2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary



## Aim of study
Aim: To determine whether ASA and antioxidant therapy, combined or alone, are more effective than placebo in reducing CVD events in pts with DM and Asx PAD.

## Study type:
Multicenter, randomized, double blind, 22 factorial, placebo controlled trial.

## Size: n=1,276 pts
Inclusion criteria: Age 40 y with type 1 or type 2 DM and ABI of 0.99 but no Sx CVD.
Exclusion criteria: People with: evidence of Sx vascular CVD; ASA or antioxidant therapy use on a regular basis; peptic ulceration, severe dyspepsia, a bleeding disorder, or intolerance to ASA; suspected serious physical illness (e.g., cancer), which could curtail life expectancy; psychiatric illness (reported by GP); pts with congenital heart disease; and pts unable to give informed consent Intervention and comparator: Daily, 100 mg ASA tablet + antioxidant capsule (n=320); ASA + placebo capsule (n=318); placebo tablet + antioxidant capsule (n=320); or placebo tablet + placebo capsule (n=318).
1 endpoint:  Death from CHD or stroke, nonfatal MI or stroke, or amputation above the ankle for CLI; and death from CHD or stroke  116 of 638 1 events in the ASA groups compared with 117 of 638 in the no ASA groups (18.2% vs. ABI provided independent risk information and almost doubled risk of total mortality CV mortality and major coronary events when combined with FRS.  Many men would move to a lower risk category, while more women would move from a lower to a higher risk category..  Difference between PAD groups also significant (HR: 1.48; 95% CI: 1.21-1..  No differences between PAD groups in MI, stroke, peripheral amputation. Sig differences in myocardial and peripheral revascularualrizations.
 1 in 5 elderly pts visiting primary care clinician had PAD.  Pts with PD regardless of severity had increased risk of CV events and death compared to those without PAD  Sx PAD had greater risk of composite outcome of all-cause death or vascular event than asx PAD pts but no greater risk of allcause mortality alone, MI, or stroke USPSTF Review 24156115

## Study type: systematic evidence review
Size: n=1 meta-analysis, 18 population-based cohorts Inclusion criteria: 3 mo follow-up; designed to evaluate treatment benefit in screen-detected persons or populations who had Asx or unrecognized PAD

## Exclusion criteria: pts with dm

# Results:
 ABI added to other risk predictors increases but questions clinical utility or significance.  No randomized studies showing improved outcomes in response to detection of Asx disease.  Benefit of reclassification including ABI may be higher and clinically important in older populations at higher risk. May be most useful for pts near the thresholds of risk categories.  Acknowledge the evidence demonstrating increased morbidity and mortality in Asx pts.
 Several studies currently ongoing that could give more definitive answers in the future.  American Heart Association, Inc. and American College of Cardiology Foundation25721066

## Study type: systematic review
Size: n=40 individual studies, 2 systematic reviews, 1 meta-analysis Inclusion criteria: Studies reporting results of screening for asx pts Exclusion criteria: Not original data, did not report on asx pts 1 endpoint: Multiple that would justify screening for asx pts: Accurate test available; disease sufficiently prevalent and mortal; screening leads to reduced morbidity and mortality; screening is not harmful

# Results:
 ABI is adequate test (diagnostic accuracy=0.87; diagnostic OR: 15.33; 95% CI: 9.39-25.02; pooled sensitivity=75%; specificity=86%);  PAD is prevalent (average screening yield=17.2%) and mortal (pooled HR=2.99 for all-cause mortality and 2.35 for CV mortality).  No studies compared screened vs. non screened populations for mortality outcomes.  ABI screening can improve FRS in risk prediction.  Some evidence that screening can lead to improved morbidity  Little evidence about potential harm or cost-effectiveness. Discussed potential bleeding risk of ASA with no proven benefit  Yield of ABI screening text in asx pts depends on prevalence of traditional risk factors  No high quality evidence supports 'pt-important' benefits from screening low-risk individuals  High-risk individuals may not need screening since there is already indication to treat their risk Health ABC Study 

# Results:
 Pts separated into groups based on physical activity level (walk 3 or more times per wk vs. less frequently).  Asx PAD pts who walked for exercise 3 or more times per wk had less functional decline than those who walked for exercise less frequently  Greater physical activity associated with less decline in physical functioning in ASX PAD pts.

## Walcs study

# Results:
 Sensitivity of the HAP and LAP ABI for diagnosis of PAD was 69% and 84%, respectively  Overall accuracy of HAP and LAP ABI was 72% and 80%,  LAP ABI has better sensitifvity and overall accuracy in comparison to the HAP ABI in diagnosing PAD  American Heart Association, Inc. and American College of Cardiology Foundation vessels  ABI >1.40 respectively ABI indicates ankle-brachial index; ASA, acetylsalicylic acid; asx, asymptomatic; BL, baseline; CAD, coronary artery disease; CHD, coronary heart disease; CI indicates confidence interval; CLI, critical limb ischemia; CT, computed tomography; CVD, cardiovascular disease; CV, cardiovascular; DM, diabetes mellitus; DSA, digital subtraction angiography; ET, endotracheal; FRS, Framingham risk score; HAP, high ankle pressure; HR, hazard ratio; HTN, hypertension; IC, intermittent claudication; LAP, low ankle pressure; MACE, major adverse cardiovascular event; LEX, lower extremity; MCS, mental health composite score; MI, myocardial infarction; MRI, magnetic resonance imaging; MWT, mean walking time; N/A, not applicable; NHANES, National Health and Nutrition Examination Survey; NPV, negative predictive value; NRI, net reclassification improvement; NNT, number needed to treat OR, odds ratio; PAD, peripheral artery disease; PCS, physical composite score, PFWT, pain free walking time; PPV, positive predictive value; pt, patient; RR, relative risk; SBP, systolic blood pressure; SCCA, significant stenosis >50%; SF, Short Form; Sx, symptomatic; TIA, transient ischemic attack; US, United States; and WIQ, Walking Impairment Questionnaire. For ACD, the reliability was significantly better for the G-protocol (0.95, 95% CI: 0.94-0.96) than for the C-protocol. Moreover, the reliability of the C-protocol was dependent on grade of the treadmill (0%, 10%, and 12%) with a mean ICC of 0. DM is associated with a higher incidence of plaque, increased incidence of mixed plaques, moderate stenosis and localization primarily in the distal lower leg segments.  The advanced and noninvasive MDCT could be used for routine preoperative evaluations of LEA.  American Heart Association, Inc. and American College of Cardiology Foundation contrast agent, liver, kidney or HF (Creatinine level 120 mol/L), pregnancy and leg amputation. The vascular exclusion criteria included vascular malformations, poor imaging and a lumen diameter <1.5 mm.

## Evidence
p<0.05). Regarding these plaques, pts with DM had a higher incidence of mixed plaques (34.2% vs. 27.1% for pts without DM). An increased moderate stenosis rate and decreased occlusion rate were observed in pts with DM relative to pts without DM (35.8% vs. 28.3%; and 6.6% vs. 11.4%; respectively). In pts with DM, 362 (53.2%) plaques were detected in the distal lower leg segments, whereas in pts without DM, 551 (64.5%) plaques were found in the proximal upper leg segments. The type IV plaque shape, in which the full lumen was involved, was detected more frequently in pts with DM than in pts without DM (13.1% vs. 8.2%). Results: In a pt-based analysis, the sensitivity of MDCT for detecting significant proximal IPA disease was 100% and, specificity 74%, positive predictive valve was 66%, and negative predictive value was 100%. In assessing the distal IPA and cavernosal arteries, the sensitivity was 100%, specificity was 64%, positive predictive value 89%, and negative predictive value of 100%. MDCT used significantly more contrast and more radiation than aortography. Exclusion criteria: N/A 1 endpoint: Conventional angiographic and CT images were analyzed independently to assess suitability for large bore (7 mm diameter) intra-arterial catheter access.
Results: Excellent CT image quality was achieved in 34 of 37 pts (92%). The mean contrast dose for CT was 122 mL. In 9 pts (24%), CT changed the assessment of femoral access feasibility. Furthermore, in another 7 pts (19%), unfavorable anatomy as shown by CT directed the avoidance of a particular side. Overall, CT findings altered the interventional approach in 16 pts (43%).
 Purpose was to evaluate the feasibility of using ultra-low-dose intraarterial contrast injection for iliofemoral CT angiography to follow diagnostic cardiac catheterization.  0 to 15 mL of contrast diluted with normal saline was injected intraarterially via the pigtail catheter while a spiral CT of the abdomen and pelvis was acquired  There was no significant deterioration detected in renal function after coronary and CT angiography (estimated glomerular filtration rate 54.83.8 mL/min before 53.33.9 mL/min after, p=0.55).  Prevalence of AAA in pts with PAD is higher than in the general population.  As in other studies, the prevalence of AAA in pts with PAD increased with age.  The prevalence was much higher in men than women. AAA indicates abdominal aortic aneurysm; CAD, coronary artery disease; CVD, cardiovascular disease; N/A, not applicable; PAD, peripheral artery disease; and PVD, peripheral vascular disease. 1 endpoint:  Platelet uptake was measured using 111 Indium-labelled platelets. Restenosis was assessed by repeat angiography at 3 mo and clinical symptoms up to 12 mo.  Median changes in platelet uptake were similar in the 3 treatment groups, but all platelet radioactivity ratios >2.0 occurred in the control group. Restenosis at 3 mo was observed in 3 control, 5 ASA and 1 iloprost pt.  Further surgical intervention was performed in 3 control and 3 ASA pts, but in none of the iloprost pts up to 12 mo after angioplasty  Limited utility as iloprost also utilized Exclusion criteria: Taking oral antithrombotic medications or NSAIDs on a long-term basis (although cyclooxygenase-2 inhibitors were permitted). Pts were also excluded if, in the judgment of the investigator, they had established indications for clopidogrel therapy (such as a recent acute coronary syndrome). Pts who were scheduled to undergo a revascularization were not allowed to enroll until the procedure had been completed; such pts were excluded if they were considered to require clopidogrel after revascularization. 1 endpoint: Antiplatelet therapy produced a highly significant (2p <0.0001) reduction in vascular occlusion, with similar proportional reductions in several different types of pts As well as preventing subclinical occlusion, antiplatelet therapy produced a significant (2p=0.002) reduction of about one quarter in the odds of suffering a "vascular event" (nonfatal MI, nonfatal stroke, or vascular death).

## Evidence

## Intervention

## Safety endpoint: no clear excess bleeding
 Allocation to antiplatelet therapy in the 14 trials with pts with PAD was associated with a proportional reduction of 43% (SD 8%) in vascular occlusion, which was highly significant. Studies of pts with saphenous vein grafts or prosthetic implants for lower limb disease contributed most of the data; of the 3 other studies, 1 assessed the patency of native vessels in pts with IC and 2 concerned pts who had had peripheral angioplasty.  allocation to a mean scheduled duration of 19 mo of antiplatelet therapy produced a substantial absolute reduction of 92 (SD 15) per 1,000 in the risk of peripheral artery occlusion ABI indicates ankle-brachial index; ACS, acute coronary syndrome; ALI, acute limb ischemia; ASA, aspirin; CHD, coronary heart disease; CI indicates confidence interval; CLI, critical limb ischemia; CV, cardiovascular; GP, general practitioner; GUSTO, Global Utilization of Streptokinase and t-PA for Occluded; Coronary Arteries HR, hazard ratio; IC, intermittent claudication; IV, intravenous; KM, Kaplan-Meier; MACE, major adverse cardiac event; MI, myocardial infarction; N/A, not applicable; NNT, number needed to treat; NS, not significant; NYHA, New York Heart Association; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio; PAD, peripheral artery disease; PTA, percutaneous transluminal angioplasty; pt, patient; PVD, peripheral vascular disease; RCT, randomized controlled trial; RR, relative risk; and TLR, target lesion revascularization.  American Heart Association, Inc. and American College of Cardiology Foundation Evidence Record review with median follow 3.2 y 1 endpoint: During 3 y of follow-up, 50 events (20%) occurred in the DAPT group vs. 59 (29%) in the ASA monotherapy group. After propensity weighting, DAPT use was associated with a decreased risk of MACEs (adjusted HR: 0.65; 95% CI: 0.44-0.96) and overall mortality (adjusted HR: 0.55; 95% CI: 0.35-0.89). No association was found between DAPT use and the risk of major amputation (adjusted HR: 0.69; 95% CI: 0.37-1.29). In a subgroup of 94 pts who underwent point-of-care platelet function testing, 21% had decreased response to ASA and 55% had a decreased response to clopidogrel. No association was found between a reduced response to ASA or clopidogrel and adverse events at 1 y. N/A ALI indicates acute limb ischemia; ASA, acetylsalicylic acid; CI, confidence interval; CLI, critical limb ischemia; DAPT, dual antiplatelet therapy; HR, hazard ratio; MACE, major adverse cardiac event; PAD, peripheral artery disease; and pt, patient. 145 pts met criteria for the mITT population and 120 pts for the per-protocol population. 74 Lcarnitine/71 placebo.

## Evidence
In the mITT (n=145), the mean ln ratio in PWT was 0.241 for cilostazol/l-carnitine vs. 0.134 for cilostazol/placebo (p=0.076), corresponding to mean increases of 1.99 and 1.36 min, respectively. In the per-protocol population (n=120), the mean ln ratio in PWT was 0.267 for cilostazol/l-carnitine vs. 0.145 for cilostazol/placebo (p=0.048).
The per-protocol population, the mean ln ratio in PWT was significantly increased in the cilostazol/l-carnitine group vs. the cilostazol/placebo group (0.267 vs. 0.145, respectively; p=0.048). This represented an arithmetic mean increase in PWT of 39.2% from baseline to d 180 for cilostazol/lcarnitine, as compared to 21.5% for cilostazol/placebo.  American Heart Association, Inc. and American College of Cardiology Foundation combination. The cilostazol group also had a significantly higher eventfree survival at 12 mo (83% vs. 71%, p=0.02), although cardiovascular event rates were similar in both groups.
ABI indicates ankle-brachial index; ACD, absolute claudication distance; CI, confidence interval; HR, hazard ratio; IC, intermittent claudication; ICD, initial claudication distance; ITT, intent-to-treat; LE, lower extremity; mITT, modified intent-to-treat; MWD, maximal walking distance; PAD, peripheral artery disease; PFWD, pain free walking distance; PTA, percutaneous transluminal angioplasty; PVD, peripheral vascular disease; PVI, peripheral vascular intervention; PWT, peak walking time; RCT, randomized controlled trial; and PTFE, polytetrafluoroethylene; pt, patient; QoL, quality of life; RCT, randomized controlled trial; RR, relative risk; and WMD, walking maximal distance. Comparator: Titled PFT. The PFT walked until initial onset of pain, stopped to rest, and then resumed walking following the same pattern as the MT group.

## Evidence
1 endpoint: Post-training MWD was prolonged by 100% (p<0.001) vs. 98% (p<0.001), and PFWT by 120% (p<0.001) vs. 93% (p<0.001) in the MT group as compared to the PFT, respectively.
Endothelial function assessed by flow-mediated dilation increased by 56% (p<0.001) in the MT group and by 36% (p<0.01) in the PFT group.
Safety endpoint: Not specified. Among 8 dropouts/withdrawal, none were reported as being related to SET in either group.
 No significant changes in the levels of hs-CRP and fibrinogen were seen after SET in either group. The smoking status and BMI did not change significantly after the program in both groups (p>0.05).

## Cetac

## Fakhry f, et al. 2013 (194) 23842830
Aim: Compare the long-term clinical effectiveness of a SET-first or an ERfirst treatment strategy in pts with IC.

## Study type: rct

## Size: n=151 pts
Inclusion criteria: Stable IC with iliac and femoropopliteal disease.

## Exclusion criteria: n/a
Intervention: 24 wk of supervised TM exercise, 30 min, 2 d/wk, and 3 d/wk walk at home.
Comparator: Endovascular revascularization with initial angioplasty and stenting as needed 1 endpoint: After 7 y, functional performance consisting of maximal walking distance and pain free walking distance (p<0.001) and QoL (p0.005) had improved after both SET and ER. Long-term comparison showed no differences between the two treatments. Except in the secondary intervention rate, which was significantly higher after SET (p=0.001). Yet, the total number of endovascular and surgical interventions  The portion of pts not needing secondary intervention rate, was significantly lower after SET, 47% vs. 73% with ER (p=0.001). Yet, the total number of endovascular and surgical interventions (primary and secondary) remained higher after ER, 21 pts (7%) withdrew, of whom 8 were in the SET group, 3 were in the PTA group, and 10 were in the combined group. 11 pts who had PTA had restenosis but none required revascularization. Intervention: Combination therapy of ER + SET. For ER, a stent was used only if the initial balloon angioplasty was not successful. SET was started 2-4 wk after ER. SET consisted primarily of intermittent bouts of treadmill walking to nearmaximum claudication pain. Frequency of 2-3 sessions for 30-45 min for initial 3 mo followed by at least 1 session per wk between mo 3-6 and then 1 session per 4 wk until 1 y.

## Erase
1 endpoint: After 1 y, MWD increased in both groups (p<0.001) with a greater improvement in the combined therapy group (p<0.001) Safety endpoint: See secondary outcomes. No study specific AE's discussed.
 After 1 y, PFWD increased in both groups (p<0.001) with a greater improvement in the combined therapy groups (p<0.001). Similarly, ABI at rest and after exercise showed significantly greater improvement in the combination therapy group. Also, measures of healthrelated QoL improved in both groups with greater improvements with combined therapy.
 A higher proportion of pts without an additional intervention in the combination group (92%) vs. the SET alone (77%), HR: 3.2; 95% CI: 1. were reviewed by study staff, and feedback was given to guide subsequent exercise sessions.
Comparator: Supervised exercise while wearing step activity monitor following similar workout protocol as home-based group. There was also an attentioncontrol, light resistance exercise group that did not walk but performed various resistance exercise. These pts also wore a step monitor to quantify time of their visits.
walking parameters from baseline. The change for PWT in the supervised exercise group was greater than the homebased group (p<0.05).
Safety endpoint: Not specified. 1 stroke and 1 MI in attention control group; 1 stroke in supervised exercise group; 1 leg revascularization in home-based walking group.
improvements from baseline in LAEI, and hs-CRP (p<0.05). Safety endpoint: N/A ABI indicates ankle-brachial index; ACC, Journal of American College of Cardiology; BMI, body mass index; CABG, coronary artery bypass graft; CI, confidence interval; CLI, critical limb ischemia; COT, claudication onset time; CV, cardiovascular; CVD, cardiovascular disease; ER, endovascular revascularization; HR: hazard ratio; HBP, high blood pressure; HR, hazard ratio; hs-CRP, high-sensitivity C-reactive Protein; IC, intermittent claudication; JAMA, Journal of American Medical Association; LAEI, large artery elasticity; LDL, low density lipoproteins; LE, lower extremity; METs, metabolic equivalent; MI, myocardial infarction; MWD, maximal walking distance; N/A, not applicable; OMC, optimal medical care; OR, odds ratio; PAD, periphery artery disease; PAQ, personal attributes questionnaire; PFT, pain free time; PFWD, pain free walking distance; PFWT, pain free walking time; PWT, peak walking time; QoL, quality of life; RCT, randomized controlled trial; RR, relative risk; RPE, ratings of perceived exertions; SBP, systolic blood pressure; SE, supervised exercise; SET, supervised exercise training; SOB, shortness of breath; StO2, tissue oxygen saturation; ST, stent revascularization; TM, treadmill; and WIQ, walking impairment questionnaire.  Sensitivity, specificity, and concordance probability of each sign as compared to microbial load (reference standard),  Sensitivity, specificity, and concordance probability of the IDSA combination of signs as compared to microbial load, and  discriminatory accuracy of a composite predictor computed from the classic and signs specific to secondary wounds as compared to microbial load.  No difference between groups  The immediate technical success rate in the PTA group was 91%; the rate was higher in the stent group (96%), but the difference was not statistically significant . Complication and mortality rates were not statistically significantly different. Analyzed data included technical failures and were adjusted for lesion type and disease severity. 4 y primary patency rates were 65% for stenoses vs. 54% for occlusions after PTA to treat claudication and were 53% for stenoses vs. 44% for occlusions after PTA to treat critical ischemia. These rates were 77% for stenoses vs. 61% for occlusions after stent placement to treat claudication and 67% for stenoses vs. 53% for occlusions after stent placement to treat critical ischemia. The risk of long-term failure was reduced by 39% after stent placement compared with PTA.  No significant difference  The average treated lesion measured 188 cm in length, and 58.8% of lesions displayed segmental or complete occlusion. At 3 y, primary patency rates (defined by peak systolic velocity ratio 2.0 and no TL revascularization) did not significantly  American Heart Association, Inc. and American College of Cardiology Foundation Exclusion criteria: Occluded popliteal artery of <1 infrapop artery patent to the ankle differ between pts treated with the VIABAHN stent graft and those who received a bare nitinol stent (24.2% vs. 25.9%; p=0.392). Stent fractures were significantly more common in bare nitinol stents (50.0%) than in the VIABAHN endoprostheses (2.6%). Primary-assisted patency rates were higher in those receiving bare nitinol stents than the VIABAHN stent graft (88.8% vs. 69.8%; p=0.04), although secondary patency rates did not differ between bare nitinol stent and stent graft recipients (89.3% vs. 79.5%; p=0.304). There were no instances of procedure-related mortality or amputation. The hemodynamic improvement and quality measures improved equally in both groups.  Viabahn superior to PTA alone  The stent-graft group had a significantly higher technical success rate (95% vs. 66%, p<0.0001) and 1 y primary vessel patency rate at duplex ultrasonography (65% vs. 40%, p=0.0003). A patency benefit was seen for lesions at least 3 cm long. At 12 mo, chronic limb ischemia status was 15% further improved for the stent-graft group (p=0.003). There were no significant differences between treatment groups with regard to the occurrence of early or late major adverse events.  DCB superior  The mean (SD) age of the pts was 688 y, 24% were smokers, and 49% had DM. 27% of the lesions were total occlusions, and 36% were restenotic lesions. The mean lesion length was 7.46.5 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 mo, the mean late lumen loss was 1.71.8 mm in the control group, as compared with 0.41.2 mm (p<0.001) in the group treated with paclitaxel-coated balloons and 2.21.6 mm (p=0.11) in the group treated with paclitaxel in the contrast medium. The rate of revascularization of TLs at 6 mo 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 mo, the rates increased to 28 of 54 (52%), 7 of 48 (15%), and 21 of 52 (40%)  American Heart Association, Inc. and American College of Cardiology Foundation

## Evidence

# Results

## Excite isr

## Intervention: cryoplasty pta
Comparator: PTA 1 endpoint: 12 mo binary restenosis  Post-dilation with cryoplasty balloon reduced binary restenosis compared to conventional balloon angioplasty  74 pts, with 90 stented superficial femoral artery lesions, were randomly assigned to post-dilation using cryoplasty (n=45 lesions) or conventional balloons (n=45 lesions). Mean lesion length was 14898 mm, mean stented length was 190116 mm, mean stent diameter was 6.10.4 mm, and  American Heart Association, Inc. and American College of Cardiology Foundation Exclusion criteria:  Allergic to ASA, clopidogrel, or iodine-based radiographic contrast  Had obstructive (50% diameter stenosis) iliofemoral artery disease  Absence 1 vessel infrapopliteal run-off. All pts had radio-opaque tape in the imaging field as a reference for determining vessel dimensions.
50% of the lesions were total occlusions. Postdilation balloon diameters were 5.230.51 mm vs. 5.510.72 mm in the cryoplasty and conventional balloon angioplasty groups, respectively (p=0.02). At 12 mo, binary restenosis was significantly lower in the cryoplasty group (29.3% vs. Endo costs more than exercise program when adjusted for QALY however this study had no difference between QoL at 12 mo  American Heart Association, Inc. and American College of Cardiology Foundation and some TASC type B and/or C lesions, such as a unilateral external iliac occlusion that involved the origins of the internal iliac and/or common femoral artery or single or multiple femoral popliteal lesions in the absence of continuous tibial vessels to improve inflow for a distal bypass procedure)  Prior treatment for the lesion (including exercise training)  Sustained improvement at 1 y in 74.3% of the pts treated with primary stenting and in 68.6% of the pts treated with PTA and bailout stenting (p>0.05).  Freedom from TLR (76.6% and 77.6%), mortality (7.4% vs 2.1%), and amputation [8.9% (major 6.7%) vs 13.2% (major 8.7%)] at 1 y were not significantly different.  Primary self-expanding nitinol stenting did not show statistically different clinical outcomes compared to PTA with bailout stenting AAA indicates abdominal aortic aneurysm; ABF, aorto-bifemoral bypass; ABI, ankle-brachial index; ABPI, ankle-brachia pressure index; AFB, aortobifemoral bypass; AIOD, aortoiliac occlusive disease; ALI, acute limb ischemia; ASA, American Society of Anesthesiologist; AUC, appropriate use criteria; AWD, absolute walking distance; BMS, bare metal stent; BP, blood pressure; CI, confidence interval; CLI, critical limb ischemia; CTA, computed tomography angiography; DCB, drug coated balloon; DEB, drug eluting balloon; DES, drug eluting stent; DS,  American Heart Association, Inc. and American College of Cardiology Foundation diameter stenosis; ECG, electrocardiogram; ELA, excimer laser antherectomy; HR, hazard ratio; IC, intermittent claudication; ICD, International Classification of Disease; Inv, intervention group; ISR, in stent restenosis; ITT, intention to treat; JACC, Journal of American College of Cardiology; LE, lower extremity; MACE, major adverse cardiac event; MWD, maximal walking distance; MWP, mean walking performance; N/A, not applicable; NEJM, New England Journal of Medicine; NHP, Nottingham Health Score; NYHA, New York Heart Association; OR, odds ratio; OMT, osteopathic manipulative treatment; PAD, periphery artery disease; PEB, paclitaxel eluting balloon; PFWD, pain free walking distance; PTA, percutaneous angioplasty; PTAS, percutaneous angioplasty stent; PVD, peripheral vascular disease; QALY, quality adjusted life year; QoL, quality of life; RCT, randomized controlled trail; R/PTAS, recanalization, percutaneous transluminal angioplasty, and stenting; RR, relative risk; SE, supervised exercise; SEP, supervised exercise; SES, self-expanding stents; SFA, superficial femoral artery, ST stent revascularization; TASC, transatlantic inter-society consensus; TL, target lesion; TLR, total lesion revascularization; TPP, treatment per-protocol; TVR, target vessel revascularization; and VIA, viabahn treatment. p=0.0051) and mean stent diameter  Stent diameter predicts restenosis  Mean age was 729 y and 31% were female pts. In total, 58% of the pts had DM and 25% were pts with CLI. Occluded length was 19489 mm, mean total stent length was 1987 mm, and mean stent diameter was 7.10.9 mm. 5 y primary and secondary patency rates were 51.8% and 79.5%, respectively, and the rates of freedom from bypass surgery, major or minor  American Heart Association, Inc. and American College of Cardiology Foundation Results: More complications in pts with occluded arteries compared to stenosed arteries; more bleeding complications in women; pts with CLI had higher mortality compared to claudication; mortality was driven by CAD and cerebrovascular disease Limitation is that this is a single center retrospective analysis ABI indicates ankle-brachial index; ALI, acute limb ischemia; CAD, coronary artery disease; CI, confidence interval; CLI, critical limb ischemia; CTO, chronic total occlusion; HF, heart failure; HR, hazard ratio; IC, intermittent claudication; ICD, International Classification of Diseases; JACC, Journal of American College of Cardiology; LE, lower extremity; MACE, major adverse cardiac event; OR, odds ratio; PAD, periphery artery disease; PTA, percutaneous angioplasty; PTAS, percutaneous angioplasty stent; pt, patient; QoL, quality of life; RR, relative risk; SES, self-expanding stents; SFA, superficial femoral artery; and TASC, Trans-Atlantic Inter-Society Consensus. Intervention: AK femoro-popliteal bypass grafts were randomly allocated to either an ePTFE (n Z 114) or a Dacron (n Z 114) vascular graft Comparator: N/A 1 endpoint: After 5 y, the primary, primary assisted and secondary patency rates were 36% (95% CI: 26%-46%), 46% (CI: 36%-56%) and 51% (95% CI: 41%-61%) for ePTFE and 52% (95% CI: 42%-62%; p=0.04), 66% (95% CI: 56%-76%; p=0.01) and 70% (95% CI: 60-80%; p=0.01) for Dacron, respectively. After 10 y these rates were respectively 28% (95% CI: 18%-38%), 31% (95% CI:19%-43%) and 35% (95% CI: 23%-47%) for ePTFE and 28% (95% CI: 18%-38%), 49% (95% CI: 37%-61%) and 49% (95% CI: 37%-61%) for Dacron. 1 endpoint: 2 y primary patency rates for Dacron and PTFE were 70% and 57% (p=0.02), whereas the secondary patency rates were 76% and 65% (p=0.04), respectively. Primary patency at 2 y was significantly influenced by the number of patent crural vessels (2 or 3 67%, 1 50%, p=0.01). At 2 y, pts treated for CLI had a major amputation more often than pts operated on for IC, 10 and 3 respectively (p=0.003), and had higher mortality rates, 20% and 8% respectively (p=0.001).

## Evidence

## Evidence

## N/a

## Revas
 Medical therapy was not standardized  Amputations at 2 y, (major in 4% and minor in 3%), 30 d mortality and complications (wound infections: 3% and other wound complications: 13%) occurred equally frequent in both groups.  American Heart Association, Inc. and American College of Cardiology Foundation trail; RE, remote endarterectomy; R/PTAS, percutaneous transluminal angioplasty, and stenting; RR-relative risk; RSFAE, remote superficial artery endarterectomy; SA-RIEA, stent assisted remote iliac endarterectomy; SFA, superficial femoral artery; SIA, subintimal angioplasty; SV, saphenous vein; TASC, transatlantic inter-society consensus; and TL, target lesion. High level evidence demonstrating the superiority of one method over the other is lacking. An endovascular first approach may be advisable in pts with significant comorbidity, whereas for fit pts with a longer term perspective a bypass procedure may be offered as a first line interventional treatment. 

## Evidence

# Results:
 Cumulative 5 y primary patencies for groups A and group B were 96% and 92%, respectively.  Secondary patency was 100% at both time points. Limb salvage was also lower in pts with RC 5 and 6 (p=0.01; p=0.02).  Overall survival was 93% at 1 y and 77% at 5 y. There was no difference in survival between the 2 groups.
 Predictors for distal revascularization were RC 5 or 6 (p<0.001), TASC D lesions (p<0.0001), DM (p=0.04), and being on anticoagulation (p=0.003). Results: Mortality and amputation rates did not differ significantly between bypass surgery and PTA; primary patency was significantly higher in the bypass group after 12 mo (OR: 1.6; 95% CI: 1.0-2.6) but not after 4 y (p=0.14). Blood flow restoration was significantly greater in bypass than in thromboendarterectomy pts (Peto OR: 9.2; 95% CI: 1.7-50.6); mortality and amputation rates did not differ. Bypass surgery outcomes did not differ significantly from exercise or spinal cord stimulation.

## 1 endpoint: pooled primary graft patency
Results: For claudication-specific meta-analysis, pooled primary graft patency was 57.4% for aboveknee polytetrafluoroethylene, 77.2% for above-knee vein, and 64.8% for below-knee vein at 5 y; there was a significant difference between above-knee grafts at 3, 4, and 5 y (p<0.05). The corresponding pooled secondary graft patency was 73.2%, 80.1%, and 79.7%, respectively (p>0.05).
The great saphenous vein performs better than polytetrafluoroethylene in femoropopliteal bypass grafting and should be used whenever possible.  PEB+BMS is superior to PTA+BMS  Mean lesion length was 9460 vs. 9669 mm in the PEB+BMS and PTA+BMS groups (p=0.8), respectively. The primary endpoint occurred in 9 (17%) vs. 26 (47.3%) of lesions in the PEB+BMS and PTA+BMS groups  American Heart Association, Inc. and American College of Cardiology Foundation Size: n=104 pts  Contraindication for combined antiplatelet therapy  Known allergy to nickel or paclitaxel  Need for major amputation at the time of enrollment  Failure to recanalize intended belowthe-knee arteries in CLI pts at risk of major amputation was also considered an exclusion criterion (p=0.008), respectively. A near-significant (p=0.07) 1-y freedom from target lesion revascularization advantage was observed in the PEB+BMS group. No major amputation occurred. No significant difference was observed according to lesion characteristics or technical approach. Inclusion criteria: CLI due to infrapop PAD Exclusion criteria:  Lesion and/or occlusions located in or extending to the popliteal artery or below the ankle joint space  Inflow lesion or occlusion in the ipsilateral iliac, SFA, or popliteal arteries with length 15 cm  Significant (50% DS) inflow lesion or occlusion in the ipsilateral iliac, SFA, or popliteal arteries left untreated  Failure to obtain <30% residual stenosis in pre-existing, hemodynamically significant (50% DS and <15 cm length) inflow lesions in the ipsilateral iliac, SFA, or popliteal artery  DES and/or DEB was not allowed for the treatment of inflow lesions GFR <30 mL/min except for pts with renal endstage disease on chronic hemodialysis

## In.pact deep

## Intervention: dcb
Comparator: PTA 1 endpoint: Clinically driven target lesion revascularization (CD-TLR) and late lumen loss (LLL).

## Safety endpoint:
The primary safety endpoint through 6 mo was a composite of allcause mortality, major amputation, and CD-TLR.
 Increased amputation with DEB  Clinical characteristics were similar between the 2 groups. Significant baseline differences between the IA-DEB and PTA arms included mean lesion length (10.2 cm vs. 12.9 cm; p=0.002), impaired inflow (40.7% vs. 28.8%; p=0.035), and previous target limb revascularization 2 endpoints:  freedom from TL revascularization, binary restenosis rate, and amputation  5-y follow up period resulted in maintained reduced TL revascularizationrate following PCB treatment. No signs of drug-related local vessel abnormalities were detected.  American Heart Association, Inc. and American College of Cardiology Foundation

## Comparator:
Plain old balloon angioplastic and standard nonionic CM (Control group) ABI indicates ankle-brachial index; AFS, amputation-free surivival; ALI, acute limb ischemia; BMS indicates bare metal stent; CD-TLR, clinically driven target lesion revascularization; CI, confidence interval; CLI, critical limb ischemia; DCB, drug coated balloon; DEB, drug eluting balloon; DES, drug eluting stent; DM, diabetes mellitus; HR, hazard ratio; IA-DEB, apmhiriondrug eluting balloon; IC, intermittent claudication; ISR, in stent restenosis; IQR, interquartile range; JACC, Journal of American College of Cardiology; LLL, late lumen loss; N/A, not applicable; OR, odds ratio; OS, overall survival; PAD, periphery artery disease; PCB, paclitaxel-coated blaoon; PEB, paclitaxel eluting balloon; PTA, percutaneous angioplasty, PTAS, percutaneous angioplasty stent; pt, patient; RCT, randomized controlled trial; RR, relative risk; SES, self-expanding stents; and SFA, superficial femoral artery; and TL, target lesion. Results: Freedom from major amputation at 1816 mo was higher in the angiosome directed group 51%8% vs. 28%8%, p=0.008  AFS higher in angiosome directed endo group  During follow-up (mean, 1816 mo), the overall limb salvage rate was 81% (300 of 369), death occurred in 36% (119 of 329), and the reintervention rate was 31% (114 of 369). After propensity score adjustment, the estimated ( standard error) rates for AFS (49%8% vs. 29%6%; p=0.0002), freedom from MALE (51%8% vs. 28%8%, p=0.008), and major amputation (82%5% vs. 68%5%, p=0.01) were significantly higher in the direct group than in the indirect group for up to 4 y after the index procedure. After multivariable Cox proportional analysis, the independent factors associated with major amputation were hemoglobin A(1c) level (HR: 1.4; 95% CI: 1.1-1.9; p=0.006) and cilostazol administration (HR: 0.28; 95% CI: 0.11-0.70; p=0.006) in the direct group, and C-reactive protein level (HR: 1.2; 95% CI: 1. ). The number of stents per limb was 1.90.9, and 35% of limbs received overlapping DES (length of 6013 mm). There were no procedural deaths, and 96% of pts were discharged within 24 h. The 3 y cumulative incidence of amputation was 62%, survival was 715%, and amputationfree-survival was 685%. Only 12% of pts who died had a preceding major amputation. Rutherford category, age,  American Heart Association, Inc. and American College of Cardiology Foundation creatinine level, and dialysis (p0.001-0.04) were predictors of death but not amputation. Target limb revascularization occurred in 15% of pts, and repeat angiography in 35% of pts revealed a binary restenosis in 12%. 1 endpoint:  Complete healing of the study ulcer (wound)  After 12 wk of treatment, 51 (37.0%) Promogran treated pts had complete wound closure compared with 39 (28.3%) control pts, but this difference was not statistically significant (p=0.12).  The difference in healing between Tx groups achieved borderline significance in the subgroup of pts with wounds of <6 mo duration. In pts with ulcers <6 mo duration, Limitations: Study did not standardize frequency of dressing changes.  American Heart Association, Inc. and American College of Cardiology Foundation necrotic/nonviable tissue at enrollment.

## Evidence

## Exclusion criteria:
 Clinical signs of infection  A target wound that had exposed bone  A concurrent illness or a condition that may have interfered with wound healing, known hypersensitivity to any of the dressing components  Unwillingness or inability of an ambulatory pt to be fitted with appropriate shoe gear or an offloading device  Multiple diabetic ulcers on the same foot.
43 (45%) of 95 Promogran-treated pts healed compared with 29 (33%) of 89 controls (p=0.056). In the group with wounds <6 mo duration, similar numbers of pts healed in the Promogran ; p=0.83) groups. No differences were seen in the safety measurements between groups.
ABI indicates ankle-brachial index; CI, confidence interval; CLI, critical limb ischemia; DM, diabetes mellitus; E2F, egifoligide; FP, femoral popliteal; HgbA1c, hemoglobin A1c; HR, hazard ratio; IC, intermittent claudication; IQR, interquartile range; LE, lower extremity; MALE, major adverse limb event; MALE-POD, major adverse limb event perioperative death; N/A, not applicable; PTA, percutaneous angioplasty; pt, patient; QoL, quality of life; RCT, randomized controlled trial; SFA, superficial femoral artery; TBI, toe-brachial index; and tx, treatment.

## Evidence

# Results:
 Duration of limb ischemia in pts with ALI was associated with much higher rates of first amputation (p= o.0002) and worse amputationfree survival (p=0.037). No significant associations were observed in pts with CLI.  Increased duration of limb ischemia in pts with ALI was associated with progressively increased 30-day ambputation (p=0.028 for trend)  The longer lower extremity symptoms in ALI occur, the less likely the possibility of salvage  Limb ALI episodes are extreamly deadly, even with limb revascularization ALI indicates acute limb ischemia; CI, confidence interval; CFA, common femoral artery; CLI, critical limb; CTA, computed tomography angiography; HR, hazard ratio; LE, lower extremity; MI, myocardial infarction; N/A, not applicable; OR, odds ratio; and RR, relative risk.

## Evidence

# Results:
 No association between the choice of initial treatment, pt characteristics, location of the occlusion, or the class of ischemia, individually or in combination  Combined endpoint of readmission and AFS was significantly lower in the CDT and CDTA groups  The cause of ALI was an occluded native vessel in 115 pts (56.1%) and an occluded bypass graft in 90 (43.9%).  Initial treatment resulted in an overall primary success of 67.3%. 60 pts (29.7%) required a second intervention, 11 (5.4%) required a third intervention, 5 (2.4%) required amputation, and 2 (1%) died ALI indicates acute limb ischemia; AFS, amputation-free survival; ASA, acetylsalicylic Acid; CA, contrast arteriography; CDTA, catheter directed thrombolysis and angioplasty; CDT, catheter directed thrombolysis; CFA, common femoral artery; CI, confidence interval; CLI, critical limb ischemia; CTA, computed tomography angiography; DSA, digital subtraction angiography; DUAM, duplex ultrasound arterial mapping; HR, hazard ratio; MI, myocardial infarction; MRA, magnetic resonance angiography; N/A, not applicable; NEJM, New England Journal of Medicine; NIS, National Inpatient Sample; OR, odds ratio; pt, patient; and RR, relative risk.. Nonrandomized Trials, Observational Studies, and/or Registries of Diagnostic Evaluation of the Cause of ALI-Section 9.2.2.

## Evidence
(There is no literature specifically addressing the diagnostic work up for the cause of ALI. This large single-center series does give etiologies. Echocardiography and telemetry seem reasonable for those without underlying PAD. Focused evaluation for hypercoagulable state seems reasonable in those with native artery thrombosis.