Comparative effectiveness of endovascular and surgical revascularization for patients with peripheral artery disease and critical limb ischemia: systematic review of revascularization in critical limb ischemia.

Peripheral Vascular Disease

Comparative effectiveness of endovascular and surgical revascularization for patients with peripheral artery disease and critical limb ischemia: Systematic review of revascularization in critical limb ischemia W. Schuyler Jones, MD, a,b Rowena J. Dolor, MD, a,c Vic Hasselblad, PhD, a Sreekanth Vemulapalli, MD, a,b Sumeet Subherwal, MD, a Kristine Schmit, MD, a,c Brooke Heidenfelder, PhD, a,c and Manesh R. Patel, MD a,b Durham, NC

Background For patients with critical limb ischemia (CLI), the optimal treatment to enhance limb preservation, prevent death, and improve functional status is unknown. We performed a systematic review and meta-analysis to assess the comparative effectiveness of endovascular revascularization and surgical revascularization in patients with CLI. Methods We systematically searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for relevant English-language studies published from January 1995 to August 2012. Two investigators screened each abstract and full-text article for inclusion, abstracted the data, and performed quality ratings and evidence grading. Random-effects models were used to compute summary estimates of effects, with endovascular treatment as the control group. Results We identified a total of 23 studies, including 1 randomized controlled trial, which reported no difference in amputation-free survival at 3 years (odds ratio [OR] 1.22, 95% CI 0.84-1.77) and all-cause mortality (OR 1.07, 0.73-1.56) between the 2 treatments. Meta-analysis of the observational studies showed a statistically nonsignificant reduction in all-cause mortality at 6 months (11 studies, OR 0.85, 0.57-1.27) and amputation-free survival at 1 year (2 studies, OR 0.76, 0.48-1.21) in patients treated with endovascular revascularization. There was no difference in overall death, amputation, or amputationfree survival at ≥2 years. Conclusions The currently available literature suggests that there is no difference in clinical outcomes for patients with CLI treated with endovascular or surgical revascularization. There is a paucity of high-quality data available to guide clinical decision making, especially as it pertains to patient subgroups or anatomical considerations. (Am Heart J 2014;167:489-498.e7.)

Critical limb ischemia (CLI) is the most severe condition that affects patients with peripheral artery disease (PAD). 1 The morbidity, mortality, and costs associated with CLI From the aDuke Clinical Research Institute, Duke University Medical Center, Durham, NC, b Division of Cardiology, Duke University Medical Center, Durham, NC, and cDuke Evidence-based Practice Center, Duke Clinical Research Institute, Duke University, Durham, NC. Funding: This project was funded under Contract No. 290-2007-10066-I from the Agency for Healthcare Research and Quality, US Department of Health and Human Services. The authors of this manuscript are responsible for its content. Statements in the manuscript should not be construed as endorsement by the Agency for Healthcare Research and Quality or the US Department of Health and Human Services. Deepak L. Bhatt, MD, MPH, served as guest editor for this article. Submitted November 3, 2013; accepted December 22, 2013. Reprint requests: W. Schuyler Jones, MD, University Medical Center, Box 3126, Durham, NC 27710. E-mail: [email protected] 0002-8703/$ - see front matter © 2014, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2013.12.012

are well documented; however, the optimal treatment to enhance limb preservation, prevent death, and improve functional capacity in these patients is unknown. With the evolution of endovascular technology for PAD, there has been a national shift in revascularization procedures from surgical to endovascular revascularization. 2 Before the publication of the 2011 focused update of the American College of Cardiology/American Heart Association guidelines, 1 there was no consensus recommendation on the use of surgical or endovascular revascularization for CLI patients. The 2011 update incorporated results from a single randomized controlled trial (RCT) called BASIL and concluded that both revascularization strategies had “broadly similar” outcomes in CLI patients who were suitable for either angioplasty or surgery. 3 In a systematic review sponsored by the Agency for Healthcare Research and Quality (AHRQ), we evaluated

American Heart Journal April 2014

490 Jones et al

Figure 1

Literature flow diagram. IC, intermittent claudication.

the comparative effectiveness of various treatments for patients with PAD. 4 In this manuscript, we specifically address the following in patients with CLI: (a) the comparative effectiveness of endovascular revascularization and surgical revascularization for outcomes including all-cause mortality, amputation, amputation-free survival, wound healing, quality of life, repeat revascularization, and vessel patency; (b) whether the effectiveness of these treatments varies based on subgroup; and (c) safety concerns associated with endovascular and surgical revascularization techniques.

search details are presented in the full AHRQ report. 4 We date limited our search to articles published since 1995, corresponding with the period when contemporary studies on endovascular and surgical revascularization were published. We supplemented the electronic searches with a manual search of references from 132 systematic review articles. We also searched the gray literature of study registries and conference abstracts for relevant articles from completed studies, including ClinicalTrials.gov, the World Health Organization's International Clinical Trials Registry Platform Search Portal, and ProQuest COS Conference Papers Index. Figure 1 depicts the flow of articles through the literature search and screening process.

Methods

Study selection

We followed established methods and adhered to the Preferred Reporting Items for Systematic Reviews and MetaAnalyses statement for reporting systematic reviews and meta-analyses in health care interventions. 5 The written protocol is posted on the AHRQ Effective Health Care Program Web site. 6

We included English-language randomized trials or observational studies with relevant treatment comparisons (endovascular vs surgical revascularization) and outcomes (all-cause mortality, cardiovascular events [myocardial infarction, stroke, cardiovascular death], lower extremity amputation, amputationfree survival, quality of life, wound healing, pain score, vessel patency, and repeat vascularization). Studies reporting safety concerns associated with each treatment strategy were also included: adverse drug reactions, bleeding, contrast nephropathy, radiation exposure, infection, and periprocedural complications causing acute limb ischemia.

Data sources and searches To identify the relevant published literature, we searched PubMed, Embase, and the Cochrane Database of Systematic Reviews from January 1, 1995, to August 13, 2012. Complete

American Heart Journal Volume 167, Number 4

Data extraction and quality assessment Abstracted data included study characteristics (design, country, funding source); patient characteristics (age, sex, race); PAD diagnosis (asymptomatic, intermittent claudication, CLI); vascular disease risk factors (diabetes, tobacco use, chronic kidney disease, hyperlipidemia); interventionspecific factors such as aspirin, dual antiplatelet therapy, type and duration of exercise training, type of endovascular revascularization (angioplasty, stenting, atherectomy), or type of surgical revascularization (endarterectomy, surgical bypass); anatomy-specific factors such as location of stenosis, pattern of stenosis, burden of disease, degree of calcification, or number of below-knee vessel runoff; and safety outcomes, including adverse drug reactions, contrast nephropathy, radiation exposure, infection, bleeding, exercise-related harms, and periprocedural complications causing acute limb ischemia. We evaluated the quality of individual studies using the approach described in AHRQ's “Methods Guide for Effectiveness and Comparative Effectiveness Reviews.” 7 To indicate the summary judgment of the quality of the individual studies, we used the ratings of good, fair, or poor based on their adherence to well-accepted standard methodologies and adequate reporting.

Data synthesis and analysis Dichotomous variables were summarized by proportions and associated P values. We then determined the feasibility of completing a quantitative synthesis (ie, meta-analysis). Feasibility depended on the volume of relevant literature, conceptual homogeneity of the studies, and completeness of the reporting of results. We considered meta-analysis for comparisons where at least 3 studies reported the same outcome. Dichotomous outcome measures comparing 2 treatments were combined, and odds ratios (ORs) were computed using a random-effects model as implemented in Comprehensive MetaAnalysis Version 2 (Biostat, Englewood, NJ). We tested for statistical heterogeneity between studies (Q and I 2 statistics) while recognizing that the power to detect such heterogeneity may be limited. Potential clinical heterogeneity between studies was reflected through the CIs of the summary statistics obtained from a random-effects approach. We present summary estimates, SEs, and CIs in our data synthesis. Two reviewers evaluated the strength of evidence using the 4 required domains described in AHRQ's “Methods Guide” 7: risk of bias, consistency, directness, and precision. We assigned an overall grade for the strength of evidence as high (evidence reflects the true effect), moderate (further research may change the estimate of effect), low (further research is likely to change the estimate), or insufficient (an estimate of effect is not possible with the available data). We assessed applicability of studies using the method described in “Methods Guide.” 7,8

Role of the funding source This topic was nominated by the American Heart Association and the American College of Cardiology and selected by AHRQ for systematic review by an Evidence-based Practice Center. A representative from AHRQ served as a Contracting Officer's Technical Representative and provided technical assistance

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during the conduct of the full evidence report and provided comments on draft versions of the full evidence report. The AHRQ did not directly participate in the literature search, determination of study eligibility criteria, data analysis or interpretation, or preparation, review, or approval of the manuscript for publication.

Results We identified 23 unique studies that evaluated the comparative effectiveness of endovascular and surgical revascularization in 12,779 patients with CLI (Table and online Appendix). 3,9-30 The mean age of study participants in the included studies was 61 to 83 years of age. The proportion of female patients ranged from 1% to 58%, with a median of 43%. Sample sizes for individual studies ranged from 73 to 4,929 patients. Study durations ranged from 30 days to 60 months. Of the 23 studies, 1 was an RCT (good quality), and 22 were observational (1 good quality, 11 fair, 10 poor). Eight studies (35%) were conducted in the United States or Canada, with the rest international. Funding source was reported in only 2 studies (9%), with government agencies funding both studies.

All-cause mortality Eighteen studies of CLI patients reported all-cause mortality rates during follow-up (Figure 2).3,9-13,15,17-22,24,26,27,29,30 In a random-effects model, overall mortality was numerically lower in patients treated with endovascular revascularization when compared with surgical revascularization at 6 months (OR 0.79, 0.54-1.15). No difference in overall mortality was observed when outcomes were reported between 1 and 2 years (OR 1.01, 0.80-1.28) or after 3 years (OR 1.06, 0.76-1.46) in patients treated with endovascular or surgical revascularization. Lower extremity amputation Seventeen studies of CLI patients reported rates of lower extremity (LE) amputation during followup (Figure 3). 3,9-13,17,18,20-24,26-29 The overall OR estimate for LE amputation at b2 years was 0.88 (0.63-1.21). There was no difference in LE amputation rates at 2 to 3 years (OR 1.05, 0.73-1.50) and N5 years (OR 1.06, 0.70-1.59) between treatment strategies. Amputation-free survival Seven studies of CLI patients reported amputation-free survival during follow-up (Figure 4). 3,11,17,21,22,26,30 At 1 year, there was a trend toward improved amputation-free survival in patients treated with endovascular revascularization when compared with surgical revascularization (summary OR 0.82, 0.61-1.11). No difference in amputation-free survival was observed at 2 to 3 years (OR 0.96, 0.74-1.24) and N5 years (OR 0.89, 0.59-1.34) between treatment strategies.


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Table. Study characteristics Study/quality

Study details

Adam et al 3 (BASIL Study)/good Ah Chong et al 9/poor

RCT Total N = 452

Dorigo et al 10/fair

Observational Total N = 73

Dosluoglu et al 11/fair


Faglia et al 12/fair


Hynes et al 13/fair Jerabek et al 14/poor

Observational Total N = 137 Observational Total N = 131

Johnson et al 15/fair Khan et al 16/poor

Observational Total N = 150 Observational Total N = 358 patients, 412 limbs Observational Total N = 858

Korhonen et al 17/good Kudo et al 18/poor


Soderstrom et a l 21/fair

Observational Total 237 limbs Observational Total 124 limbs Observational Total 99 procedures Observational Total

Sultan and Hymes22,37/fair Taylor et al 23/fair Taylor et al 24/poor

Observational Total N = 309 Observational Total N = 122 Observational Total N = 841

Taylor et al 25/poor


Varela et al 26/fair

Observational Total N = 88 patients, 91 limbs Observational Total N = 188

Laurila et al 19/poor 20

Loor et al /fair

Varty et al 27,38/fair Venermo et a l 28/poor

N = 192 patients, N = 118 patients, N = 92 patients, N = 1023

Wolfle et al 29/poor

Observational Total N = 597 patients, 732 procedures Observational Total N = 209

Zdanowski et al 30/poor


Intervention (n) Percutaneous transluminal angioplasty (n = 224) Percutaneous transluminal angioplasty (n = 92) Percutaneous transluminal angioplasty (n = 34) Percutaneous transluminal angioplasty (n = 295) Percutaneous transluminal angioplasty (n = 292) Subintimal angioplasty (n = 88) Percutaneous transluminal angioplasty (n = 36) Angioplasty (n = 26) Unspecified endovascular intervention (n = 197 patients, 236 limbs) Percutaneous transluminal angioplasty (n = 517) Angioplasty ± stent (n = 153 limbs)

Comparator (n) Surgical bypass (n = 228) Surgical bypass (n = 364) ± stent

Surgical bypass (n = 39)

± stent

Surgical bypass (n = 138)

± stent

Proximal or distal bypass grafting (n = 40) Surgical bypass (49) Surgical bypass (n = 95)

± stent

Surgical bypass (n = 44) Surgical bypass (n = 161 patients, 176 limbs) Surgical bypass (n = 341)

Percutaneous transluminal angioplasty (n = 86) Atherectomy (n = 33 patients, 34 procedures) Percutaneous transluminal angioplasty (n = 262) Subintimal angioplasty (n = 190) Percutaneous transluminal angioplasty ± stent (n = 65) Unspecified endovascular intervention (n = 299) Percutaneous transluminal angioplasty (n = 316) Unspecified endovascular intervention (n = 42 limbs) Percutaneous transluminal angioplasty (n = 108 procedures) Percutaneous transluminal angioplasty (n = 377 procedures) Percutaneous transluminal angioplasty (n = 84) Percutaneous transluminal angioplasty (n = 1199)

Vessel patency Nine studies of CLI patients reported primary or secondary patency rates during study follow-up (online Appendix Supplementary Figure). 9-11,13,14,18,20,23,26 Rates of primary patency favored endovascular revascularization when compared with surgical revascularization at 1 year (OR 0.63, 0.46-0.86). Rates of secondary patency favored endovascular revascularization at both 1 year (OR 0.57, 0.40-0.82) and 2 to 3 years (OR 0.49, 0.28-0.85). Other clinical end points Only 1 study reported the incidence of wound healing in CLI patients during study follow-up. 26 This study showed that the percentage of patients with wound healing and the mean time to wound healing were both improved with

Surgical bypass (n = 84 limbs) Surgical bypass (n = 38) Surgical bypass (n = 59 patients, 65 procedures) Surgical bypass (n = 761) Surgical bypass (n = 119) Surgical bypass (n = 57) Surgical bypass (n = 519) Open surgery (n = 361) Surgical bypass (n = 49 limbs) Surgical bypass (n = 68 procedures) Surgical bypass (n = 355 procedures) Surgical bypass (n = 125) Surgical bypass (n = 3730)

surgical revascularization when compared with endovascular revascularization. No study reported the effect of endovascular and surgical revascularization on analog pain scale. Nine studies reported hospital length of stay during the index hospitalization. 3,9,12-14,18,20,22,26 The range of length of stay was 1 to 15 days in the endovascular revascularization group and 2 to 37 days in the surgical revascularization group.

Variations in treatment effectiveness Seven studies in CLI patients reported variations in treatment effectiveness by subgroup (age, anatomical factors, presence of tissue loss at index procedure, use of bypass conduit, use of subintimal angioplasty technique). 3,11,20,21,23,30 Data derived from the observational


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Figure 2

Forest plots of all-cause mortality in CLI patients: b6 months (A), 1 to 2 years (B), N3 years (C). Obs, observational study.

studies showed that, with advanced age, patients in the endovascular group generally fared worse in terms of mortality and amputation. In the single RCT of CLI patients, the use of an autologous vein was associated with improved outcomes when compared with prosthetic conduit. 3 In

addition, the performance of subintimal angioplasty was associated with statistically nonsignificant worse outcomes when compared with standard angioplasty in this study. No studies reported results based on sex, race, smoking status, or the presence of renal disease.


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Figure 3

Forests plots of LE amputation in CLI patients: b2 years (A), 2 to 3 years (B), N5 years (C).

Discussion We identified 23 studies (1 RCT, 22 observational) that evaluated the comparative effectiveness and safety of endovascular and surgical revascularization in 12,779 patients with CLI. Of the clinical outcomes that were reported, including overall mortality, amputation rates, and amputation-free survival, there were trends favoring endovascular revascularization when compared with

surgical revascularization in short-term follow-up (6 months to 1 year), but no differences between the 2 treatment strategies were observed during longer followup. In addition, all results were nonsignificant and inconsistent. There were few studies that assessed functional outcomes, quality of life, or cardiovascular outcomes (cardiovascular mortality, nonfatal stroke, nonfatal myocardial infarction, or composite events).


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Figure 4

Forests plots of amputation-free survival in CLI patients: b1 years (A), 2 to 3 years (B), N5 years (C).

Furthermore, few studies measured the effect of treatment based on subgroups or the safety of these treatments. The strength of evidence was rated low or insufficient for most findings (online Appendix Supplementary Table II). The results from this meta-analysis highlight the relative dearth of high-quality data available to aid clinical decision making around revascularization options in patients with CLI. The available evidence for CLI revascularization is also significantly limited with regard to applicability to current practice. The sole RCT conducted in the CLI population, the BASIL study, 3 enrolled patients N10 years ago, and in that study, endovascular stent placement was not allowed in the angioplasty arm. Subsequent introduction of newer atherectomy devices, drug-coated balloons, nitinol stents, and drug-eluting stents has the potential to improve the durability and long-term clinical outcomes in

patients treated with endovascular therapy. The recent announcement by the National Institutes of Health that funding has been approved for the BEST Trial is a positive step forward for the field of vascular medicine and for patients with PAD and CLI. We identified numerous limitations, areas of evidence gaps, and areas for potential future research in PAD. The primary limitation of the available evidence for the CLI population was the lack of RCTs comparing endovascular with surgical revascularization. The current literature search for PAD also revealed many single-center, singlemodality observational studies that were not included in our comparative effectiveness review based on our inclusion/exclusion criteria. In addition, our literature search identified many within-treatment comparisons, for example, studies comparing 2 types of surgical bypass or 2 types of endovascular interventions, but few studies


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evaluated direct comparisons between treatments. Given this lack of direct comparisons, objective performance goals have been proposed as a method to compare novel device therapies for patients with CLI. However, these criteria are highly biased toward surgical revascularization, and comparison of endovascular therapies to the objective performance goal remains difficult. 31 Of the identified studies included in our review, there was notable variation in the type of outcomes reported and follow-up time points, making it difficult to draw meaningful conclusions. In addition, there was a lack of assessment of functional capacity or quality-of-life measures in the mainly retrospective, observational studies. Although amputation-free survival has been reported more frequently over the past decade, very few studies reported other vascular events such as myocardial infarction, stroke, or minor amputations. The relationship between vessel patency and functional outcomes or quality of life is not well established, so this is viewed more as a surrogate clinical outcome and not a direct clinical outcome. Recent efforts have attempted to better define crucial end points for studies of PAD and CLI patients, 32-35 and an ongoing effort (Peripheral Academic Research Consortium) continues to harmonize outcomes for PAD studies with broad representation from academia (vascular surgery, vascular medicine, cardiology, radiology), industry, and regulatory agencies (US Food and Drug Administration and Japan's Pharmaceuticals and Medical Devices Agency). Ultimately, more RCTs or welldesigned, prospective cohort studies with assessment of limb outcomes, mortality, functional capacity, quality of life, and additional vascular outcomes are needed. The major difference between our findings and the National Institute for Health and Clinical Excellence guidelines 36 is the exclusion of studies before 1995 in our report. This decision was made due to the continued improvement in technology of endovascular revascularization since this time. Both the American College of Cardiology/American Heart Association guidelines and National Institute for Health and Clinical Excellence guidelines recommend that patient-specific factors (age, diabetes mellitus, renal disease), anatomical factors, and patient preferences be accounted for in the decisionmaking process. We found no evidence to support or refute these recommendations and no comparative safety evidence for either strategy.

Conclusions The available evidence for treatment of patients with CLI is limited by few RCTs that provide direct comparisons of revascularization treatment options. There do not appear to be significant differences in mortality or limb outcomes between endovascular and surgical revascularization in CLI patients. However, these data are derived from 1 RCT and many observational studies, and the

presence of clinical heterogeneity of these results makes conclusions for clinical outcomes uncertain and highlights the need for further research. Clinical decision making for patients with CLI will continue to be limited by revascularization choices based on treating physician preference and clinical judgment rather than on sound data until RCTs and well-designed prospective cohort studies are performed. This meta-analysis should serve as notice to those who make clinical and health policy decisions that the current evidence base is insufficient in this high-risk population.

Acknowledgements We thank Megan von Isenburg, MSLS, for help with the literature search and retrieval; Rachael Posey, MSLS, and Megan Chobot, MSLS, for project coordination; and Liz Wing, MA, for editorial help.

Disclosures M.R.P. reports research grants from AstraZeneca, NHLBI, Maquet, Johnson & Johnson, and Genzyme and consultant fees/honoraria from Bayer Healthcare, OrthoMcNeil-Janssen, theheart.org, Ikaria, and Duke CME. W.S.J. reports research grants to the DCRI from AstraZeneca and Bristol-Myers Squibb. All other coauthors have no conflicts of interest to disclose. Author contributions: W.S.J., R.J.D., S.V., S.S., K.S., B.H., and M.R.P. conceived the study concept and design. W.S.J., R.S.D., S.V., S.S., K.S., and M.R.P. were responsible for data collection. W.S.J., R.J.D., V.H., and S.V. were responsible for data analysis. All authors took part in the interpretation of the data. W.S.J., R.J.D., and M.R.P. drafted the report, and all authors were given the opportunity to comment on the report and provided critical revisions for intellectual content.

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20. Loor G, Skelly CL, Wahlgren CM, et al. Is atherectomy the best firstline therapy for limb salvage in patients with critical limb ischemia? Vasc Endovasc Surg 2009;43:542-50. 21. Soderstrom MI, Arvela EM, Korhonen M, et al. Infrapopliteal percutaneous transluminal angioplasty versus bypass surgery as firstline strategies in critical leg ischemia: a propensity score analysis. Ann Surg 2010;252:765-73. 22. Sultan S, Hynes N. Five-year Irish trial of CLI patients with TASC II type C/D lesions undergoing subintimal angioplasty or bypass surgery based on plaque echolucency. J Endovasc Ther 2009;16: 270-83. 23. Taylor SM, Kalbaugh CA, Blackhurst DW, et al. Postoperative outcomes according to preoperative medical and functional status after infrainguinal revascularization for critical limb ischemia in patients 80 years and older. Am Surg 2005;71:640-5 [discussion 645–6]. 24. Taylor SM, Kalbaugh CA, Blackhurst DW, et al. Determinants of functional outcome after revascularization for critical limb ischemia: an analysis of 1000 consecutive vascular interventions. J Vasc Surg 2006;44:747-55 [discussion 755–6]. 25. Taylor SM, York JW, Cull DL, et al. Clinical success using patient-oriented outcome measures after lower extremity bypass and endovascular intervention for ischemic tissue loss. J Vasc Surg 2009; 50:534-41 [discussion 541]. 26. Varela C, Acin F, De Haro J, et al. Influence of surgical or endovascular distal revascularization of the lower limbs on ischemic ulcer healing. J Cardiovasc Surg (Torino) 2011;52:381-9. 27. Varty K, Nydahl S, Butterworth P, et al. Changes in the management of critical limb ischaemia. Br J Surg 1996;83:953-6. 28. Venermo M, Biancari F, Arvela E, et al. The role of chronic kidney disease as a predictor of outcome after revascularisation of the ulcerated diabetic foot. Diabetologia 2011;54(12):2971-7. 29. Wolfle KD, Bruijnen H, Reeps C, et al. Tibioperoneal arterial lesions and critical foot ischaemia: successful management by the use of short vein grafts and percutaneous transluminal angioplasty. Vasa 2000; 29:207-14. 30. Zdanowski Z, Troeng T, Norgren L. Outcome and influence of age after infrainguinal revascularisation in critical limb ischaemia. The Swedish Vascular Registry. Eur J Vasc Endovasc Surg 1998;16: 137-41. 31. Conte MS, Geraghty PJ, Bradbury AW, et al. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg. 2009; 50:1462–73 e1-3. 32. Creager MA, Belkin M, Bluth EI, et al. 2012 ACCF/AHA/ACR/SCAI/SIR/STS/SVM/SVN/SVS key data elements and definitions for peripheral atherosclerotic vascular disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Clinical Data Standards for Peripheral Atherosclerotic Vascular Disease). Circulation 2012;125:395-467. 33. Olin JW, Allie DE, Belkin M, et al. ACCF/AHA/ACR/SCAI/SIR/SVM/SVN/SVS 2010 performance measures for adults with peripheral artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on performance measures, the American College of Radiology, the Society for Cardiac Angiography and Interventions, the Society for Interventional Radiology, the Society for Vascular Medicine, the Society for Vascular Nursing, and the Society for Vascular Surgery (Writing Committee to Develop Clinical Performance Measures for Peripheral Artery Disease). Circulation 2010;122:2583-618.

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34. Diehm N, Pattynama PM, Jaff MR, et al. Clinical endpoints in peripheral endovascular revascularization trials: a case for standardized definitions. Eur J Vasc Endovasc Surg 2008;36:409-19. 35. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007;33(Suppl 1):S1-S75. 36. National Institute for Health and Clinical Excellence. Lower limb peripheral arterial disease: diagnosis and management. NICE Clinical


Guideline [draft]. March 2012. http://www.nice.org.uk/guidance/ index.jsp?action=folder&o=58406. Accessed May 22, 2012. 37. Sultan S, Hynes N. Mid-term results of subintimal angioplasty for critical limb ischemia 5-year outcomes. Vasc Dis Manage 2011;8: E155-63. 38. Varty K, Nydahl S, Nasim A, et al. Results of surgery and angioplasty for the treatment of chronic severe lower limb ischaemia. Eur J Vasc Endovasc Surg 1998;16:159-63.


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Appendix Supplementary Table I. Study characteristics

Study/quality

Study details

Adam, 2005 (4) Bradbury, 2010 (38-42) Forbes, 2010 (43) (BASIL Study)

RCT Multicenter

Good

Total N = 452 Mean age: NR Female n = 183 % Female: 40% Race: NR Observational Single center Asia Funding: NR Total N = 405 Median age: 74 Female n = 196 % Female: 48% Race: NR Observational Single center Europe Funding: NR Total N = 73 Mean age: 73-75 Female n = 21 % Female: 29% Race: NR

Ah Chong, 2009 (10) Poor

Dorigo, 2009 (11) Fair

Europe Funding: government

Dosluoglu, 2012 (12) Fair

Observational Single center US Funding: NR Total N = 433 Mean age: 69-73 N Female: NR % Female: NR Race: NR

Faglia, 2012 (13) Fair

Observational Single center US Funding: NR Total N = 344

Intervention (n) and Comparator (n)

Use of medical therapy and presence of concomitant CAD in each group

Timing and outcomes reported

Intervention Percutaneous transluminal angioplasty (n = 224) Concomitant therapy: Could include antiplatelet agent, statin, or warfarin Comparator Surgical bypass (n = 228) Concomitant therapy (both groups): Could include antiplatelet agent, statin, or warfarin Intervention Percutaneous transluminal angioplasty (n = 92) Comparator Surgical bypass (n = 364) Concomitant therapy (both groups): NR

PTA group: Statin, 34%

Timing: 36 m Individual

Antiplatelet, 54% Prior MI, 20%

Mortality Amputation-free survival

Surgical bypass group: Statin, 33% Antiplatelet, 62% Prior MI, 15%

Myocardial infarction Stroke Length of stay Quality of life

PTA group: Statin, NR Antiplatelet, NR Coronary disease, 48% Surgical bypass group: Statin, NR Antiplatelet, NR Coronary disease, 44%

Timing: 24 m Individual Mortality Length of stay Vessel patency Limb salvage

Intervention Percutaneous transluminal angioplasty ± stent (n = 34) Comparator Surgical bypass (n = 39) Concomitant therapy (both groups): Could include oral anticoagulant, antiplatelet drug(s), or LMWH (postoperative) Intervention Percutaneous transluminal angioplasty ± stent (n = 295) Comparator Surgical bypass (n = 138) Concomitant therapy (both groups): ASA and/or other antiplatelet agents


Timing: 13 m Individual Mortality Repeat revascularization Length of stay Major amputation Quality of life

PTA group: Statin, NR Antiplatelet, NR Coronary disease, 58% Surgical bypass group: Antiplatelet, NR Statin, NR Coronary disease, 60%

Timing: 30 d, 1 y, 2 y, 3 y, 4 y, 5 y Individual Total mortality Repeat revascularization Vessel patency Amputation-free survival Limb salvage ABI Composite Total mortality Cardiovascular mortality Nonfatal myocardial infarction Stroke Limb ischemia Timing: 30 d, 6 m, 16 m, 18 m

Intervention Percutaneous transluminal angioplasty (n = 292) Comparator

PTA group: Statin, NR Antiplatelet, NR Coronary disease, 57% Surgical bypass group:

Individual Total mortality Repeat revascularization Length of stay (continued on next page)


498.e2 Jones et al

Supplementary Supplementary Table Table II (continued) (continued )

Study/quality

Study details Mean age: 73-76 % Female: 35% Female n = 119 Race: NR

Hynes, 2004 (14) Fair

Observational Single center Europe Funding: NR Total N = 137 Mean age: 70 Female n = 74 % Female: 54% Race: NR

Jerabek, 2003 (15) Poor

Observational Single center Europe Funding: NR Total N = 131 Female n = 30 % Female: 23% Mean age: 61-62 Race: NR Observational Single center UK Funding: NR Total N = 150 Mean age: 71 Female n = 58 % Female: 39% Race: NR Observational Single center US Funding: NR Total N = 358 patients, 412 limbs Mean age: 69-72 Female n = 3 % Female: 1% Race: NR Observational Single center Funding: NR Europe Total N = 858 Mean age: 72-75 Female n = 374 % Female: 44% Race: NR

Johnson, 1997 (16) Fair

Khan, 2009 (17) Poor

Korhonen, 2011 (18) Good



Proximal or distal bypass grafting (n = 40) Concomitant therapy (both groups): Aspirin and/or other antiplatelet agents Intervention Subintimal angioplasty (n = 88) Comparator Surgical bypass (49) Concomitant therapy (both groups): Aspirin, pravastatin, and cardioselective β-blockers during and after treatment; postprocedure, clopidogrel was added for 1 y Intervention Percutaneous transluminal angioplasty ± stent (n = 36) Comparator Surgical bypass (n = 95) Concomitant therapy (both groups): NR

Statin, NR

Timing and outcomes reported Major amputation

Coronary disease, 73%

Restenosis

Antiplatelet, NR

Periprocedural complications

PTA group: Statin, NR Antiplatelet, NR Coronary disease, NR Surgical bypass group: Statin, NR Antiplatelet, NR Coronary disease, NR

Timing: 15 m Individual Mortality Myocardial infarction Length of stay Limb salvage Vessel patency Change in ABI

PTA group: Statin, NR Antiplatelet, NR Coronary disease, NR Statin, NR Surgical bypass group: Antiplatelet, NR Coronary disease, NR

Timing: 2-105 d Individual Length of stay

Intervention Angioplasty (n = 26) Comparator Surgical bypass (n = 44) Concomitant therapy (both groups): NR


Intervention Unspecified endovascular intervention (n = 197 patients, 236 limbs) Comparator Surgical bypass (n = 161 patients, 176 limbs) Concomitant therapy (both groups): NR


Timing: 6 m, 1 y Individual Total mortality Quality of life Pain Anxiety Depression ADL index Mobility score Timing: 36 m Individual Limb salvage

Intervention Percutaneous transluminal angioplasty ± stent (n = 517) Comparator Surgical bypass (n = 341) Concomitant therapy (Endovascular): Clopidogrel 300 mg once, then 75 mg daily at least 1 m (unless already on anticoagulation); ASA 100 (Surgical): LMWH during hospital; ASA 100 mg daily


Timing: 2.6 y Individual Mortality Limb salvage Amputation-free survival Freedom from repeat revascularization


Jones et al 498.e3

Supplementary Table I (continued) (continued )

Study/quality

Study details

Kudo, 2006 (19) Poor

Observational Single center US Funding: NR Total N = 192 patients, 237 limbs Mean age: 70 N Female: NR % Female: NR Race: NR Observational Multicenter Europe Funding: NR Total N = 118 patients, 124 limbs Mean age: 70-74 N Female: NR % Female: NR Race: NR Observational Single center US Funding: NR Total N = 92 patients, 99 procedures Mean age: 64-69 N Female: NR % Female: NR Race: NR

Laurila, 2000 (20) Poor

Loor, 2009 (21) Fair

Soderstrom, 2010 (22) Fair

Sultan, 2011 (44) Sultan, 2009 (23) Fair

Taylor, 2005 (24) Fair

Observational Single center Europe Total N = 1023 Funding: NR Female n = 589 Mean age: 74-75 % Female: 58% Race: NR Single center Observational Europe Funding: NR Total N = 309 Mean age: 70-73 Female n = 146 Race: NR % Female: 47%

Observational Single center US




Intervention Angioplasty ± stent (n = 153 limbs) Comparator Surgical bypass (n = 84 limbs) Concomitant therapy (both groups): NR


Timing: 23 m Individual Mortality Length of stay Vessel patency Limb salvage Clinical improvement

Intervention Percutaneous transluminal angioplasty (n = 86) Comparator Surgical bypass (n = 38) Concomitant therapy (both groups): ASA 50-100 mg daily


Timing: 20 m Individual Mortality

Intervention Atherectomy (n = 33 patients, 34 procedures) Comparator Surgical bypass (n = 59 patients, 65 procedures) Concomitant therapy (Postintervention, both groups): Antiplatelet agents (ASA or clopidogrel or anticoagulants (warfarin, heparin or enoxaparin) Intervention Percutaneous transluminal angioplasty (n = 262) Comparator Surgical bypass (n = 761) Concomitant therapy (both groups): NR


Individual Timing: 17 m Mortality Length of stay Vessel patency Limb salvage

PTA group: Statin, NR Antiplatelet, NR Coronary disease, 66% Surgical bypass group: Statin, NR

Timing: 2.4 y Individual Mortality Repeat revascularization Limb salvage Amputation-free survival

Subintimal angioplasty (n = 190) Intervention Comparator Surgical bypass (n = 119) Concomitant therapy: (Preintervention, both groups) ASA, pravastatin, cardioselective beta-blocker and/or calcium channel blocker; (Postintervention, both groups) clopidogrel

Statin, NR PTA group: Antiplatelet, NR Coronary disease, 48% Surgical bypass group: Statin, NR Antiplatelet, NR Coronary disease, 45%

Intervention Percutaneous transluminal angioplasty ± stent (n = 65)

PTA group: Statin, NR Antiplatelet, NR

Antiplatelet, NR Coronary disease, 65%

Freedom from repeat revascularization Timing: 5 y Individual Mortality Length of stay Major amputation Amputation-free survival Total mortality Clinical improvement Nonfatal myocardial infarction Repeat revascularization Composite Stroke Major amputation Timing: 36 m Individual Vessel patency (continued on next page)


498.e4 Jones et al


Study/quality

Taylor, 2006 (25) Poor

Taylor, 2009 (26) Poor

Varela, 2011 (27) Fair

Varty, 1996 (28) Varty, 1998 (45) Fair

Venermo, 2011 (29) Poor

Wolfle, 2000 (30) Poor

Study details




Funding: NR Total N = 122 Mean age: 83 Female n = 49 % Female: 40% Race: 80% White Observational Single center US Funding: NR Total N = 841 Mean age: 68 Female n = 362 % Female: 43% Race: 76.1% White, 23.1% Black, 0.8% Other Observational Single center US Funding: NR Total N = 677 Mean age: 69 Female n = 297 % Female: 44% Race: 72% white Observational Single center Europe Funding: NR Total N = 88 patients, 91 limbs Mean age: NR N Female: NR % Female: NR Race: NR Observational Single center UK Funding: NR Total N = 188 Mean age: 74 Female n = 81 % Female: 43% Race: NR

Comparator Surgical bypass (n = 57) Concomitant therapy (both groups): NR

Coronary disease, NR Surgical bypass group: Statin, NR Antiplatelet, NR Coronary disease, NR

Wound healing Mortality Limb salvage Amputation-free survival Maintenance of ambulation

Intervention Unspecified endovascular intervention (n = 299) Comparator Surgical bypass (n = 519) Concomitant therapy (both groups): NR


Timing: 24 m, 60 m Individual Vessel patency Limb salvage Maintenance of ambulation

Intervention Percutaneous transluminal angioplasty (n = 316) Comparator Open surgery (n = 361) Concomitant therapy (both groups): NR


Timing: 6 m, 1 y Individual Vessel patency Wound healing Limb salvage Survival

Intervention Unspecified endovascular intervention (n = 42 limbs) Comparator Surgical bypass (n = 49 limbs) Concomitant therapy (both groups): NR


Timing: 310 d Individual Mortality Hospitalization Vessel patency Wound healing Major amputation Limb salvage Amputation-free survival

Intervention Percutaneous transluminal angioplasty (n = 108 procedures) Comparator Surgical bypass (n = 68 procedures) Concomitant therapy (both groups): NR


Timing: 12 m Individual Mortality Major amputation Limb salvage

Observational Single center Europe Funding: NR Total N = 597 patients, 732 procedures Mean age: 72 N Female: NR % Female: NR Race: NR Observational Single center Europe Funding: Government

Intervention Percutaneous transluminal angioplasty (n = 377 procedures) Comparator Surgical bypass (n = 355 procedures) Concomitant therapy (both groups): NR


Timing: 2.8 y Individual Limb salvage

Intervention Percutaneous transluminal angioplasty (n = 84) Comparator

PTA group: Statin, NR Antiplatelet, NR Coronary disease, NR

Timing: 84 m Individual Mortality Limb salvage


Jones et al 498.e5


Study/quality

Zdanowski,1998 (31) Poor

Study details Total N = 209 Mean age: 68-70 N Female: NR % Female: NR Race: NR Observational Single center Europe Funding: NR Total N = 4929 Mean age: 76 Female n = 2612 % Female: 53% Race: NR



Surgical bypass (n = 125) Concomitant therapy (Postintervention, both groups): ASA 100 mg daily

Surgical bypass group: Statin, NR Antiplatelet, NR Coronary disease, NR

Intervention Percutaneous transluminal angioplasty (n = 1199) Comparator Surgical bypass (n = 3730) Concomitant therapy (both groups): NR



Timing: 12 m Individual Mortality Amputation-free survival

Abbreviations: ABI, ankle-brachial index; ADL, activities of daily living; ASA, acetylsalicylic acid (aspirin); LMWH, low-molecular-weight heparin; NR, not reported.


498.e6 Jones et al

Supplementary Table II. Strength of evidence ratings for endovascular versus surgical revascularization in CLI Outcome strength of evidence All-cause mortality ≤6 m

Results or effect estimate (95% CI)

CLI-Obs (11 studies, 8249 patients), OR 0.85 (0.57-1.27) SOE = Low CLI-RCT (1 study, 452 patients), OR 0.51 (0.20-1.35) Favors endovascular All-cause mortality at 1-2 y CLI-Obs (12 studies, 7850 patients), OR 1.01 (0.80-1.28) SOE = Low No difference All-cause mortality at ≥3 y CLI-Obs (7 studies, 7176 patients), OR 1.05 (0.54-2.06) SOE = Low CLI-RCT (1 study, 452 patients), OR 1.07 (0.73-1.56) No difference Nonfatal myocardial infarction CLI-RCT (1 study, 452 patients) SOE = Insufficient Inconclusive evidence due to imprecision, with 1 study reporting myocardial infarction rates (endovascular group 3% and surgical group 8%) Amputation at b2 y CLI-Obs (11 studies, 4490 patients), OR 0.73 (0.48-1.09) SOE = Low CLI-RCT (1 study, 452 patients), OR 1.23 (0.72-2.11) No difference Amputation at 2-3 y CLI-Obs (4 studies, 3187 patients), OR 1.08 (0.62-1.89) SOE = Low CLI-RCT (1 study, 452 patients), OR 1.02 (0.64-1.63) No difference Amputation after 5 y CLI-Obs (7 studies, 3101 patients), OR 1.06 (0.70-1.59) SOE = Low No difference Amputation-free survival at 1 y CLI-Obs (2 studies, 1881 patients), OR 0.76 (0.48-1.21) SOE = Low CLI-RCT (1 study, 452 patients), OR 0.87 (0.58-1.30) No difference Amputation-free survival at 2-3 CLI-Obs (3 studies, 1972 patients), y OR 0.75 (0.53-1.09) SOE = Low CLI-RCT (1 study, 452 patients), OR 1.22 (0.84-1.77) No difference Amputation-free survival after 5 CLI-Obs (4 studies, 2190 patients), y OR 0.89 (0.59-1.34) SOE = Low No difference Wound healing CLI-Obs (1 study, 91 patients) SOE = Insufficient Inconclusive evidence due to imprecision, with 1 study reporting similar rates of wound healing in the surgical revascularization group (83%) and endovascular revascularization group (80%). Primary patency at 1 y CLI-Obs (5 studies, 890 patients), OR 0.63 (0.46-0.86) SOE = Moderate No difference Primary patency at 2-3 y CLI-Obs (4 studies, 768 patients), OR 0.77 (0.24-2.42)

Supplementary Table II (continued) (continued ) Outcome strength of evidence SOE = Insufficient Secondary patency at 1 y SOE = Low Secondary patency at 2-3 y SOE = Low Length of stay SOE = Insufficient

Modifiers of effectiveness (subgroups)

SOE = Insufficient Nonfatal stroke Composite cardiovascular events Maximal walking distance or absolute claudication distance Initial claudication distance or pain-free walking distance Quality of life Analog pain scale Safety concerns (subgroups) SOE = Insufficient

Results or effect estimate (95% CI) Inconclusive evidence due to imprecision CLI-Obs (4 studies, 759 patients), OR 0.57 (0.40-0.82) Favors endovascular intervention CLI-Obs (4 studies, 815 patients), OR 0.49 (0.28-0.85) Favors endovascular intervention CLI-Obs (8 studies, 1745 patients) CLI-RCT (1 study, 452 patients) Inconclusive evidence due to inconsistency and imprecision, with individual studies reporting length of stay longer in surgical group with large SD in 3 observational studies and no variability reported in 4 observational studies and 1 RCT. Inconclusive evidence due to heterogeneity in subgroups assessed across individual studies and inability to quantitatively synthesize results. One RCT showed higher survival in autologous vein graft compared with prosthetic graft. An observational study showed worse survival in advanced age, renal failure, and with higher PAD severity. (0 studies)

Abbreviations: NR, Not reported; Obs, observational study. Gray background indicates insufficient strength of evidence.


Jones et al 498.e7

Supplementary Figure

Patency outcomes. A, Primary patency at 1 year. B, Primary patency at 2 to 3 years. C, Secondary patency at 1 year. D, Secondary patency at 2 to 3 years. Obs, observational study.

Comparison of Clinical Outcomes after Surgical and Endovascular Revascularization in Hemodialysis Patients with Critical Limb Ischemia.

Angiosome-directed revascularization for critical limb ischemia.

Predictive scoring model of mortality after surgical or endovascular revascularization in patients with critical limb ischemia.

Surveillance and follow-up after revascularization for critical limb ischemia.

Does patency matter in patients with critical limb ischemia undergoing endovascular revascularization?

Efficacy of revascularization for critical limb ischemia in patients with end-stage renal disease.

The Importance of Patency in Patients with Critical Limb Ischemia Undergoing Endovascular Revascularization for Infrapopliteal Arterial Disease.

Endovascular therapy for critical limb ischemia.

Comparison of venous and HePTFE tibial and peroneal bypasses in critical limb ischemia patients unsuitable for endovascular revascularization.

Endovascular intervention for tibial artery occlusive disease in patients with critical limb ischemia.

Intravenous iloprost for treatment of critical limb ischemia in patients unsuitable for revascularization.

Effect of single tibial artery revascularization on microcirculation in the setting of critical limb ischemia.

Graz Critical Limb Ischemia Score: A Risk Score for Critical Limb Ischemia in Peripheral Arterial Occlusive Disease.

Hybrid revascularization procedures in acute limb ischemia.

Critical limb Ischemia. Introduction.

[Distal revascularization in diabetic patients with chronic limb ischemia].

Direct Revascularization With the Angiosome Concept for Lower Limb Ischemia: A Systematic Review and Meta-Analysis.

Critical limb ischemia.

Determinants of survival and major amputation after peripheral endovascular intervention for critical limb ischemia.

Tibio-pedal arterial minimally invasive retrograde revascularization: pushing the limits of endovascular therapy in critical limb ischemia.

Management of Critical Limb Ischemia.

Preliminary study of laser doppler perfusion signal by wavelet transform in patients with critical limb ischemia before and after revascularization.

Endovascular therapy with novel high anterior tibial artery puncture for limb salvage in a case of critical lower limb ischemia.

Improving outcomes for diabetic patients undergoing revascularization for critical limb ischemia: does the quality of outpatient diabetic care matter?