 to 5.4 Women: HR: 3.5; 95% CI: 2.4 to 5.1	Measurement of ABI may improve accuracy of CV risk prediction beyond FRS.	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 ABI combined with text words and medical subject headings to capture prospective cohort designs.
Outcomes following endovascular vs open repair of AAA: a randomized trial60	To compare postoperative outcomes up to 2 y after endovascular or open repair of AAA (interim report of a 9-y trial)	Randomized, multicenter clinical trial; elective endovascular (n=444) or open (n=437) repair of AAA	881	Veterans (49 y old) from 42 VA Medical Centers with eligible AAA who were candidates for both elective endovascular repair and open repair of AAA	N/A	Long-term (5 to 9 y) all-cause mortality	2° outcomes included: 1) procedure failure, 2) short-term major morbidity, 3) in-hospital and ICUs associated with initial repair, 4) other procedure-related morbidities such as incisional hernia or new or worsened claudication, 5) HRQOL, and 6) erectile dysfunction. 2°outcomes cover short-term perioperative period	Perioperative mortality (30-d or inpatient) was lower for endovascular repair (0.5% vs 3.0%; P=0.004); no significant difference in mortality at 2 y (7.0% vs 9.8%; P=0.13). Patients in endovascular repair group had reduced median procedure time (2.9 vs 3.7 h), blood loss (200 vs 1000 mL), transfusion requirement (0 vs 1.0 units), duration of mechanical ventilation (3.6 vs 5.0 h), hospital stay (3 vs 7 d), and ICU stay (1 vs 4 d), but required substantial exposure to fluoroscopy and contrast. No differences between the 2 groups in major morbidity, procedure failure, 2° therapeutic procedures, aneurysm-related hospitalizations, HRQOL, or erectile function.	Perioperative mortality: P=0.004; Mortality at 2 y: P=0.13	HR: 0.7; 95% CI: 0.4 to 1.1	Short-term outcomes after elective AAA repair, perioperative mortality was low for both procedures and lower for endovascular than open repair. Early advantage of endovascular repair was not offset by increased morbidity or mortality in the first 2 y after repair. Long-term outcome data are needed.	Analysis by ITT. Trial is ongoing, and report covers October 15, 2002 through October 15, 2008.
Aspirin for prevention of CV events in patients with PAD: a meta-analysis of randomized trials51	To investigate the effect of ASA on CV event rates in patients with PAD	Meta-analysis (18 trials involving 5269 persons were identified)	N=5269; 2823 patients taking ASA (alone or with dipyridamole) and 2446 in control group	Inclusion criteria: 1) prospective, RCTs either open-label or blinded; 2) assignment of PAD participants to ASA treatment or placebo or control group; and 3) available data on all-cause mortality, CV death, MI, stroke, and major bleeding	N/A	CV events (nonfatal MI, nonfatal stroke, and CV death)	All-cause mortality, major bleeding, and individual components of the 1° outcome measure	5000 patient meta-analysis with ~88% power to detect a 25% difference (from 10% to 7.5%) and 70% power to detect a 20% difference (from 10% to 8%) in RR of CV death, MI, or stroke in the ASA group vs placebo or control groups. Patient characteristics, ASA dosages, and length of follow-up differed across studies, so RR for each study was assumed to have a random offset from the population mean RR (ie, a random-effects model). The Cochran Q statistic and I2 statistic were calculated by study authors to assess degree of heterogeneity among the trials.	Effect of any ASA on prevention of composite CV endpoints, P=0.13. Effect of any ASA on prevention of nonfatal MI, nonfatal stroke, and CV death P=0.81; Nonfatal stroke, P=0.02; CV death, P=0.59 Effect of any ASA on prevention of any death and major bleeding: Any death, P=0.85 Major bleeding, P=0.98. Effect of ASA monotherapy on prevention of adverse outcomes composite CV endpoints, P=0.21	Effect of any ASA on prevention of composite CV endpoints: RR: 0.88; 95% CI: 0.76 to 1.04 Effect of any ASA on prevention of nonfatal MI, nonfatal stroke, and CV death: Nonfatal MI: RR: 1.04; 95% CI: 0.78 to 1.39 Nonfatal stroke: RR: 0.66; 95% CI: 0.47 to 0.94 CV death: RR: 0.94; 95% CI: 0.74 to 1.19 ASA effect on prevention of any death and major bleeding: Any death RR: 0.98; 95% CI: 0.83 to 1.17 Major bleeding: RR: 0.99; 95% CI: 0.66 to 1.50 Effect of ASA monotherapy on prevention of adverse outcomes: Composite CV endpoints: RR: 0.75; 95% CI: 0.48 to 1.18 Nonfatal stroke: RR: 0.64; 95% CI: 0.42 to 0.99	In patients with PAD, treatment with ASA alone or with dipyridamole resulted in a statistically nonsignificant decrease in the 1° endpoint of CV events and a significant reduction in nonfatal stroke. Results for the 1° endpoint may reflect limited statistical power. Additional RCTs are needed to establish a net benefit and bleeding risks in PAD.	Outcome measures: 1°outcome was RR reduction of ASA therapy on composite endpoint of nonfatal MI, nonfatal stroke, and CV death in the population of patients who received any ASA therapy (with or without dipyridamole). 2° outcomes were all-cause mortality with each component of the 1° endpoint. The 1° safety outcome evaluated occurrence of major bleeding as defined by each study. ITT analysis used.
Aspirin for prevention of CV events in a general population screened for a low ABI: an RCT47	To determine effectiveness of ASA in preventing events in people with a low ABI identified on screening of the general population	ITT, double-blind RCT	28 980 men and women 50 to 75 y old	N/A	N/A	Composite of initial fatal or nonfatal coronary event or stroke or revascularization	All initial vascular events, defined as a composite of a 1° endpoint event or angina, intermittent claudication, or TIA; and all-cause mortality	1° endpoint event: 13.5 per 1000 person-years; 95% CI: 12.2 to 15.0. No statistically significant difference was found between groups (13.7 events per 1000 person-years in the ASA group vs 13.3 in the placebo group; HR: 1.03; 95% CI: 0.84 to 1.27). 2° endpoint (vascular event): 22.8 per 1000 person-years; 95% CI: 21.0 to 24.8, and no statistically significant difference was found between groups (22.8 events per 1000 person-years in the ASA group vs 22.9 in the placebo group; HR: 1.00; 95% CI: 0.85 to 1.17). No significant difference in all-cause mortality between groups, 176 vs 186 deaths, respectively; HR: 0.95; 95% CI: 0.77 to 1.16. An initial event of major hemorrhage requiring admission to hospital occurred in 34 participants (2.5 per 1000 person-years) in the ASA group and 20 (1.5 per 1000 person-years) in the placebo group (HR: 1.71; 95% CI: 0.99 to 2.97).		1° endpoint: No statistically significant difference was found between groups. HR: 1.03; 95% CI: 0.84 to 1.27 2° endpoint (vascular event): No statistically significant difference between groups, HR: 1.00; 95% CI: 0.85 to 1.17 All-cause mortality: HR: 0.95; 95% CI: 0.77 to 1.16 An initial event of major hemorrhage requiring admission: HR: 1.71; 95% CI: 0.99 to 2.97	Among participants without clinical CV disease, identified with a low ABI based on screening a general population, administration of ASA compared with placebo did not result in a significant reduction in vascular events.	Interventions: Once-daily 100 mg ASA (enteric coated) or placebo. Statistics: The trial was powered to detect a 25% proportional risk reduction in major vascular events. Predicted risk reduction evidence from 1) event rates in asymptomatic participants with a low ABI were similar to those with symptomatic PAD, suggesting that the risk reduction could be comparable with patients who have clinical disease (~25% to 15%), and 2) in stable angina, unlike ACS with thrombosis complicating atherosclerotic plaque, risk reduction could reach 33%. Study termination: Subsequently, DSMB stopped the trial 14 mo early due to the improbability of finding a difference in the 1° endpoint by the end date and an increase in major bleeding (P=0.05) in the ASA group. Even though the trial was stopped early, the required number of events was achieved.
Prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomized placebo-controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic PAD46	To determine whether ASA and antioxidant therapy, combined or alone, are more effective than placebo in reducing development of CV events in patients with diabetes mellitus and asymptomatic PAD	Multicenter, randomized, double-blind, 2×2 factorial, placebo-controlled trial	1276	Adults of either sex, >40 y old, with type 1 or type 2 diabetes who were determined to have asymptomatic PAD as detected by lower-than-normal ABI (≤0.99). The trial used a higher cut-off point (0.99 vs 0.9) because it is recognized that calcification in the vessels of people with diabetes can produce a normal or high ABI, even in the presence of arterial disease.	People with evidence of symptomatic CV disease; those who use ASA or antioxidant therapy on a regular basis; those with peptic ulceration, severe dyspepsia, a bleeding disorder, or intolerance to ASA; those with suspected serious physical illness (such as cancer), which might have been expected to curtail life expectancy; those with psychiatric illness (reported by their general practitioner); those with congenital heart disease; and those unable to give informed consent	2 hierarchical composite 1° endpoints of death from CAD or stroke, nonfatal MI or stroke, or amputation above the ankle for CLI; and death from CAD or stroke	N/A	Overall, 116 of 638 1° events occurred in the ASA groups compared with 117 of 638 in the no-ASA groups (18.2% vs 18.3%); 43 deaths from CAD or stroke in the ASA groups compared with 35 in the no-ASA groups (6.7% vs 5.5%). Among the antioxidant groups, 117 of 640 (18.3%) 1° events occurred compared with 116 of 636 (18.2%) in the no-antioxidant groups. There were 42 deaths (6.6%) from CAD or stroke in the antioxidant groups compared with 36 deaths (5.7%) in the no-antioxidant groups.	Comparison of ASA and no-ASA groups—Composite endpoint: P=0.86 Death from CAD or stroke: P=0.36 Comparison of antioxidant and no-antioxidant groups—Composite endpoint: P=0.85 Death from CAD or stroke: P=0.40	ASA groups 1° events: HR: 0.98; 95% CI: 0.76 to 1.26 ASA groups deaths from CAD or stroke HR: 1.23 (0.79 to 1.93) Antioxidant groups 1° events: HR: 1.03; 95% CI: 0.79 to 1.33 Antioxidant groups deaths from CAD or stroke: HR: 1.21; 95% CI: 0.78 to 1.89	This trial does not provide evidence to support the use of ASA or antioxidants in primary prevention of CV events and mortality in the population with diabetes studied.	Power: 1276 patients were recruited, and final power calculations, undertaken in 2003, projected that if follow-up continued until June 2006, then 256 events would be expected to occur during the trial. This would give 73% power to detect a 25% relative reduction in event rate and 89% power to detect a 30% reduction in event rate if only 1 treatment was effective. Interventions were daily ASA 100 mg or placebo tablet, plus antioxidant or placebo capsule. The antioxidant capsule contained á-tocopherol 200 mg, ascorbic acid 100 mg, pyridoxine hydrochloride 25 mg, zinc sulphate 10 mg, nicotinamide 10 mg, lecithin 9.4 mg, and sodium selenite 0.8 mg.
Endovascular vs open repair of AAA: the United Kingdom EVAR Trial Investigators56	To investigate the long-term outcome of endovascular repair of AM compared with open repair	Randomized trial	1252	N/A (published in previous reports)61	N/A (published in previous reports)61	Death from any cause. Also assessed: aneurysm-related death, graft-related complications, and graft-related reinterventions	N/A	30-d operative mortality was 1.8% in the endovascular repair group and 4.3% in the open-repair group.	30-d operative mortality (for endovascular repair compared with open repair): P=0.02 Aneurysm-related mortality: P=0.73 Rate of death from any cause: P=0.72	30-d operative mortality (for endovascular repair compared with open repair): adjusted OR: 0.39; 95% CI: 0.18 to 0.87 Aneurysm-related mortality: adjusted HR: 0.92; 95% CI: 0.57 to 1.49 Rate of death from any cause: adjusted HR: 1.03; 95% CI: 0.86 to 1.23	Endovascular repair of AAA was associated with a significantly lower operative mortality than open surgical repair. However, no differences were seen in total mortality or aneurysm-related mortality in the long term. Endovascular repair was associated with increased rates of graft-related complications and reinterventions and was more costly.	Rates of graft-related complications and reinterventions were higher with endovascular repair, and new complications occurred up to 8 y after randomization, contributing to higher overall costs. Per-protocol analysis yielded results very similar to those of ITT analysis.
Endovascular repair of aortic aneurysm in patients physically ineligible for open repair: the United Kingdom EVAR Trial Investigators59	To investigate whether endovascular repair reduces the rate of death among patients who were considered physically ineligible for open surgical repair	Randomized trial	404	N/A (see original study61)	N/A (see original study61)	Death from any cause. Also assessed: aneurysm-related death, graft-related complications, and graft-related reinterventions	N/A	30-d operative mortality was 7.3% in the endovascular repair group. The overall rate of aneurysm rupture in the no-intervention group was 12.4 (95% CI: 9.6 to 16.2) per 100 person-years. A total of 48% of patients who survived endovascular repair had graft-related complications, and 27% required reintervention within the first 6 y.	Aneurysm-related mortality: P=0.02 Total mortality: P=0.97	Aneurysm-related mortality was lower in the endovascular repair group. Adjusted HR: 0.53; 95% CI: 0.32 to 0.89. Total mortality: adjusted HR: 0.99; 95% CI: 0.78 to 1.27	This RCT involved patients who were physically ineligible for open repair; endovascular repair of AAA was associated with a significantly lower rate of aneurysm-related mortality than no repair. However, endovascular repair was not associated with reduction in the rate of death from any cause. Rates of graft-related complications and reinterventions were higher with endovascular repair, and it was more costly.	During 8 y of follow-up, endovascular repair was considerably more expensive than no repair (cost difference, £9826 [US $14 867]; 95% CI: £7638 to £12 013 [$11 556 to $18 176]).
BASIL54	An ITT analysis of AFS and OS in patients randomized to a BSX-first or a BAP-first revascularization strategy	Randomized trial	452	BASIL trial methods have been published in detail elsewhere.55	BASIL trial methods have been published in detail elsewhere.55	1° aim: determine whether a BSX-first or a BAP-first revascularization strategy was associated with better clinical outcome for patients. Defined better as improved AFS; used this as 1° endpoint for power calculation and prespecified statistical plan design.	2° outcomes included postprocedural morbidity, reinterventions, HRQOL, and use of hospital resources.	For those patients who survived for 2 y after randomization: initial randomization to a BSX-first revascularization strategy was associated with an increase in subsequent restricted mean overall survival of 7.3 mo (95% CI: 1.2 to 13.4 mo) and an increase in restricted mean AFS of 5.9 mo (95% CI: 0.2 to 12.0 mo) during the subsequent mean follow-up of 3.1 y (range: 1 to 5.7 y).	For those patients surviving 2 y from randomization: BSX-first revascularization was associated with subsequent AFS of P=0.108 and subsequent OS of P=0.009. For those patients who survived for 2 y after randomization: initial randomization to a BSX-first revascularization strategy was associated with an increase in subsequent restricted mean overall survival, P=0.02, and an increase in restricted mean AFS, P=0.06.	For those patients surviving 2 y from randomization: BSX-first revascularization was associated with reduced HR for subsequent AFS of 0.85 (95% CI: 0.5 to 1.07) in an adjusted, time-dependent Cox proportional hazards model and subsequent OS of 0.61 (95% CI: 0.50 to 0.75) in an adjusted, time-dependent Cox proportional hazards model.	Overall there was no significant difference in AFS or OS between the 2 strategies. However, for those patients who survived for ≥2 y after randomization, a BSX-first revascularization strategy was associated with a significant increase in subsequent OS and a trend toward improved AFS.	The sample size calculations proposed that 223 patients per treatment would be needed for 90% power to detect a 15% difference in 3-y AFS at the 5% significance level. This calculation was based on the assumption that the 3-y survival value might be 50% in 1 group and 65% in the others).
Statins are independently associated with reduced mortality in patients undergoing IBG surger for CLI (PREVENT III)62	To determine efficacy of edifoligide for ed prevention of graft failure	Multicenter, randomized, prospective trial	1404 patients with CLI	Patients ≥18y old who underwent IBG with autogenous vein for CLI, defined as gangrene, nonhealing ischemic ulcer, or ischemic rest pain. See primary trial report for further information.63	Claudication as an indication for IBG surgery or use of a nonautogenous conduit. See primary trial report for further information.63	Major adverse CV events <30 d, vein graft patency, and 1-y survival assessed by Kaplan-Meier method	N/A	Patient treatment breakdown: 636 patients (45%) were taking statins, 835 (59%) were taking beta blockers, and 1121 (80%) were taking antiplatelet drugs. Perioperative major adverse CV events (7.8%) and early mortality (2.7%) were not measurably affected by use of any drug class. Use of beta blockers and antiplatelet drugs had no appreciable impact on survival. None of the drug classes were associated with graft patency measures at 1 y. Statin use was associated with a significant survival advantage at 1 y of 86% vs 81% by analysis of both unweighted and propensity score-weighted data.	Statin use associated with significant survival advantage at 1 y: P=0.03 Significant predictors of 1-y mortality by Cox regression modeling were: Statin use P=0.001 Age >75 y, P=0.001 CAD, P=0.001 CKD stage 4, P=0.001 CKD stage 5, P<0.001 Tissue loss, P=0.003	Statin use associated with a significant survival advantage at 1 y: HR: 0.71; 95% CI 0.52 to 0.98 Significant predictors of 1-y mortality by Cox regression modeling were: Statin use HR: 0.67; 95% CI: 0.51 to 0.90 Age >75 y HR: 2.1; 95% CI: 1.60 to 2.82 CAD HR: 1.5; 95% CI: 1.15 to 2.01 CKD stage 4 HR: 2.0; 95% CI: 1.17 to 3.55 CKD stage 5 HR: 3.4; 95% CI: 2.39 to 4.73 Tissue loss HR: 1.9; 95% CI: 1.23 to 2.80	Statin use was associated with improved survival in CLI patients 1 y after surgical revascularization. Further studies are indicated to determine optimal dosing in this population and to definitively address the question of relationship to graft patency. These data add to the growing literature supporting statin use in patients with advanced PAD.	Propensity scores used to evaluate the influence of statins, beta blockers, and antiplatelet agents on outcomes while adjusting for demographics, comorbidities, medications, and surgical variables that may influence drug use.
Mortality and vascular morbidity in older adults with asymptomatic vs symptomatic PAD (getABI)11	To assess risk of mortality and vascular morbidity in elderly persons with asymptomatic vs symptomatic PAD in the primary care setting	Prospective cohort study	6880 representative unselected patients 65 y of age: 5392 patients had no PAD, 836 had asymptomatic PAD (ABI: 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 ABI)	Age 65 y, legally competent, and able to cooperate appropriately and provide written informed consent64	Life expectancy of 6 mo as judged by the general practitioner64	1° outcomes and identification of CV events during follow-up: severe vascular events were defined as follows: CV, including MI or coronary revascularization; cerebrovascular, including stroke or carotid revascularization; and lower extremity peripheral vascular, including peripheral revascularization or amputation because of PAD during follow-up.	N/A	Lower ABI categories were associated with increased risk. PAD was a strong factor for prediction of the composite endpoint in an adjusted model.		Risk of symptomatic compared with asymptomatic PAD patients: Composite of all-cause death or severe vascular event HR: 1.48; 95% CI: 1.21 to 1.80 All-cause death alone HR: 0.13, 95% CI: 0.89 to 1.43 All-cause death/MI/stroke (excluding lower extremity peripheral vascular events and any revascularizations) HR: 1.18; 95% CI: 0.92 to 1.52 CV events alone HR: 1.20; 95% CI: 0.89 to 1.60 Cerebrovascular events alone HR: 1.33; 95% CI: 0.80 to 2.20	Asymptomatic PAD diagnosed through routine screening in offices of PCPs has a high and/or vascular event risk. Notably, 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.	Incidence rates and 95% CIs were calculated as events per 1000 person-years. The composite endpoint of all-cause mortality or severe vascular events occurred in 27.2 (no PAD), 60.4 (asymptomatic PAD), and 104.7 (symptomatic PAD) cases per 1000 patient-years. In analysis by ABI category, patients with an ABI of 1.1 to 1.5 had the lowest event rate per 1000 patient-years (24.3 events), whereas event rates increased substantially with decreasing ABI. In patients with an ABI of 0.5, lower extremity peripheral revascularization, or amputation resulting from PAD, event rates were increased 6-fold (146.3), and the corresponding adjusted risk was increased 4.65-fold (95% CI: 3.57 to 6.05).
Effectiveness of a smoking cessation program for PAD patients65	To test the effectiveness of a smoking cessation program designed for patients with PAD	RCT	124	Diagnosis of lower extremity PAD, defined as at least 1 of the following: ABI <0.90 in at least 1 lower extremity; toe brachial index <0.60; objective evidence of arterial occlusive disease in 1 lower extremity by duplex ultrasound, MRA, or CTA; prior leg arterial revascularization or amputation due to PAD, and current smoking (defined as smoking at least 1 cigarette/d, at least 6 d/wk). Additional inclusion criteria: desire to quit smoking in the next 30 d, age >18 y, ability to speak and write English, no participation in a smoking cessation program in the past 30 d, and consumption of <21 alcoholic drinks per wk.	N/A	Tobacco use 7-d point prevalence of smoking (ie, “Have you smoked a cigarette, even a puff, in the past 7 d?”), at the 3- and 6-mo follow-ups	N/A	Participants randomized to the intensive intervention group were significantly more likely to be confirmed abstinent at 6-mo follow-up: 21.3% vs 6.8% in the minimal intervention group: chi-squared=5.21.	Members of the intensive intervention group were significantly more likely to be confirmed abstinent at 6-mo follow-up: P=0.023.	N/A	Many long-term smokers with PAD are willing to initiate a serious quit attempt and to engage in an intensive smoking cessation program. Intensive intervention for tobacco dependence is a more effective smoking cessation intervention than minimal care. Studies should be conducted to examine the long-term effectiveness of intensive smoking cessation programs in this population in order to examine the effect of this intervention on clinical outcomes related to PAD.
Prevention of serious vascular events by aspirin among patients with PAD: randomized, double-blind trial: CLIPS Group45	To assess the prophylactic efficacy of ASA and a high-dose antioxidant vitamin combination in patients with PAD in terms of reduction of risk of a first vascular event (MI, stroke, vascular death) and CLI	RCT, double-blind clinical trial with 2×2 factorial design	366 outpatients with stage I to II PAD documented by angiography or ultrasound, with ABI <0.85 or toe index <0.6	Study involved outpatients with symptomatic (claudicant) or asymptomatic PAD documented by angiography or ultrasound, who had 1 ABI <0.85 or 1 toe index <0.6. Patients were referred either by the GP or ER physician for a diagnostic workup. Diabetic persons could be included, provided metabolic control was stable (HbA1c). Only patients who accepted randomization (ie, continuation after run-in period) were included in the study.	Exclusion criteria: Fontaine stage III or IV PVD; life expectancy <24 mo; vascular surgery or angioplasty in the last 3 mo; pregnancy or lactation; contraindication to ASA; major CV events requiring antiplatelet therapy; participation in another clinical trial; uncooperative patients; treatment with drugs that interfere with hemostasis, such as anticoagulants, antiplatelet agents, and prostanoids, peripheral vasodilators, ASA and/or supplementary vitamins that could not be discontinued or had to be introduced	Major vascular events: CV death, MI, or stroke and CLI	N/A	7 of 185 patients who were allocated to ASA and 20 of 181 patients who were allocated to placebo suffered a major vascular event (risk reduction 64%). 5 and 8 patients, respectively, suffered CLI (total 12 vs 28). There was no evidence that antioxidant vitamins were beneficial (16/185 vs 11/181 vascular events). Neither treatment was associated with any significant increase in adverse events.	Major vascular event: P=0.022; CLI: P=0.014	N/A	For the first time direct evidence shows that low-dose ASA should routinely be considered for patients with PAD, including those with concomitant type 2 diabetes.	The safety endpoint was incidence of bleeding. Inclusion of this trial in a meta-analysis of other RCTs of antiplatelet therapy in PAD makes the overall results highly significant (P<0.001) and suggests that low-dose ASA reduces the incidence of vascular events by 26%.
Patients with PAD in the CHARISMA trial49	To determine whether clopidogrel plus ASA provides greater protection against major CV events than ASA alone in patients with PAD	Prospective, multicenter, randomized, double-blind, placebo-controlled study	3096 patients with symptomatic (2838) or asymptomatic (258) PAD	To fulfill the symptomatic PAD inclusion criterion, patients had to have either current intermittent claudication together with an ABI of 0.85 or a history of intermittent claudication together with a previous related intervention (amputation, surgical or catheter-based peripheral revascularization). Asymptomatic patients with an ABI of 0.90 were identified among those with multiple risk factors.	The details of the trial design have been published previously66	1° efficacy endpoint: first occurrence of MI, stroke (of any cause), or death from CV causes (including hemorrhage). 1° safety endpoint: severe bleeding according to the GUSTO definition	Principal 2° efficacy endpoints: first occurrence of MI, stroke, death from CV causes, hospitalization for UA, TIA, or a revascularization procedure (coronary, cerebral, or peripheral)	Post hoc analysis of the 3096 patients with symptomatic (2838) or asymptomatic (258) PAD from the CHARISMA trial. CV death, MI, or stroke rates (1° endpoint) were higher in PAD patients than in those without PAD: 8.2% vs 6.8%. Severe, fatal, or moderate bleeding rates did not differ between groups, whereas minor bleeding was increased with clopidogrel: 34.4% vs 20.8%. Among patients with PAD: The 1° endpoint occurred in 7.6% in the clopidogrel plus ASA group and 8.9% in the placebo plus ASA group. The rate of MI was lower in the dual antiplatelet arm than the ASA-alone arm: 2.3% vs 3.7%. The rate of hospitalization for ischemic events: 16.5% vs 20.1%.		Rates of minor bleeding: OR: 1.99; 95% CI: 1.69 to 2.34. Among the patients with PAD: 1° endpoint: HR: 0.85; 95% CI: 0.66 to 1.08 Rate of MI: HR: 0.63; 95% CI: 0.42 to 0.96 Rate of hospitalization: HR: 0.81; 95% CI: 0.68 to 0.95 Rate of hospitalization for ischemic events: HR: 0.81; 95% CI: 0.68 to 0.95	Dual therapy provided some benefit over ASA alone in PAD patients for the rate of MI and the rate of hospitalization for ischemic events, at cost of an increase in minor bleeding.	N/A
CHARISMA48	To view dual antiplatelet therapy with clopidogrel plus low-dose ASA in a broad population of patients at high risk for atherothrombotic events	Prospective, multicenter, randomized, double-blind, placebo-controlled study	15603	See study for the inclusion criteria for those with multiple risk factors and those with established vascular disease.	Patients were excluded from the trial if they were taking oral antithrombotic medications or NSAIDs on a long-term basis (although COX-2 inhibitors were permitted). Patients were also excluded if, in the judgment of the investigator, they had established indications for clopidogrel therapy (such as recent ACS). Patients who were scheduled to undergo revascularization were not allowed to enroll until the procedure had been completed; such patients were excluded if they were considered to require clopidogrel after revascularization.	1° efficacy endpoint: composite of MI, stroke, or death from CV causes. 1° safety endpoint: severe bleeding, according to the GUSTO definition	Principal 2° efficacy endpoint: first occurrence of MI, stroke, death from CV causes, or hospitalization for UA, TIA, or a revascularization procedure (coronary, cerebral, or peripheral)	1° efficacy rate endpoint: 6.8% with clopidogrel plus ASA and 7.3% with placebo plus ASA. Principal 2° efficacy rate endpoint, including hospitalizations for ischemic events, was 16.7% and 17.9%. Principal 2° efficacy endpoint, including the rate of severe bleeding, 1.7% and 1.3%. 1° endpoint rate among patients with multiple risk factors was 6.6% with clopidogrel and 5.5% with placebo. The rate of death from CV causes also was higher with clopidogrel (3.9% vs 2.2%). In the subgroup with clinically evident atherothrombosis, the rate was 6.9% with clopidogrel and 7.9% with placebo.	1 endpoint rate among patients with multiple risk factors: P=0.20 1° endpoint rate in the subgroup with clinically evident atherothrombosis: P=0.046 Rate of death from CV causes: P=0.01 1° efficacy endpoint rate: P=0.22 Principal 2° efficacy rate endpoint, including rate of severe bleeding: P=0.09 Principal 2° efficacy rate endpoint, including hospitalizations for ischemic events: P=0.04	1° efficacy endpoint rate: RR 0.93; 95% CI: 0.83 to 1.05 1° endpoint rate in subgroup with clinically evident atherothrombosis: RR: 0.88; 95% CI: 0.77 to 0.998 1° endpoint rate among patients with multiple risk factors: RR: 1.2; 95% CI: 0.91 to 1.59 Principal 2° efficacy endpoint, including the rate of severe bleeding: RR: 1.25, 95% CI: 0.97 to 1.61. Principal 2° efficacy rate endpoint, including : hospitalizations for ischemic events: RR: 0.92; 95% CI: 0.86 to 0.995	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 ASA was not significantly more effective than ASA alone in reducing rate of MI, stroke, or death from CV causes.	Other efficacy endpoints included death from any cause and death from CV causes, as well as MI, ischemic stroke, any stroke, and hospitalization for UA, TIA, or revascularization considered separately.
Oral anticoagulant and antiplatelet therapy an PAD: the WAVE trial Investigators50	To view the role of oral anticoagulants in prevention of CV complications in patients with PAD	Randomized, open-label, clinical trial	2161 patients	Men and women who were 35 to 85 y old and had PAD	Patients who had an indication for oral anticoagulant treatment, were actively bleeding or at high risk for bleeding, had had a stroke within 6 mo before enrollment, or required dialysis	First coprimary outcome: MI, stroke, or death from CV causes. Second coprimary outcome: MI, stroke, severe ischemia of the peripheral or coronary arteries leading to urgent intervention, or death from CV causes	N/A	MI, stroke, or death from CV causes occurred in 132 of 1080 patients receiving combination therapy (12.2%) and in 144 of 1081 patients receiving antiplatelet therapy alone (13.3%). MI, stroke, severe ischemia, or death from CV causes occurred in 172 patients receiving combination therapy (15.9%) compared with 188 patients receiving antiplatelet therapy alone (17.4%). Life-threatening bleeding occurred in 43 patients receiving combination therapy (4.0%) compared with 13 patients receiving antiplatelet therapy alone (1.2%).	MI, stroke, or death from CV causes: P=0.48 MI, stroke, severe ischemia, or death from CV causes: P=0.37 Life-threatening bleeding: P<0.001	MI, stroke, or death from CV causes: RR: 0.92; 95% CI: 0.73 to 1.16 MI, stroke, severe ischemia, or death from CV causes: RR: 0.91; 95% CI: 0.74 to 1.12 Life-threatening bleeding: RR: 3.41; 95% CI: 1.84 to 6.35	The combination of an oral anticoagulant and antiplatelet therapy was no more effective than antiplatelet therapy alone in preventing major CV complications and was associated with an increase in life-threatening bleeding.	Safety outcomes were life-threatening, moderate, or minor bleeding episodes.

AAA indicates Abdominal Aortic and Iliac Aneurysms; ABI, ankle brachial index; ACS, acute coronary syndrome; AFS, amputation-free survival; ASA, aspirin; ASTRAL, Angioplasty and Stent for Renal Artery Lesions trial; BAP, balloon angioplasty; BASIL, Bypass versus Angioplasty in Severe Ischaemia of the Leg trial; BSX-first, bypass surgery; CAD, coronary artery disease; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CI, confidence interval; CKD, chronic kidney disease; CLI, critical limb ischemia; CLIPS, Critical Leg Ischemia Prevention Study; COX-2, cyclooxygenase; CTA, computed tomographic angiography; CV, cardiovascular; DSMB, data safety monitoring board; Embase, Excerpta Medica Database; ER, emergency room; EVAR, endovascular aneurysm repair; FRS, Framingham Risk Score; GP, general practitioner; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; HbA1c, hemoglobin A1c; HR; hazard ratio; HRQOL, health-related quality of life; IBG, infrainguinal bypass graft; ICU, intensive care unit; ITT, intention-to-treat; MEDLINE, Medical Literature Analysis and Retrieval System Online; MI, myocardial infarction; N/A, not available; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds radio; OS, overall survival; MRA, magnetic resonance angiography; PAD, peripheral artery disease; PCP, primary care physician; POPADAD, prevention of progression of arterial disease and diabetes; PREVENT III, The Project of Ex-Vivo Vein Graft Engineering via Transfection III; PVD, peripheral vascular disease; RAS, renal artery stenosis; RCT, randomized controlled trial; RR, relative risk; SLI, severe leg ischemia; TIA, transient ischemic attack; UA, unstable angina; VA, Department of Veterans Affairs; WAVE, Warfarin Antiplatelet Vascular Evaluation trial; 1°, primary; and 2°, secondary.