A systematic review of treatment of intermittent claudication in the ...

A systematic review of treatment of intermittent claudication in the lower extremities Rafael D. Malgor, MD,a,b Fares Alalahdab, MD,a Tarig A. Elraiyah, MBBS,a Adnan Z. Rizvi, MD,c Melanie A. Lane, BA,a Larry J. Prokop, MLS,a Olivia J. Phung, PharmD,d Wigdan Farah, MBBS,a Victor M. Montori, MD, MSc,a,e Michael S. Conte, MD,f and Mohammad Hassan Murad, MD, MPH,a,g Rochester and Minneapolis, Minn; Tulsa, Okla; and Pomona and San Francisco, Calif Background: Peripheral arterial disease is common and is associated with significant morbidity and mortality. Methods: We conducted a systematic review to identify randomized trials and systematic reviews of patients with intermittent claudication to evaluate surgery, endovascular therapy, and exercise therapy. Outcomes of interest were death, amputation, walking distance, quality of life, measures of blood flow, and cost. Results: We included eight systematic reviews and 12 trials enrolling 1548 patients. Data on mortality and amputation and on cost-effectiveness were sparse. Compared with medical management, each of the three treatments (surgery, endovascular therapy, and exercise therapy) was associated with improved walking distance, claudication symptoms, and quality of life (high-quality evidence). Evidence supporting superiority of one of the three approaches was limited. However, blood flow parameters improved faster and better with both forms of revascularization compared with exercise or medical management (low- to moderate-quality evidence). Compared with endovascular therapy, open surgery may be associated with longer length of hospital stay and higher complication rate but resulted in more durable patency (moderate-quality evidence). Conclusions: In patients with claudication, open surgery, endovascular therapy, and exercise therapy were superior to medical management in terms of walking distance and claudication. Choice of therapy should rely on patients’ values and preferences, clinical context, and availability of operative expertise. (J Vasc Surg 2015;61:54S-73S.)

Peripheral arterial disease (PAD) remains a serious public health issue in the population older than 40 years in the United States.1 After the flow-limiting atherosclerotic plaque is established, claudication impairs walking distance and quality of life. Current care includes lifestyle modification (exercise2 and smoking cessation3), medical therapy (antiplatelet agents such as aspirin or clopidogrel, cilostazol, lipid-lowering drugs, and adequate blood pressure control), and revascularization (surgical or endovascular). In addition to their potential impact on outcomes in patients with PAD, lifestyle interventions and medical treatments are also recommended as they can effectively reduce cardiovascular morbidity and mortality in at-risk patients.

From the Knowledge and Evaluation Research Unit, Department of Medicine,a Division of Endocrinology,e and Division of Preventive, Occupational and Aerospace Medicine,g Mayo Clinic, Rochester; the Division of Vascular Surgery, University of Oklahoma, Tulsab; the Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Vascular and Endovascular Surgery, Minneapolisc; the College of Pharmacy, Western University of Health Sciences, Pomonad; and the Division of Vascular and Endovascular Surgery, University of California, San Francisco.f This study was funded by the Society for Vascular Surgery. Author conflict of interest: none. Reprint requests: Mohammad Hassan Murad, MD, MPH, Professor, Mayo Clinic, Program Director, Preventive Medicine Fellowship, Knowledge and Evaluation Research Unit, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2015 by the Society for Vascular Surgery. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jvs.2014.12.007

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The relative effectiveness of the available treatments for patients with intermittent claudication (IC), such as exercise therapy and revascularization (either by surgical bypass or endovascular interventions), is not well established. Studies of supervised exercise for people with IC have yielded inconsistent results.2,4,5 Revascularization treats hemodynamically significant arterial lesions, increasing the blood flow to distal segments that are underperfused and improving pain-free walking distance. Endovascular therapy has evolved during the past 20 years, gaining popularity as a safe, minimally invasive, and feasible option.6 Early promising results of endovascular interventions compared with exercise therapy have been questioned by randomized trials showing lower durability and increased costs with endovascular procedures.7-9 Conversely, surgical bypass in people with claudication leads to immediate and sustained improvement with higher success rates compared with exercise therapy but with greater morbidity and mortality.5 Last, although claudication is often caused by multilevel arterial occlusive disease of the lower extremity,10 worse outcomes have been reported for endovascular interventions performed in the femoropopliteal region than in the aortoiliac segment.11 The Society for Vascular Surgery (SVS) and its member surgeons have been major advocates of promoting prevention and treatment strategies for PAD. In this endeavor, a committee of experts in PAD treatment commissioned the conduct of this systematic review to evaluate the available modalities and their efficacy for the treatment of patients with claudication. This study will aid in the development of clinical practice guidelines

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by the Society to guide patients and surgeons in the decision-making process. METHODS This systematic review is conducted following recommendations from the Cochrane Collaboration12 and is reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.13 The lower extremity revascularization committee of the SVS approved the protocol of this review. Study eligibility. Studies were eligible for this review if they were (1) randomized trials or systematic reviews; (2) enrolled patients with claudication (ie, symptomatic patients with peripheral vascular disease who had exertional pain with walking); (3) evaluated open bypass, endovascular revascularization, or exercise therapy; and (4) measured the outcomes of interest. Trials exclusively enrolling patients with critical limb ischemia (CLI), defined as rest pain or tissue loss, were excluded. For each comparison of interest, evidence was derived from a credible systematic review if it existed; if not, individual studies were evaluated. The primary outcomes of interest were mortality, amputation, and quality of life, which are patientimportant outcomes14 and are considered to be critical and most relevant for the development of clinical practice guidelines. These outcomes are rare in claudicants, however; therefore, we included other outcomes, such as walking distance, measures of flow (ie, ankle-brachial index [ABI]), patency, cost, and health care utilization data. Search strategy. Exploratory search revealed six existing well-conducted published systematic reviews that searched multiple electronic bibliographic databases between 2005 and 2011. Watson et al15 compared exercise vs control; Spronk et al16 compared exercise vs angioplasty; Fowkes and Gillespie17 compared conservative treatment vs angioplasty; Fowkes and Leng18 compared bypass vs angioplasty; Bachoo et al19 compared angioplasty vs all other treatments; and Murphy et al20 compared optimal medical care (OMC) vs OMC þ supervised exercise vs OMC þ stent revascularization. We updated these search strategies through June 2014. The details of the search strategies are in the Appendix. Data extraction and analysis. Teams of reviewers working in duplicates reviewed abstracts and full-text articles and extracted descriptive, methodologic quality, and outcome data. Article review and data extraction were done using online systematic review software (DistillerSR, Ottawa, Ontario, Canada). Online electronic data extraction forms were piloted, then used. Chance-adjusted interreviewer agreement averaged 0.80. Mixed treatment meta-analysis was planned but was later deemed not feasible because of the small number of trials included in each comparison in addition to the heterogeneity of trial populations. Descriptive narrative of the results is presented. Continuous variables were reported as mean, median, and standard-deviation, and categorical variables were reported as percentages.

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RESULTS The original search in 2011 identified 853 references and the update in 2014 identified 207 additional ones. We excluded 1041 citations for being duplicates of included studies, having no original data, or having an irrelevant population (majority of patients with CLI). After screening abstracts and full-text references, we finally included 8 systematic reviews (3 Cochrane systematic reviews of randomized trials on exercise therapy,21-23 2 systematic reviews that compared supervised exercise with endovascular therapy,24,25 and 3 systematic reviews of nonrandomized surgical case series26-28) and 12 trials evaluating endovascular or open surgical approaches. The characteristics of the included trials are described in Table I, and the quality of these trials is described in Table II. Overall, the quality was fair (about 50% of the trials concealed allocation, loss to follow-up varied from 0% to 13% with a median of 6%, and with no significant imbalances at baseline in most studies). There was no study that was stopped early for benefit, an action that is usually associated with large effect sizes.29 The included trials enrolled a total of 1548 patients with a median sample size of 84 (range, 36-264). The average age was 65 years, 70% of patients were males, 18% had diabetes, and 67% had history of smoking. The median length of follow-up was 15 months (range, 6-84). Mortality and amputation events were rare. Overall death rate was 4% in the control groups, 6% in the supervised exercise groups, 23% in the angioplasty groups, and 22% in the surgery groups. The majority of death rates reported were based on either 1- or 2-year follow-up data, and only one study reported mortality rate obtained throughout a 6-year period. Two studies reported amputation rates in patients with claudication. Wolf et al30 found amputation rate at 30-day follow-up to be 1% (2 of 133) and 0% (0 of 130) in patients who underwent percutaneous transluminal angioplasty (PTA) and surgery, respectively. Gelin et al,5 analyzing 1-year follow-up data on 264 patients, reported 2% (2 of 89), 1% (1 of 89), and 0% (0 of 88) amputation rate for control, surgery, and exercise treatment groups, respectively. The small size of the trials indicates that randomization has likely failed to achieve prognostic balance between the two study arms. Comparative effectiveness inference is quite limited. Low mortality rate, scarce long-term follow-up data, and different medical treatment regimens used in the included literature make inferences difficult as to whether medical treatment or exercise plus medical treatment decreases long-term mortality rates. Thus, mortality in patients with claudication is likely related to cardiovascular events and not necessarily attributable to the interventions.31 Table III summarizes the rates and follow-up intervals of these events across trial arms. The Fig depicts a summary of the results of this systematic review with the quality of evidence for each comparison. A narrative with the rationale for these results is presented thereafter.

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Table I. Characteristics of included trials Study, year Creasy,33 1990

Gelin,5,40 2001

Greenhalgh,34 2008

Hobbs,35 2006

Lundgren,32 1989

Murphy,20 2012

Nylaende,6 2007 Perkins,36 1996 Spronk,7,8,37 2009

Whyman,9 1997

Wolf,30 1993

Population description

Interventions

Total sample Follow-up, Age, Female, DM, Smokers, FD, size months years % % % %

Elderly, symptomatic Wire and angioplasty 36 (IC), and other risk balloon catheter factors presenting technique to the Oxford Supervised exercise Regional Vascular (30 minutes of Service walking, bicycling, twice weekly for 6 months) Elderly patients with Endovascular 264 IC Open surgery Supervised exercise program Observation group Elderly patients with PTA of femoral or iliac 93 stable mild to stenosis þ supervised moderate IC exercise þ best medical therapy Supervised exercise þ best medical therapy Elderly with IC PTA þ medical 23 with different risk treatment factors for PAD Supervised exercise (12-week course of twice weekly 1-hour exercise sessions) þ medical treatment Medical treatment Patients between Surgery 75 40 and 80 years Surgery þ exercise of age with IC program Exercise alone

9-10

62.9

25

12

66.6

24

Other risk factors (%)

5.5

63.8

28

34.3

16.3

51.3

NR NR

64.7

36.2

NR

85

73.3 AO (26.7), CAD (33)

6

67

30.4

43.4

91.3

100 NR

13

64

21

93

45

Elderly patients with OMC 111 6 IC seen in multiple OMC þ supervised centers exercise OMC þ stenting revascularization Elderly patients with PTA þ medical 56 24 IC treatment Medical therapy alone Elderly patients with Balloon angioplasty 56 70-74 IC Supervised exercise program Elderly patients with Endovascular 151 12 IC seen in a large revascularization community hospital Hospital-based exercise (treadmill walking for 30 minutes twice weekly) Men and women PTA þ medical 62 24 with claudication, treatment (aspirin, no prior intervention advice on smoking cessation and exercise) Medical treatment alone Elderly men with Surgical bypass 263 48 symptomatic PAD Balloon angioplasty

64

38.7

21.3

53.8

Angina (25), MI (19), HTN (31), CHF (7), TIA (3), AO (55) NR AO (100)

68.5

44.6

17.5

69.6

NR CAD (12)

8

AO (17), HTN (36)

NR NR

NR NR

50

AO (50)

65.5

46.7

17.3

67.3

29

AO (71), CRF (3), Lip (69)

61.6

17.7

8

50

76

AO (24)

61.5

0

22.4

78.3

55.2 AO (44.8), MI (15.6), angina (17.1), CHF (4.6), stroke (10.3), alcoholism (14.1) (Continued on next page)


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Table I. Continued. Study, year Mazari,42 2012

Nordanstig,41 2014

Population description Symptomatic unilateral IC Femoropopliteal lesion amenable to angioplasty Stable ($6 months) IC symptoms, without any other important activity-limiting medical condition and an age #80 years

Interventions

Total sample Follow-up, Age, Female, DM, Smokers, FD, size months years % % % %

Other risk factors (%)

Angioplasty Supervised exercise Combined

178

12

70

29

14

31

100 HTN (40)

Invasive strategy (endovascular or open) Medical management

158

12

68

47

19

63

58

MI (14), angina (11)

AO, Aortoiliac disease; CAD, coronary artery disease; CHF, congestive heart failure; CRF, chronic renal failure; DM, diabetes mellitus; FD, femoropopliteal disease; HTN, hypertension; IC, intermittent claudication; Lip, hyperlipidemia; MI, myocardial infarction; NR, not reported; OMC, optimal medical care; PAD, peripheral arterial disease; PTA, percutaneous transluminal angioplasty; TIA, transient ischemic attack.

Table II. Risk of bias of included trials

Study, year Creasy,33 1990 Gelin,5,40 2001 Greenhalgh,34 2008 Hobbs,35 2006 Lundgren,32 1989 Murphy,20 2012 Nylaende,6 2007 Perkins,36 1996 Spronk,7,8,37 2009 Whyman,9 1997 Wolf,30 1993 Mazari,42 2012 Nordanstig,41 2014

Blinding of outcome assessors/data analysts

Allocation concealment

No No Outcome assessors No NR Observer blinded NR NR Outcome assessors, data analysts NR NR NR No

No Yes Probably No Probably Yes Probably NR Probably

yes no yes yes

NR NR NR Yes

Did authors report any imbalances at baseline?

Lost to follow-up, %

Funding

No No No No No No No No No

NR 5.7 5.5 NR 13.3 2.7 8.9 NR 1.3

Not-for-profit Not-for-profit Includes a for-profit Not-for-profit Not-for-profit Unclear Includes a for-profit Unclear Not-for-profit

No No No No

3.2 7.3 8 NR

Unclear Includes a for-profit Not-for-profit Not-for-profit

NR, Not reported.

Exercise therapy We identified three Cochrane systematic reviews21-23 that evaluated the effect of exercise programs in patients with IC. The first review compared exercise programs with placebo or usual care and demonstrated high-quality evidence supporting benefit of exercise on walking performance parameters. However, data on amputation and mortality were limited because these events are rare in claudicants and there was no effect on ABI.21 Similarly, the second review compared supervised exercise therapy with unsupervised exercise and showed high-quality evidence favoring supervised exercise on walking performance.23 Table IV presents the details of these two reviews that summarized 36 trials. A third systematic review attempted to answer the question of which mode of supervised exercise is most effective. However, data comparing cycling, strength training, and upper arm

ergometry were very imprecise (only 136 patients enrolled in 5 trials).22 Revascularization Randomized controlled trials (RCTs) comparing surgery with medical management or exercise. Lundgren et al32 demonstrated that maximum and symptomfree walking distances improved the most in patients randomized to surgery with an added physical training program, then in patients receiving surgery alone, then in the exercise-alone group. ABI and hallux pressure improved significantly in patients randomized to surgery with an added physical training program or to surgery alone, but not in the exercise-alone group. RCTs comparing endovascular approaches with medical management or exercise. Creasy et al33 showed that exercise therapy compared with PTA led to better


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Table III. Death and amputation reported in trials Trial arm Gelin,5 2001 Greenhalgh,34 2008 6

Nylaende, 2007 Perkins,36 1996 7,8,37

Spronk,

2009

Whyman,9 1997 Wolf,30 1993

Treatment

Sample size

Death

Amputation

Control Surgery Exercise therapy Angioplasty Exercise therapy Control Angioplasty Angioplasty Exercise therapy Angioplasty Angioplasty Exercise therapy Control Angioplasty Angioplasty Surgery

89 87 88 67 60 28 28 30 26 75 75 75 32 30 133 130

4 5 5 3 4 0 1 4 6 5 5 3 2 0 31 42

2 1 0

mean claudicating distance. The PTA group had initial improvement in this distance at 3 months without subsequent improvement, whereas the exercise group had progressive improvements through a follow-up of 15 months. The PTA group had higher mean ABI. The MIMIC trial (adjuvant benefit of angioplasty in patients with mild to moderate IC)34 compared PTA vs no PTA in patients already receiving supervised exercise and best medical therapy and followed them up for 24 months. The PTA group had higher adjusted absolute walking distance and ABI but not quality of life. Nylaende et al6 showed that early intervention with PTA and medical management seems to be superior to medical management alone in terms of improvements in the minimal and pain-free walking distances and perception of pain in the patients’ primary symptomatic leg just before they had to stop when walking as measured by a visual analog scale. PTA and medical management seemed also to be superior to medical management alone in terms of improvements in the quality of life. The greatest difference between the groups was obtained after 3 months in the 36-Item Short Form Health Survey (SF-36) domains of physical functioning, bodily pain, and reported health transition. Only with regard to physical functioning did this positive effect last for 2 years. Results from the Claudication Scale (CLAU-S) form showed superiority of the combined approach in the two domains of pain during activity and pain severity. This difference, however, was noted only at 3 and 12 months but not after 2 years, when no differences between groups were observed. The PTA group had more improvements in the ABI up to 2 years of follow-up. Hobbs at al35 demonstrated that PTA was superior to supervised exercise and best medical treatment on the basis of significant improvement in mean ABI and both initial claudication distance and absolute claudication distance at 6 months of follow-up. Perkins et al36 showed early superiority of an exercise training program over PTA on claudication and maximum

Observation time 1 year 2 years 2 years 6 years 1 year 2 years

2 0

Not specified for death; amputation 30-day outcome

walking distances; however, at long-term follow-up, there was no significant difference between the groups. PTA led to constant increases of ABI, whereas an exercise training program did not. Spronk et al7,8 compared endovascular revascularization with a hospital-based exercise program. The two groups had similar and statistically significant improvements in maximum and pain-free walking distances. After follow-up, there were no significant differences in the adjusted 6- and 12-month EuroQol, rating scale, and SF36 physical functioning values. The two groups had similar improvements in ABI at rest and with exercise; however, the endovascular approach had somewhat more immediate improvement. Seven-year follow-up also showed similar functional performance and quality of life between the two groups.37 Whyman et al9 demonstrated that after 2 years of follow-up, the addition of PTA to medical treatment (aspirin, advice on smoking cessation and exercise) did not result in a significant difference in patient-reported maximum walking, treadmill onset to claudication, treadmill maximum walking distances, ABI, or any of the items of the Nottingham Health Profile score. The CLEVER trial (Claudication: Exercise vs Endoluminal Revascularization) randomized patients to supervised exercise, OMC, and stent treatment. All patients received cilostazol 100 mg twice daily during the study period. At 6 months, the peak walking time was much improved in the supervised exercise group compared with both the OMC-alone group (eg, risk factor management, use of antiplatelet therapy, and use of claudication pharmacotherapy) and the stent treatment group (mean change vs baseline, 5.8 6 4.6, 3.7 6 4.9, and 1.2 6 2.6 minutes, respectively; P < .001 for the comparison of supervised exercise vs OMC, P < .02 for stent treatment vs OMC, and P < .04 for supervised exercise vs stent treatment).20 After 6 months of follow-up, the CLEVER study, using two dedicated claudication questionnaires, the Walking Impairment Questionnaire and the Peripheral Artery


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Fig. Summary of the quality of evidence. The quality of evidence is rated as high (4444), moderate (444O), and low (44OO). EVT, Endovascular therapy; LOS, length of hospital stay; QOE, quality of evidence; SET, supervised exercise therapy.

Questionnaire, showed that the stent revascularization group had better patient-reported quality of life compared with the supervised exercise and OMC groups.20 As the CLEVER trial was not designed to address the reasons for better pain severity, walking speed scores, and less physical limitation and overall quality of life in the stent treatment group, further investigation of long-term results was recommended by the CLEVER study investigators.20 There was no significant improvement of baseline ABI compared with 6-month follow-up in either the OMC or supervised exercise treatment group; however, resting ABI improved by 0.29 6 0.33 in the stenting revascularization group (P < .0001).20 Results presented from a recent trial of 212 claudicants compared endovascular revascularization combined with supervised exercise to exercise alone. After 12 months, the combination therapy resulted in significant greater improvements in pain-free and maximum walking distance and health-related quality of life scores.38 Two systematic reviews of the randomized trials that compared endovascular therapies with supervised exercise therapy concluded that they are likely equal and that the combination of both is likely better than either approach

in terms of improving walking distance and some domains of the quality of life scales.24,25 RCTs comparing endovascular approaches with open surgery. van der Zaag et al39 showed that bypass had higher clinical improvement on the Rutherford classification than PTA (53% of patients improved vs 33%, an absolute difference of clinical success of 20%; 95% confidence interval [CI], 26%-46%). Bypass also had higher cumulative 1-year primary patency (82%) compared with PTA (43%) and less incidence of a reocclusion (hazard ratio for PTA, 2.24; 95% CI, 0.9-5.58). Wolf et al30 compared surgery with PTA. Patients in both treatment groups had improvement in functional status measured by the Sickness Impact Profile, although no difference was demonstrated according to treatment received. Two systematic reviews add evidence to the comparison between open surgery and endovascular therapy, although they included patients with CLI. A systematic review and meta-analysis evaluated the clinical outcomes of 5358 patients undergoing direct open bypass or endovascular treatment for aortoiliac occlusive disease. Comparisons of these nonrandomized surgical series showed that open bypass had longer hospital stay (13 days vs 4 days;


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Table IV. Systematic reviews of exercise therapy Comparison

Data source

Methodologic limitations

Finding

Quality of evidence

Exercise program vs no exercise21

30 RCTs enrolling 1816 patients

Low risk of bias Patients with various medical conditions or other pre-existing limitations to exercise were generally excluded.

A (for walking performance parameters) C (for mortality and amputation)

Supervised exercise vs nonsupervised23

14 RCTs enrolling 1002 patients

Low risk of bias Follow-up is short and variable (6 weeks to 12 months).

The control group was usual care or placebo in 20 trials; in the remainder of the trials, it was pentoxifylline, iloprost, antiplatelet agents and vitamin E, or pneumatic calf compression. Exercise significantly improved maximal walking time compared with usual care or placebo (MD, 4.51 minutes; 95% CI, 3.11-5.92), with an overall improvement in walking ability of approximately 50% to 200%, pain-free walking distance (MD, 82.29 meters; 95% CI, 71.86-92.72), and maximum walking distance (MD, 108.99 meters; 95% CI, 38.20-179.78). Improvements were seen for up to 2 years. Exercise did not improve the ABI (MD, 0.05; 95% CI, 0.00-0.09). The effect of exercise, compared with placebo or usual care, was inconclusive on mortality, amputation, and peak exercise calf blood flow because of limited data. No data were given on nonfatal cardiovascular events. Quality of life measured with the 36-Item Short Form Health Survey significantly improved with exercise. Supervised exercise therapy showed statistically significant improvement in maximal treadmill walking distance compared with nonsupervised exercise therapy regimens, with an overall effect size of 0.69 (95% CI, 0.51-0.86) and 0.48 (95% CI, 0.32-0.64) at 3 and 6 months, respectively. This translates to an increase in walking distance of approximately 180 meters that favored the supervised group. Supervised exercise was still beneficial for maximal and pain-free walking distances at 12 months, but it did not have a significant effect on quality of life parameters.

ABI, Ankle-brachial index; CI, confidence interval; MD, mean difference; RCTs, randomized controlled trials.

A (for walking performance parameters)


P < .001) and higher complications rate (18.0% vs 13.4%; P < .001) and 30-day mortality (2.6% vs 0.7%; P < .001). Patency and durability of bypass were superior, however.26 A second systematic review compared open surgical and percutaneous transluminal methods for the treatment of femoropopliteal arterial disease and showed that open surgery was associated with higher 30-day morbidity but no difference in 30-day mortality. Higher primary patency in the surgical treatment arm was also found.28 RCTs comparing any revascularization with medical management or exercise. Gelin et al5,40 demonstrated that invasive revascularization (open surgical or endovascular procedures) increased walking capacity (treadmill exercise power and maximum treadmill walking distance) and was more effective than supervised training in alleviating illnessspecific symptoms and improving certain aspects of physical functioning, the primary health-related quality of life domains affected by claudication. However, the treatment effect sizes were modest, and untreated claudicants reported at most small deterioration in health-related quality of life. Invasive revascularization increased leg blood pressure and flow parameters (maximum postischemic calf blood flow after treadmill exercise, hallux systolic pressure, and ABI). Similarly, a recent trial of 158 patients randomized patients to an invasive strategy (open repair for Trans-Atlantic Inter-Society Consensus [TASC] II D lesions and endovascular intervention for the aortoiliac and femoropopliteal TASC II A-C lesions) vs noninvasive strategy (education, exercise encouragement, cilostazol, and statins). Compared with the noninvasive group, the invasive group had better SF-36 physical component summary and two of its physical subscales, overall Vascular Quality of Life questionnaire score and three of five domain scores, and IC distance (þ124 m vs þ50 m; P ¼ .003) but not maximum walking distance.41 Aortoiliac vs femoropopliteal disease in patients with claudication. Perkins et al36 compared PTA with supervised exercise and found that patients with femoropopliteal disease and no aortoiliac involvement had improvement in the claudication distance at 6, 9, 12, and 15 months of follow-up after treatment with supervised exercise. In comparison, patients with aortoiliac disease with or without femoropopliteal disease failed to improve after either treatment. The MIMIC trial34 stratified patients by anatomic location and showed that PTA added to supervised exercise and best medical therapy was associated with increased adjusted absolute walking distance in patients with femoropopliteal disease (38% greater; 95% CI, 1-90) and in patients with aortoiliac disease (78% greater; 95% CI, 0-216). Wolf et al30 showed that patients with iliac disease fared better than those with femoropopliteal disease in terms of limb survival and primary patency, although no difference was demonstrated according to treatment received (surgery vs PTA). Patency rates for both PTA and surgery were reduced in the femoropopliteal segment compared with the same treatment applied to the aortoiliac segment.

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A trial of 178 patients with IC due to femoropopliteal arterial disease compared angioplasty, a supervised exercise program, and combined treatment. The trial demonstrated that all three treatments were equally effective in improving walking distance and quality of life after 12 months.42 Because data from RCTs regarding the relative efficacy of the different PAD treatments stratified by the anatomic location of the disease were sparse, meta-analyses of nonrandomized case series are included. Aortoiliac occlusive disease. Endovascular vs open surgery for aortoiliac occlusive disease was compared in a meta-analysis of mostly nonrandomized series,26 and most of these studies included patients with CLI. The open bypass groups experienced more complications and greater 30-day mortality. At 1, 3, and 5 years, primary patency rates were greater in the open bypass group. In extensive aortoiliac occlusive disease, meta-analysis of nonrandomized series27 showed that with an endovascular approach, mortality ranged from 1.2% to 6.7%, and complications ranged from 3% to 45%. Clinical symptoms improved in 83% to100%. Technical success was achieved in 86% to 100% of the patients. The 4- or 5-year primary and secondary patency rates ranged from 60% to 86% and 80% to 98%, respectively. Femoropopliteal occlusive disease. A systematic review summarized four RCTs and six observational studies reporting on a total of 2817 patients with femoropopliteal arterial disease (includes CLI patients).28 Endovascular treatment was associated with lower 30-day morbidity (odds ratio [OR], 2.93; 95% CI, 1.34-6.41) and higher technical failure (OR, 0.10; 95% CI, 0.05-0.22) than bypass surgery. No difference was noted in 30-day mortality (OR, 0.92; 95% CI, 0.55-1.51). Higher primary patency in the surgical treatment arm was found at 1 year (OR, 2.42; 95% CI, 1.37-4.28), 2 years (OR, 2.03; 95% CI, 1.20-3.45), and 3 years (OR, 1.48; 95% CI, 1.12-1.97) of intervention. Progression to amputation was found to occur more commonly in the endovascular group at the end of the second year (OR, 0.60; 95% CI, 0.42-0.86) and third year (OR, 0.55; 95% CI, 0.39-0.77) of intervention. Higher amputation-free (OR, 1.31; 95% CI, 1.07-1.61) and overall survival (OR, 1.29; 95% CI, 1.04-1.61) rates were found in the bypass group at 4 years. Cost and utilization data There is a paucity of data on cost analysis of treatments of IC. Three of four RCTs that were excluded from analysis because of inclusion of patients with CLI or mixing of claudication and CLI reported cost analysis.43-45 A single-center Dutch RCT discussed the cost in patients with claudication treated by either endovascular revascularization or supervised exercise.7 In this trial, Spronk et al7 demonstrated that endovascular revascularization had higher total mean cumulative costs per patient compared with a hospital-based exercise program (mean difference, V2318; 99% CI, V2130-V 2506; P < .001).7 The gain in total mean quality-adjusted life-years


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accumulated during 12 months, adjusted for baseline values, was not statistically different between the two groups. The follow-up costs are provided, showing that endovascular treatment carried significantly higher expenses compared with an exercise program; however, it is not reported whether it is related exclusively to a higher reintervention rate in the endovascular group. Nonetheless, in all instances, endovascular revascularization was more expensive compared with hospital-based exercise but with similar clinical outcomes at 12-month follow-up. It is also important to realize the differences in billing and reimbursement systems in Europe, which were assessed in this study, from those in the United States. One cost-effectiveness study showed that compared with unsupervised exercise, supervised exercise was cost-effective in >75% of model simulations, with an incremental cost-effectiveness ratio of 711 to 1608 per quality-adjusted life-year gained.46 Another economic analysis of patients with IC due to femoropopliteal arterial disease suggested that supervised exercise is more costeffective than angioplasty and that the combination of the two treatments is also more cost-effective than angioplasty alone.47 On the basis of the concept of supervised exercise as the most cost-effective first-line treatment for IC, a cost analysis using a large Dutch health care insurance company database of 4954 patients was performed to evaluate the impact of a stepped care claudication treatment approach.48 Three groups were created, supervised exercise, intervention, and no treatment group, aiming to identify the related costs to supervised exercise and intervention and how many patients would eventually need intervention after being enrolled in a supervised exercise program. The authors also computed the financial burden of reinterventions added to each patient’s follow-up costs. The main conclusion of this cost-analysis study suggested that supervised exercise must be always attempted as a first-line IC treatment before any intervention is performed to save thousands of Euros spent in perhaps unnecessary interventions. Several variables play a role in whether an intervention should be pursued first instead of a long exercise program. The study did not clearly state the severity of claudication (breakdown in Fontaine IIa and IIb not provided) and stratification of PAD extent and its impact on the treatment decision-making process (aortoiliac, femoropopliteal, or crural involvement or a combination of all three levels). Open and endovascular interventions overlap throughout the study regardless of their magnitude and were bundled together in a single “intervention” group for calculation purposes, which by itself is not ideal from a clinical (ie, complications, durability) or cost-savings perspective (ie, hospital stay, rehabilitation costs). Most important, the study did not explore the reasons (ie, age, work, daily physical and recreational activities) that some patients decided to initially proceed with a long supervised exercise program or for how long it would be tolerable instead of having first an intervention to quickly improve

their clinical limitations (work and leisure activities) and quality of life.48 DISCUSSION We conducted a systematic review to evaluate the relative efficacy of surgery, endovascular therapy, and exercise therapy. Data regarding patient-important outcomes (mortality, amputation, and quality of life) were sparse, limiting inference. The three treatments appear to be superior to medical management in terms of walking distance, pain, and claudication. The quality of such evidence is high. Blood flow parameters (eg, ABI) improve faster and better with both forms of revascularization compared with nonsurgical management with exercise or medical management; this improvement, however, may not necessarily correlate with clinical and patient-important improvement. Evidence supporting superiority of one of the three approaches is limited, although it seemed that the combination of supervised exercise therapy and invasive revascularization may be superior to exercise alone. A network meta-analysis49 similarly concluded that the three active treatments are more effective than medical management, with limited comparative evidence between the three. Data on cost-effectiveness and utilization in IC were minimal. This conclusion is similar to a systematic review commissioned by the SVS that evaluated the economicbased literature with respect to open and endovascular treatment of PAD.50 A summary of 3 model-based, 12 cost-consequence, and 4 cost analyses suggested a trend favoring initial cost savings with endovascular therapy. Whether this benefit is sustained over time is unknown. Cost-efficacy inferences cannot be drawn from the existing literature because of a noted lack of standardized patientcentric outcomes, longitudinal data, and reintervention data. The available economic analyses emphasized the significant cost-effectiveness of supervised exercise therapy. We attempted to compare intervention efficacy on the basis of anatomic location. Limited evidence suggests that patients with isolated iliac or femoropopliteal occlusive disease compared with those with combined iliac and femoropopliteal disease fare better in terms of symptom relief and improvement in walking distance, regardless of the type of intervention (supervised exercise, PTA, or surgical bypass). Because a hemodynamically acceptable inflow is deemed mandatory for infrainguinal repair, many trials aimed only to assess interventions in the femoropopliteal segment and purposely excluded patients with significant aortoiliac disease. Studies also did not stratify outcomes on the basis of the anatomic level of the disease, probably because of their small sample size. The limitations of this report mainly relate to the small body of literature and a small number of trials that do not allow stratification according to prognostic factors and patient characteristics. Knowing the relative efficacy of interventions in various subgroups of patients is important for decision-making. Methodologic limitations of the included trials, imprecision (small numbers of patients and events


leading to wide CIs), and inconsistency across studies affected our ability to draw inferences.51 Dependence on surrogate outcomes is another challenge in the field because hard end points (mortality and amputations) are rare in claudicants. New modalities of surrogate measurement, such as the response of the endothelium to exercise in patients with claudication (eg, the brachial artery flowmediated dilation), are being developed and tested.52 Practice and research implications. This study demonstrates that compared with medical management alone, interventions such as supervised exercise, endovascular interventions, or surgical bypass result in improvement in claudication symptoms, walking distance, and quality of life in most patients. Unfortunately, endovascular interventions and surgical bypass come at a significant expense, can have limited durability, and may be associated with morbidity and mortality. Data on which intervention is best suited for a particular patient to obtain the best outcome are lacking. Therefore, patients should be informed of the current uncertainty and the pros and cons of these treatments. Patients’ values and preferences and availability of operative expertise should help guide this decision. The accompanying guidelines by the SVS provide details of this process. This report highlights the need for larger trials to evaluate the relative efficacy of the available treatments for PAD. PAD is a common chronic and disabling condition that deserves appropriate and rigorous evaluation. Trials should follow the comparative effectiveness agenda and needs; thus, they should not include comparisons with placebo or inferior medical management, they should evaluate patient-important outcomes and quality of life, and they should have long-term follow-up. Trials should conceal allocation and blind outcome assessors and seek a high rate of follow-up. Data from registries are also important and can support conclusions from trials as long as registries are protected from selection bias (ie, include complete consecutive cohorts). Cost-effectiveness analysis built alongside these larger trials would be very important for decision-making. CONCLUSIONS In patients with claudication, open surgery, endovascular therapy, and exercise therapy are superior to medical management in terms of walking distance, pain, and claudication. Blood flow parameters improve faster and better with both forms of revascularization compared with nonsurgical management with exercise or medical management. AUTHOR CONTRIBUTIONS Conception and design: MM, MC, VM, RM Analysis and interpretation: MM, MC, VM, RM Data collection: RM, FA, TE, AR, ML, LP, WF, OP Writing the article: MM, MC, VM, RM Critical revision of the article: MM, MC, VM, RM, FA, TE, AR, ML, LP, WF, OP Final approval of the article: MM, MC, VM, RM, FA, TE, AR, ML, LP, WF, OP

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Statistical analysis: MM, FA, OP Obtained funding: MM Overall responsibility: MM

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APPENDIX Search strategies. Ovid EBM ReviewsdCochrane Central Register of Controlled Trials 1st Quarter 2010 (updated through June 2014) #

Searches

Results

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exp Peripheral Vascular Diseases/ peripheral blood vessel disease*.mp. peripheral vessel disease*.mp. blackfoot disease*.mp. cold limb*.mp. erythromelalgia*.mp. glomus tumor*.mp. peripheral blood vessel malformation*.mp. (Raynaud* adj2 (phenomenon or disease* or disorder*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] telangiectasia*.mp. blue toe syndrome*.mp. Livedo Reticularis*.mp. Phlebitis*.mp. Postphlebitic Syndrome.mp. Thrombophlebitis.mp. CREST Syndrome*.mp. peripheral angiopath*.mp. exp Arterial Occlusive Diseases/ (arter* adj3 occlus*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] Arteriolosclerosis.mp. Atherosclerosis.mp. (Monckeberg adj3 Sclerosis).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] Thromboangiitis Obliterans.mp. (Buerger disease or buergers disease).mp. (pvd or paod or pad).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] (peripheral adj3 (vascular or arter*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] (obstruct* adj3 arter*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] exp intermittent claudication/ angina cruris.mp. angiosclerotica intermittens.mp. claudic*.mp. exp peripheral occlusive artery disease/ (arter* adj3 obliter*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] ((athero* or arterio* or arter* or vascular) adj3 (obliter* or occlus* or obstruc* or insuffic*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] ((leg or limb) adj3 isch*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] or/1-35 exp Exercise/ or exp Exercise Therapy/ (walk* or runni* or exerc* or train* or treadmill*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] activi*.mp. 37 or 38 or 39 36 and 40 limit 41 to yr¼“2008 -Current” from 42 keep 1-194

1827 0 1 0 25 6 0 0 401

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

155 0 2 376 31 1257 2 5 4292 1706 4 3020 0 20 15 869 2619 417 572 0 0 1073 0 153 2806 499 12902 9287 43145 45015 80791 2284 194 194

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Scopus 1

2 3 4 5

TITLE-ABS-KEY(“peripheral vascular disease” OR “peripheral arteriopath*” OR “peripheral blood vessel disease” OR “peripheral vascular disorder” OR “peripheral vessel disease” OR “blackfoot disease” OR “cold limb” OR “erythromelalgia*” OR “glomus tumor” OR “peripheral blood vessel malformation” OR “Raynaud? phenomenon” OR “Raynaud? disease” OR “Raynaud? disorder” OR “telangiectasia*” OR “blue toe syndrome” OR “Livedo Reticularis*” OR “Phlebitis*” OR “Postphlebitic Syndrome” OR “Thrombophlebitis” OR “CREST Syndrome” OR “peripheral angiopath*” OR “peripheral arterial disease” OR “claudic*” OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*” OR (arter* W/3 occlus*) OR Arteriolosclerosis OR Atherosclerosis OR (Monckeberg W/3 Sclerosis) OR “Thromboangiitis Obliterans” OR “Buerger disease” OR “buergers disease” OR pvd OR paod OR pad OR (peripheral w/3 vascular) OR (peripheral w/3 arter*) OR (athero* W/3 obliter*) OR (athero* W/3 occlus*) OR (athero* W/3 obstruc*) OR (athero* W/3 insuffic*) OR (arterio* W/3 obliter*) OR (arterio* W/3 occlus*) OR (arterio* W/3 obstruc*) OR (arterio* W/3 insuffic*) OR (arter* W/3 obliter*) OR (arter* W/3 occlus*) OR (arter* W/3 obstruc*) OR (arter* W/3 insuffic*) OR (vascular W/3 obliter*) OR (vascular W/3 occlus*) OR (vascular W/3 obstruc*) OR (vascular W/3 insuffic*)) TITLE-ABS-KEY(walk* OR runni* OR exerc* OR train* OR treadmill* OR activi*) TITLE-ABS-KEY((evidence W/1 based) OR (meta W/1 analys*) OR “systematic review” OR guideline OR (control* W/2 stud*) OR (control* W/2 trial*) OR (randomized W/2 stud*) OR (randomized W/2 trial*)) PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR PMID(7*) OR PMID(8*) OR PMID(9*) (1 and 2 and 3) and not 4

CINAHL 1

2 3 4 5 6 7 8 9 10 11 12 13

“peripheral vascular disease” OR “peripheral arteriopath*” OR “peripheral blood vessel disease” OR “peripheral vascular disorder” OR “peripheral vessel disease” OR “blackfoot disease” OR “cold limb” OR “erythromelalgia*” OR “glomus tumor” OR “peripheral blood vessel malformation” OR “Raynaud? phenomenon” OR “Raynaud? disease” OR “Raynaud? disorder” OR “telangiectasia*” OR “blue toe syndrome” OR “Livedo Reticularis*” OR “Phlebitis*” OR “Postphlebitic Syndrome” OR “Thrombophlebitis” OR “CREST Syndrome” OR “peripheral angiopath*” OR “peripheral arterial disease” OR “claudic*” OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*” OR (arter* N3 occlus*) OR Arteriolosclerosis OR Atherosclerosis OR (Monckeberg N3 Sclerosis) OR “Thromboangiitis Obliterans” OR “Buerger disease” OR “buergers disease” OR pvd OR paod OR pad OR (peripheral N3 vascular) OR (peripheral N3 arter*) OR (athero* N3 obliter*) OR (athero* N3 occlus*) OR (athero* N3 obstruc*) OR (athero* N3 insuffic*) OR (arterio* N3 obliter*) OR (arterio* N3 occlus*) OR (arterio* N3 obstruc*) OR (arterio* N3 insuffic*) OR (arter* N3 obliter*) OR (arter* N3 occlus*) OR (arter* N3 obstruc*) OR (arter* N3 insuffic*) OR (vascular N3 obliter*) OR (vascular N3 occlus*) OR (vascular N3 obstruc*) OR (vascular N3 insuffic*) (MH “Peripheral Vascular Diseasesþ”) (MH “Intermittent Claudication”) (MH “Arterial Occlusive Diseasesþ”) 1 or 2 or 3 or 4 (MH “Exerciseþ”) (MH “Therapeutic Exerciseþ”) walk* OR runni* OR exerc* OR train* OR treadmill* OR activi* 6 or 7 or 8 (evidence N1 based) OR (meta N1 analys*) OR “systematic review” OR guideline OR (control* N2 stud*) OR (control* N2 trial*) OR (randomized N2 stud*) OR (randomized N2 trial*) (MH “Clinical Trialsþ”) 10 or 11 5 and 9 and 12


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Ovid EMBASE, Ovid MEDLINE, CCTR, CDSR #

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Results

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exp intermittent claudication/ angina cruris.mp. angiosclerotica intermittens.mp. leg ischemia*.mp. claudic*.mp. or/1-5 exp Angioplasty/ angioplast*.mp. atherectom*.mp. blunt microdissection*.mp. pta.mp. balloon dilation.mp. exp Exercise/ or exp Exercise Therapy/ (walk* or runni* or exerc* or train* or treadmill* or gymnastics or activi*).mp. exp Stents/ stent*.mp. or/7-16 quality of life.mp. or exp “Quality of Life”/ qol.mp. health status.mp. or exp Health Status/ geriatric assessment.mp. hrql.mp. life quality.mp. international classification of functioning.mp. quality adjusted life.mp. “short form 12”.mp. “short form 20”.mp. “short form 36”.mp. “short form 8”.mp. or/18-29 functional capacity.mp. ankle brachial index.mp. or exp Ankle Brachial Index/ walking distance.mp. exp functional status/ functional status.mp. or/31-35 6 and 17 and 30 and 36 remove duplicates from 37 limit 38 to yr¼“2003 -Current” from 39 keep 193-219 39 not 40 exp controlled study/ exp evidence based medicine/ evidence-based.mp. meta analysis/ meta-analys$.mp. exp “systematic review”/ systematic review$.mp. exp Guideline/ or exp Practice Guideline/ guideline$.ti. ((control* or randomized) adj2 (study or studies or trial or trials)).mp. exp cohort analysis/ (cohort adj (study or studies or analysis)).mp. [mp¼ti, ab, sh, hw, tn, ot, dm, mf, nm, ui, kw, tx, ct] or/42-53 41 and 54 from 41 keep 91-192 limit 56 to (controlled clinical trial or guideline or meta analysis or practice guideline or randomized controlled trial) [Limit not valid in EMBASE,CDSR; records were retained] 55 or 57

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58

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Scopus 1 2 3 4 5 6 7

TITLE-ABS-KEY(claudic* OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*”) TITLE-ABS-KEY(angioplast* OR atherectom* OR “blunt microdissection” OR pta OR “balloon dilation” OR walk* OR runni* OR exerc* OR train* OR treadmill* OR activi* OR gymnastics OR stent*) TITLE-ABS-KEY((quality W/2 life) OR qol OR “health status” OR “geriatric assessment” OR hrql OR “life quality” OR “international classification of functioning” OR “quality adjusted life” OR “short form 12” OR “short form 20” OR “short form 36” OR “short form 8”) TITLE-ABS-KEY(“functional capacity” OR “ankle brachial index” OR “walking distance” OR “functional status”) TITLE-ABS-KEY((evidence W/1 based) OR (meta W/1 analys*) OR “systematic review” OR guideline OR (control* W/2 stud*) OR (control* W/2 trial*) OR (randomized W/2 stud*) OR (randomized W/2 trial*) OR (cohort W/2 stud*) OR (cohort W/2 analysis)) PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR PMID(7*) OR PMID(8*) OR PMID(9*) (1 and 2 and 3 and 4 and 5) and not 6

CINAHL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

(MH “Intermittent Claudication”) “claudic*” OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*” 1 or 2 (MH “Angioplastyþ”) angioplast* OR atherectom* OR “blunt microdissection” OR pta or “balloon dilation” (MH “Exerciseþ”) (MH “Therapeutic Exerciseþ”) walk* OR runni* OR exerc* OR train* OR treadmill* OR activi* or gymnastics (MH “Stentsþ”) stent* 4 or 5 or 6 or 7 or 8 or 9 or 10 (MH “Quality of Life”) or (MH “Quality-Adjusted Life Years”) or (MH “Ferrans and Powers Quality of Life Index”) or (MH “Health and Life Quality (Iowa NOC) (Non-Cinahl)þ”) or (MH “Quality of Life (Iowa NOC)”) (MH “Health Statusþ”) (quality n2 life) or qol or “health status” or “geriatric assessment” or hrql or “life quality” or “international classification of functioning” or “quality adjusted life” OR “short form 12” OR “short form 20” OR “short form 36” OR “short form 8” 12 or 13 or 14 (MH “Functional Status”) (MH “Ankle Brachial Index”) “functional capacity” OR “ankle brachial index” OR “walking distance” OR “functional status” 16 or 17 or 18 (MH “Clinical Trialsþ”) (evidence N1 based) OR (meta N1 analys*) OR “systematic review” OR guideline OR (control* N2 stud*) OR (control* N2 trial*) OR (randomized N2 stud*) OR (randomized N2 trial*) or (cohort N1 analysis) or (cohort N1 stud*) 20 or 21 3 and 11 and 15 and 19 and 22


Malgor et al 69S

Ovid EBM ReviewsdCochrane Central Register of Controlled Trials 1st Quarter 2010 (updated through June 2014)

#

Searches

Results

1 2 3 4 5 6 7 8 9

exp Peripheral Vascular Diseases/ peripheral blood vessel disease*.mp. peripheral vessel disease*.mp. blackfoot disease*.mp. cold limb*.mp. erythromelalgia*.mp. glomus tumor*.mp. peripheral blood vessel malformation*.mp. (Raynaud* adj2 (phenomenon or disease* or disorder*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] telangiectasia*.mp. blue toe syndrome*.mp. Livedo Reticularis*.mp. Phlebitis*.mp. Postphlebitic Syndrome.mp. Thrombophlebitis.mp. CREST Syndrome*.mp. peripheral angiopath*.mp. exp Arterial Occlusive Diseases/ (arter* adj3 occlus*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] Arteriolosclerosis.mp. Atherosclerosis.mp. (Monckeberg adj3 Sclerosis).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] Thromboangiitis Obliterans.mp. (Buerger disease or buergers disease).mp. (pvd or paod or pad).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] (peripheral adj3 (vascular or arter*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] (obstruct* adj3 arter*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] exp intermittent claudication/ angina cruris.mp. angiosclerotica intermittens.mp. claudic*.mp. exp peripheral occlusive artery disease/ (arter* adj3 obliter*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] ((athero* or arterio* or arter* or vascular) adj3 (obliter* or occlus* or obstruc* or insuffic*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] ((leg or limb) adj3 isch*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] or/1-35 exp Angioplasty/ angioplast*.mp. atherectom*.mp. blunt microdissection*.mp. pta.mp. or/37-41 36 and 42 limit 43 to yr¼“2006 -Current”

1827 0 1 0 25 6 0 0 401

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

155 0 2 376 31 1257 2 5 4292 1706 4 3020 0 20 15 869 2619 417 572 0 0 1073 0 153 2806 499 12902 2924 3995 169 0 254 4170 914 261

70S Malgor et al


Scopus 6

7 8 9 10

TITLE-ABS-KEY(“peripheral vascular disease” OR “peripheral arteriopath*” OR “peripheral blood vessel disease” OR “peripheral vascular disorder” OR “peripheral vessel disease” OR “blackfoot disease” OR “cold limb” OR “erythromelalgia*” OR “glomus tumor” OR “peripheral blood vessel malformation” OR “Raynaud? phenomenon” OR “Raynaud? disease” OR “Raynaud? disorder” OR “telangiectasia*” OR “blue toe syndrome” OR “Livedo Reticularis*” OR “Phlebitis*” OR “Postphlebitic Syndrome” OR “Thrombophlebitis” OR “CREST Syndrome” OR “peripheral angiopath*” OR “peripheral arterial disease” OR “claudic*” OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*” OR (arter* W/3 occlus*) OR arteriolosclerosis OR atherosclerosis OR (monckeberg W/3 sclerosis) OR “thromboangiitis obliterans” OR “buerger disease” OR “buergers disease” OR pvd OR paod OR pad OR (peripheral W/3 vascular) OR (peripheral W/3 arter*) OR (athero* W/3 obliter*) OR (athero* W/3 occlus*) OR (athero* W/3 obstruc*) OR (athero* W/3 insuffic*) OR (arterio* W/3 obliter*) OR (arterio* W/3 occlus*) OR (arterio* W/3 obstruc*) OR (arterio* W/3 insuffic*) OR (arter* W/3 obliter*) OR (arter* W/3 occlus*) OR (arter* W/3 obstruc*) OR (arter* W/3 insuffic*) OR (vascular W/3 obliter*) OR (vascular W/3 occlus*) OR (vascular W/3 obstruc*) OR (vascular W/3 insuffic*)) TITLE-ABS-KEY(angioplast* OR atherectom* OR “blunt microdissection” OR pta) TITLE-ABS-KEY((evidence W/1 based) OR (meta W/1 analys*) OR “systematic review” OR guideline OR (control* W/2 stud*) OR (control* W/2 trial*) OR (randomized W/2 stud*) OR (randomized W/2 trial*)) PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR PMID(7*) OR PMID(8*) OR PMID(9*) (1 and 2 and 3) and not 4

CINAHL 14

15 16 17 18 19 20 21 22 23 24 25

“peripheral vascular disease” OR “peripheral arteriopath*” OR “peripheral blood vessel disease” OR “peripheral vascular disorder” OR “peripheral vessel disease” OR “blackfoot disease” OR “cold limb” OR “erythromelalgia*” OR “glomus tumor” OR “peripheral blood vessel malformation” OR “Raynaud? phenomenon” OR “Raynaud? disease” OR “Raynaud? disorder” OR “telangiectasia*” OR “blue toe syndrome” OR “Livedo Reticularis*” OR “Phlebitis*” OR “Postphlebitic Syndrome” OR “Thrombophlebitis” OR “CREST Syndrome” OR “peripheral angiopath*” OR “peripheral arterial disease” OR “claudic*” OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*” OR (arter* N3 occlus*) OR Arteriolosclerosis OR Atherosclerosis OR (Monckeberg N3 Sclerosis) OR “Thromboangiitis Obliterans” OR “Buerger disease” OR “buergers disease” OR pvd OR paod OR pad OR (peripheral N3 vascular) OR (peripheral N3 arter*) OR (athero* N3 obliter*) OR (athero* N3 occlus*) OR (athero* N3 obstruc*) OR (athero* N3 insuffic*) OR (arterio* N3 obliter*) OR (arterio* N3 occlus*) OR (arterio* N3 obstruc*) OR (arterio* N3 insuffic*) OR (arter* N3 obliter*) OR (arter* N3 occlus*) OR (arter* N3 obstruc*) OR (arter* N3 insuffic*) OR (vascular N3 obliter*) OR (vascular N3 occlus*) OR (vascular N3 obstruc*) OR (vascular N3 insuffic*) (MH “Peripheral Vascular Diseasesþ”) (MH “Intermittent Claudication”) (MH “Arterial Occlusive Diseasesþ”) 1 or 2 or 3 or 4 (MH “Angioplastyþ”) angioplast* OR atherectom* OR “blunt microdissection” OR pta 6 or 7 (evidence N1 based) OR (meta N1 analys*) OR “systematic review” OR guideline OR (control* N2 stud*) OR (control* N2 trial*) OR (randomized N2 stud*) OR (randomized N2 trial*) (MH “Clinical Trialsþ”) 10 or 11 5 and 8 and 11


Malgor et al 71S

Ovid EBM ReviewsdCochrane Central Register of Controlled Trials 1st Quarter 2010 (updated through June 2014)

#

Searches

Results

1 2 3 4 5 6 7 8 9

exp Peripheral Vascular Diseases/ peripheral blood vessel disease*.mp. peripheral vessel disease*.mp. blackfoot disease*.mp. cold limb*.mp. erythromelalgia*.mp. glomus tumor*.mp. peripheral blood vessel malformation*.mp. (Raynaud* adj2 (phenomenon or disease* or disorder*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] telangiectasia*.mp. blue toe syndrome*.mp. Livedo Reticularis*.mp. Phlebitis*.mp. Postphlebitic Syndrome.mp. Thrombophlebitis.mp. CREST Syndrome*.mp. peripheral angiopath*.mp. exp Arterial Occlusive Diseases/ (arter* adj3 occlus*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] Arteriolosclerosis.mp. Atherosclerosis.mp. (Monckeberg adj3 Sclerosis).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] Thromboangiitis Obliterans.mp. (Buerger disease or buergers disease).mp. (pvd or paod or pad).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] (peripheral adj3 (vascular or arter*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] (obstruct* adj3 arter*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] exp intermittent claudication/ angina cruris.mp. angiosclerotica intermittens.mp. claudic*.mp. exp peripheral occlusive artery disease/ (arter* adj3 obliter*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] ((athero* or arterio* or arter* or vascular) adj3 (obliter* or occlus* or obstruc* or insuffic*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] ((leg or limb) adj3 isch*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] or/1-35 (graft or bypass).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] 36 and 37 limit 38 to yr¼“2007 -Current”

1827 0 1 0 25 6 0 0 401

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

155 0 2 376 31 1257 2 5 4292 1706 4 3020 0 20 15 869 2619 417 572 0 0 1073 0 153 2806 499 12902 13557 1327 231

Scopus 1

2 3 4 5

TITLE-ABS-KEY(“peripheral vascular disease” OR “peripheral arteriopath*” OR “peripheral blood vessel disease” OR “peripheral vascular disorder” OR “peripheral vessel disease” OR “blackfoot disease” OR “cold limb” OR “erythromelalgia*” OR “glomus tumor” OR “peripheral blood vessel malformation” OR “Raynaud? phenomenon” OR “Raynaud? disease” OR “Raynaud? disorder” OR “telangiectasia*” OR “blue toe syndrome” OR “Livedo Reticularis*” OR “Phlebitis*” OR “Postphlebitic Syndrome” OR “Thrombophlebitis” OR “CREST Syndrome” OR “peripheral angiopath*” OR “peripheral arterial disease” OR “claudic*” OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*” OR (arter* W/3 occlus*) OR arteriolosclerosis OR atherosclerosis OR (monckeberg W/3 sclerosis) OR “thromboangiitis obliterans” OR “buerger disease” OR “buergers disease” OR pvd OR paod OR pad OR (peripheral W/3 vascular) OR (peripheral W/3 arter*) OR (athero* W/3 obliter*) OR (athero* W/3 occlus*) OR (athero* W/3 obstruc*) OR (athero* W/3 insuffic*) OR (arterio* W/3 obliter*) OR (arterio* W/3 occlus*) OR (arterio* W/3 obstruc*) OR (arterio* W/3 insuffic*) OR (arter* W/3 obliter*) OR (arter* W/3 occlus*) OR (arter* W/3 obstruc*) OR (arter* W/3 insuffic*) OR (vascular W/3 obliter*) OR (vascular W/3 occlus*) OR (vascular W/3 obstruc*) OR (vascular W/3 insuffic*)) TITLE-ABS-KEY(bypass OR graft) TITLE-ABS-KEY((evidence W/1 based) OR (meta W/1 analys*) OR “systematic review” OR guideline OR (control* W/2 stud*) OR (control* W/2 trial*) OR (randomized W/2 stud*) OR (randomized W/2 trial*)) PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR PMID(7*) OR PMID(8*) OR PMID(9*) (1 and 2 and 3) and not 4


72S Malgor et al

CINAHL 26

27 28 29 30 31 32 33 34 35 36 37

“peripheral vascular disease” OR “peripheral arteriopath*” OR “peripheral blood vessel disease” OR “peripheral vascular disorder” OR “peripheral vessel disease” OR “blackfoot disease” OR “cold limb” OR “erythromelalgia*” OR “glomus tumor” OR “peripheral blood vessel malformation” OR “Raynaud? phenomenon” OR “Raynaud? disease” OR “Raynaud? disorder” OR “telangiectasia*” OR “blue toe syndrome” OR “Livedo Reticularis*” OR “Phlebitis*” OR “Postphlebitic Syndrome” OR “Thrombophlebitis” OR “CREST Syndrome” OR “peripheral angiopath*” OR “peripheral arterial disease” OR “claudic*” OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*” OR (arter* N3 occlus*) OR Arteriolosclerosis OR Atherosclerosis OR (Monckeberg N3 Sclerosis) OR “Thromboangiitis Obliterans” OR “Buerger disease” OR “buergers disease” OR pvd OR paod OR pad OR (peripheral N3 vascular) OR (peripheral N3 arter*) OR (athero* N3 obliter*) OR (athero* N3 occlus*) OR (athero* N3 obstruc*) OR (athero* N3 insuffic*) OR (arterio* N3 obliter*) OR (arterio* N3 occlus*) OR (arterio* N3 obstruc*) OR (arterio* N3 insuffic*) OR (arter* N3 obliter*) OR (arter* N3 occlus*) OR (arter* N3 obstruc*) OR (arter* N3 insuffic*) OR (vascular N3 obliter*) OR (vascular N3 occlus*) OR (vascular N3 obstruc*) OR (vascular N3 insuffic*) (MH “Peripheral Vascular Diseasesþ”) (MH “Intermittent Claudication”) (MH “Arterial Occlusive Diseasesþ”) 1 or 2 or 3 or 4 (“graft”) or (MH “Graftsþ”) “bypass” 6 or 7 (evidence N1 based) OR (meta N1 analys*) OR “systematic review” OR guideline OR (control* N2 stud*) OR (control* N2 trial*) OR (randomized N2 stud*) OR (randomized N2 trial*) (MH “Clinical Trialsþ”) 10 or 11 5 and 8 and 11

Ovid EBM ReviewsdCochrane Central Register of Controlled Trials 1st Quarter 2010 (updated through June 2014) #

Searches

Results

1 2 3 4 5 6 7 8 9

exp Peripheral Vascular Diseases/ peripheral blood vessel disease*.mp. peripheral vessel disease*.mp. blackfoot disease*.mp. cold limb*.mp. erythromelalgia*.mp. glomus tumor*.mp. peripheral blood vessel malformation*.mp. (Raynaud* adj2 (phenomenon or disease* or disorder*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] telangiectasia*.mp. blue toe syndrome*.mp. Livedo Reticularis*.mp. Phlebitis*.mp. Postphlebitic Syndrome.mp. Thrombophlebitis.mp. CREST Syndrome*.mp. peripheral angiopath*.mp. exp Arterial Occlusive Diseases/ (arter* adj3 occlus*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] Arteriolosclerosis.mp. Atherosclerosis.mp. (Monckeberg adj3 Sclerosis).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] Thromboangiitis Obliterans.mp. (Buerger disease or buergers disease).mp. (pvd or paod or pad).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] (peripheral adj3 (vascular or arter*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] (obstruct* adj3 arter*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] exp intermittent claudication/ angina cruris.mp. angiosclerotica intermittens.mp. claudic*.mp. exp peripheral occlusive artery disease/ (arter* adj3 obliter*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] ((athero* or arterio* or arter* or vascular) adj3 (obliter* or occlus* or obstruc* or insuffic*)).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] ((leg or limb) adj3 isch*).mp. [mp¼title, original title, abstract, mesh headings, heading words, keyword] or/1-35 exp Stents/ stent*.mp. 37 or 38 36 and 39 limit 40 to yr¼“2009 -Current”

1827 0 1 0 25 6 0 0 401

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

155 0 2 376 31 1257 2 5 4292 1706 4 3020 0 20 15 869 2619 417 572 0 0 1073 0 153 2806 499 12902 1730 2851 2851 535 60


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Scopus . 11

12 13 14 15

TITLE-ABS-KEY(“peripheral vascular disease” OR “peripheral arteriopath*” OR “peripheral blood vessel disease” OR “peripheral vascular disorder” OR “peripheral vessel disease” OR “blackfoot disease” OR “cold limb” OR “erythromelalgia*” OR “glomus tumor” OR “peripheral blood vessel malformation” OR “Raynaud? phenomenon” OR “Raynaud? disease” OR “Raynaud? disorder” OR “telangiectasia*” OR “blue toe syndrome” OR “Livedo Reticularis*” OR “Phlebitis*” OR “Postphlebitic Syndrome” OR “Thrombophlebitis” OR “CREST Syndrome” OR “peripheral angiopath*” OR “peripheral arterial disease” OR “claudic*” OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*” OR (arter* W/3 occlus*) OR arteriolosclerosis OR atherosclerosis OR (monckeberg W/3 sclerosis) OR “thromboangiitis obliterans” OR “buerger disease” OR “buergers disease” OR pvd OR paod OR pad OR (peripheral W/3 vascular) OR (peripheral W/3 arter*) OR (athero* W/3 obliter*) OR (athero* W/3 occlus*) OR (athero* W/3 obstruc*) OR (athero* W/3 insuffic*) OR (arterio* W/3 obliter*) OR (arterio* W/3 occlus*) OR (arterio* W/3 obstruc*) OR (arterio* W/3 insuffic*) OR (arter* W/3 obliter*) OR (arter* W/3 occlus*) OR (arter* W/3 obstruc*) OR (arter* W/3 insuffic*) OR (vascular W/3 obliter*) OR (vascular W/3 occlus*) OR (vascular W/3 obstruc*) OR (vascular W/3 insuffic*)) TITLE-ABS-KEY(stent*) TITLE-ABS-KEY((evidence W/1 based) OR (meta W/1 analys*) OR “systematic review” OR guideline OR (control* W/2 stud*) OR (control* W/2 trial*) OR (randomized W/2 stud*) OR (randomized W/2 trial*)) PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR PMID(7*) OR PMID(8*) OR PMID(9*) (1 and 2 and 3) and not 4

CINAHL 38

39 40 41 42 43 44 45 46 47 48 49

“peripheral vascular disease” OR “peripheral arteriopath*” OR “peripheral blood vessel disease” OR “peripheral vascular disorder” OR “peripheral vessel disease” OR “blackfoot disease” OR “cold limb” OR “erythromelalgia*” OR “glomus tumor” OR “peripheral blood vessel malformation” OR “Raynaud? phenomenon” OR “Raynaud? disease” OR “Raynaud? disorder” OR “telangiectasia*” OR “blue toe syndrome” OR “Livedo Reticularis*” OR “Phlebitis*” OR “Postphlebitic Syndrome” OR “Thrombophlebitis” OR “CREST Syndrome” OR “peripheral angiopath*” OR “peripheral arterial disease” OR “claudic*” OR “angina cruris” OR “angiosclerotica intermittens” OR “leg isch*” OR “limb isch*” OR (arter* N3 occlus*) OR Arteriolosclerosis OR Atherosclerosis OR (Monckeberg N3 Sclerosis) OR “Thromboangiitis Obliterans” OR “Buerger disease” OR “buergers disease” OR pvd OR paod OR pad OR (peripheral N3 vascular) OR (peripheral N3 arter*) OR (athero* N3 obliter*) OR (athero* N3 occlus*) OR (athero* N3 obstruc*) OR (athero* N3 insuffic*) OR (arterio* N3 obliter*) OR (arterio* N3 occlus*) OR (arterio* N3 obstruc*) OR (arterio* N3 insuffic*) OR (arter* N3 obliter*) OR (arter* N3 occlus*) OR (arter* N3 obstruc*) OR (arter* N3 insuffic*) OR (vascular N3 obliter*) OR (vascular N3 occlus*) OR (vascular N3 obstruc*) OR (vascular N3 insuffic*) (MH “Peripheral Vascular Diseasesþ”) (MH “Intermittent Claudication”) (MH “Arterial Occlusive Diseasesþ”) 1 or 2 or 3 or 4 (MH “Stentsþ”) Stent* 6 or 7 (evidence N1 based) OR (meta N1 analys*) OR “systematic review” OR guideline OR (control* N2 stud*) OR (control* N2 trial*) OR (randomized N2 stud*) OR (randomized N2 trial*) (MH “Clinical Trialsþ”) 10 or 11 5 and 8 and 11

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