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Open surgical or endovascular revascularization for acute limb ischemia

Open ArchivePublished:November 18, 2015DOI:https://doi.org/10.1016/j.jvs.2015.09.055
      Acute limb ischemia (ALI) is one of the most common vascular emergencies, with high risk for limb loss if it is not treated expediently. Endovascular therapy is less invasive and used increasingly because of patient factors that disfavor open surgery despite limited quality data to support its safety and efficacy. This evidence summary reviews literature from 1990 to 2014, comparing contemporary surgical and endovascular revascularization. Systematic review was performed with emphasis on acuity of presentation, study design, revascularization techniques, limb salvage and mortality rates, and complications. There were 2999 articles identified and 563 abstracts reviewed; 68 articles were reviewed fully and 26 critically appraised. Limb salvage, amputation-free survival, overall survival and mortality, and treatment complications were elucidated, including Medicare outcomes data. Risk factors for amputation and mortality were identified. Surgical or endovascular revascularization for ALI is achievable with acceptable limb salvage and amputation rates, which are not markedly different between the two modalities in the short term. Endovascular therapy and surgery are complementary rather than competing strategies for ALI. Further good-quality clinical trial data are needed to define longer term outcomes.
      Peripheral arterial disease affects approximately 10 million Americans.
      • Hirsch A.T.
      • Hartman L.
      • Town R.J.
      • Virnig B.A.
      National health care costs of peripheral arterial disease in the Medicare population.
      It can lead to lower extremity ischemic rest pain or tissue loss (Rutherford classification 4 to 6, or Fontaine classification III and IV). Acute limb ischemia (ALI) is defined as the presence of symptoms within 2 weeks of onset.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      • et al.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      ALI pathogenesis includes vascular stenoses with subsequent in situ thrombosis or thromboembolism from a cardiac or aortoiliac source. Stenotic lesions may indicate untreated comorbidities (eg, hypertension, hypercholesterolemia, diabetes, or tobacco use), whereas thromboembolisms implicate undiagnosed cardiac arrhythmias, myocardial infarction (MI), or mural thrombus. Limb loss risk due to ALI can be as high as 40% with an attendant mortality rate of 15% to 20%.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      • et al.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      Limb salvage (LS) revascularization is traditionally achieved with emergent surgical thromboembolectomy or bypass. Catheter-based technologic advancements have afforded a wide array of endovascular therapy (ET) amenable for treating ALI, including catheter-directed thrombolysis (CDT), pharmacomechanical thrombolysis (PMT), angioplasty, and stenting.
      • Ouriel K.
      • Shortell C.K.
      • DeWeese J.A.
      • Green R.M.
      • Francis C.W.
      • Azodo M.V.
      • et al.
      A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      Thrombolysis or peripheral arterial surgery: phase I results. TOPAS Investigators.
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
      Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
      • Weaver F.A.
      • Comerota A.J.
      • Youngblood M.
      • Froehlich J.
      • Hosking J.D.
      • Papanicolaou G.
      Surgical revascularization versus thrombolysis for nonembolic lower extremity native artery occlusions: results of a prospective randomized trial. The STILE Investigators. Surgery versus Thrombolysis for Ischemia of the Lower Extremity.
      • Kashyap V.S.
      • Gilani R.
      • Bena J.F.
      • Bannazadeh M.
      • Sarac T.P.
      Endovascular therapy for acute limb ischemia.
      • Sobel M.
      • Verhaeghe R.
      American College of Chest Physicians; American College of Chest Physicians
      Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      • Byrne R.M.
      • Taha A.G.
      • Avgerinos E.
      • Marone L.K.
      • Makaroun M.S.
      • Chaer R.A.
      Contemporary outcomes of endovascular interventions for acute limb ischemia.
      There are limited high-quality data to provide level I evidence and best practice guidelines. This evidence summary reviews current data for ALI management with open or endovascular surgery, their outcomes, and complications.

      Methods

      Systematic literature review using MEDLINE (1990-2014) was performed with querying keywords acute limb ischemia, acute occlusion, peripheral arteries, thrombectomy, thrombolysis, and complications. Clinical trials, registry reports, open vs endovascular arterial revascularization, and review articles were included. Attention was given to revascularization techniques, short- and long-term patency, LS rates, amputation-free survival (AFS), overall survival (OS), and complications.

      Results

      MEDLINE identified 2999 articles, from which 563 abstracts were reviewed; 68 articles were reviewed fully, and of these, 26 were critically evaluated.
      • Hirsch A.T.
      • Hartman L.
      • Town R.J.
      • Virnig B.A.
      National health care costs of peripheral arterial disease in the Medicare population.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      • et al.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      • Ouriel K.
      • Shortell C.K.
      • DeWeese J.A.
      • Green R.M.
      • Francis C.W.
      • Azodo M.V.
      • et al.
      A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      Thrombolysis or peripheral arterial surgery: phase I results. TOPAS Investigators.
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
      Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
      • Weaver F.A.
      • Comerota A.J.
      • Youngblood M.
      • Froehlich J.
      • Hosking J.D.
      • Papanicolaou G.
      Surgical revascularization versus thrombolysis for nonembolic lower extremity native artery occlusions: results of a prospective randomized trial. The STILE Investigators. Surgery versus Thrombolysis for Ischemia of the Lower Extremity.
      • Kashyap V.S.
      • Gilani R.
      • Bena J.F.
      • Bannazadeh M.
      • Sarac T.P.
      Endovascular therapy for acute limb ischemia.
      • Sobel M.
      • Verhaeghe R.
      American College of Chest Physicians; American College of Chest Physicians
      Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      • Byrne R.M.
      • Taha A.G.
      • Avgerinos E.
      • Marone L.K.
      • Makaroun M.S.
      • Chaer R.A.
      Contemporary outcomes of endovascular interventions for acute limb ischemia.
      • Han S.M.
      • Weaver F.A.
      • Comerota A.J.
      • Perler B.A.
      • Joing M.
      Efficacy and safety of alfimeprase in patients with acute peripheral arterial occlusion (PAO).
      • Earnshaw J.J.
      • Whitman B.
      • Foy C.
      National Audit of Thrombolysis for Acute Leg Ischemia (NATALI): clinical factors associated with early outcome.
      • Taha A.G.
      • Byrne R.M.
      • Avgerinos E.D.
      • Marone L.K.
      • Makaroun M.S.
      • Chaer R.A.
      Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia.
      • Kempe K.
      • Starr B.
      • Stafford J.M.
      • Islam A.
      • Mooney A.
      • Lagergren E.
      • et al.
      Results of surgical management of acute thromboembolic lower extremity ischemia.
      • Baril D.T.
      • Ghosh K.
      • Rosen A.B.
      Trends in the incidence, treatment, and outcomes of acute lower extremity ischemia in the United States Medicare population.
      • Blaisdell F.W.
      • Steele M.
      • Allen R.E.
      Management of acute lower extremity arterial ischemia due to embolism and thrombosis.
      • Jivegard L.
      • Holm J.
      • Schersten T.
      Acute limb ischemia due to arterial embolism or thrombosis: influence of limb ischemia versus pre-existing cardiac disease on postoperative mortality rate.
      • Yeager R.A.
      • Moneta G.L.
      • Taylor Jr., L.M.
      • Hamre D.W.
      • McConnell D.B.
      • Porter J.M.
      Surgical management of severe acute lower extremity ischemia.
      • Conte M.S.
      • Belkin M.
      • Upchurch G.R.
      • Mannick J.A.
      • Whittemore A.D.
      • Donaldson M.C.
      Impact of increasing comorbidity on infrainguinal reconstruction: a 20-year perspective.
      • Albers M.
      • Romiti M.
      • Brochado-Neto F.C.
      • De Luccia N.
      • Pereira C.A.
      Meta-analysis of popliteal-to-distal vein bypass grafts for critical ischemia.
      • Feinglass J.
      • Pearce W.H.
      • Martin G.J.
      • Gibbs J.
      • Cowper D.
      • Sorensen M.
      • et al.
      Postoperative and amputation-free survival outcomes after femorodistal bypass grafting surgery: findings from the Department of Veterans Affairs National Surgical Quality Improvement Program.
      • Adam D.J.
      • Beard J.D.
      • Cleveland T.
      • Bell J.
      • Bradbury A.W.
      • Forbes J.F.
      • et al.
      Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial.
      • Conte M.S.
      • Bandyk D.F.
      • Clowes A.W.
      • Moneta G.L.
      • Seely L.
      • Lorenz T.J.
      • et al.
      Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery.
      • Giles K.A.
      • Pomposelli F.B.
      • Spence T.L.
      • Hamdan A.D.
      • Blattman S.B.
      • Panossian H.
      • et al.
      Infrapopliteal angioplasty for critical limb ischemia: relation of TransAtlantic InterSociety Consensus class to outcome in 176 limbs.
      • Vogel T.R.
      • Dombrovskiy V.Y.
      • Carson J.L.
      • Graham A.M.
      In-hospital and 30-day outcomes after tibioperoneal interventions in the US Medicare population with critical limb ischemia.
      • Conrad M.F.
      • Crawford R.S.
      • Hackney L.A.
      • Paruchuri V.
      • Abularrage C.J.
      • Patel V.I.
      • et al.
      Endovascular management of patients with critical limb ischemia.
      Four randomized prospective clinical trials and five other study reports form the basis of this evidence summary.

       Randomized controlled trials

       Rochester trial

      In this trial, 114 patients with ALI <7 days in duration were randomized to surgery or urokinase (UK) CDT.
      • Ouriel K.
      • Shortell C.K.
      • DeWeese J.A.
      • Green R.M.
      • Francis C.W.
      • Azodo M.V.
      • et al.
      A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
      About 70% of the endovascular arm had successful initial revascularization; the remainder required subsequent surgical intervention. CDT had PMT superior 30-day AFS, but 12-month LS rates did not differ (Table I). Cardiopulmonary complications, especially MIs, were higher in surgical revascularization (Table II). Major bleeding was more frequent with CDT, including one fatal hemorrhagic stroke. Median length of stay (LOS) between the two arms was similar. Treatment cost was higher with thrombolysis ($15,672 vs $12,253).
      Table ISummary of major outcomes of five randomized controlled trials
      AuthorInclusion criteriaTreatmentPatientsRevascularization success, No. (%)LOS, daysFollow-up, monthsLS, % patientsAvoidance of open vascular surgery, % patientsOS, % patientsAFS, % patients
      Ouriel et al
      • Ouriel K.
      • Shortell C.K.
      • DeWeese J.A.
      • Green R.M.
      • Francis C.W.
      • Azodo M.V.
      • et al.
      A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.


      Rochester trial, 1994
      Rutherford class II ALI with symptoms <7 days caused by occlusion of native artery or bypass graftsOperative vs CDT with UK (mean, 35.6 hours; max, 48 hours)Operative (n = 56/57)
      • Thrombectomy (n = 16, 28%)
      • Revision bypass (n = 9, 16%)
      • New bypass (n = 27, 47%)
      • Amputation (n = 3, 5.3%)
      1117.6 ± 1.882 at 12 months58 at 12 months52 at 12 months
      UK therapy (n = 55/57)40 (70)1120.5 ± 1.882 at 12 months36 at 12 months84 at 12 months; P = .0175 at 12 months; P = .02
      Ouriel et al
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      Thrombolysis or peripheral arterial surgery: phase I results. TOPAS Investigators.


      TOPAS trial phase I, 1996
      Rutherford class II ALI with symptoms <14 days caused by occlusion of native artery or bypass graftsOperative vs CDT with rUK (mean, 22-24 hours)Operative (n = 54/58)
      • Thrombectomy (n = 40, 40%)
      • Revision/insertion bypass (n = 17, 29%)
      • Above-knee amputation (n = 1, 1.7%)
      12-15; P = NS1294.8 at 30 days

      87.9 at 6 months

      84.3 at 12 months
      86.2 at 30 days

      74.1 at 6 months

      65.4 at 12 months
      rUK
      • 4000 IU/min (n = 49/52)
      35 (71.4)12-15; P = NS12100 at 30 days; P = NS

      90.2 at 6 months; P = NS

      86.1 at 12 months; P = NS
      90.4 at 30 days; P = NS

      78.6 at 6 months; P = NS

      74.6 at 12 months; P = NS
      Ouriel et al
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.


      TOPAS trial phase II, 1998
      Rutherford class II ALI with symptoms <14 days caused by occlusion of native artery or bypass graftsOperative vs CDT with rUK (initial dose of 4000 IU/min; mean, 24.4 hours; max, 48 hours)Operative (n = 272)
      • Thrombectomy (66%)
      • New bypass (32%)
      101287.1 at 6 months

      86.9 at 12 months
      87.7 at 6 months

      83 at 12 months
      74.8 at 6 months

      69.9 at 12 months
      rUK (n = 272)196 (79.7)10; P = NS1287.8 at 6 months

      85 at 12 months
      84 at 6 months; P = NS

      80 at 12 months; P = NS
      71.8 at 6 months, P = NS

      65 at 12 months; P = NS
      STILE trial
      Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.


      1994
      Lower extremity ischemic symptoms <6 months (30% <14 days) caused by occlusion of native artery or bypass graftsOperative vs CDT with rt-PA (0.05 mg/kg/h; max, 12 hours) or UK (bolus, 250,000 U; initial, 4000 U/min × 4 hours, then 2000 U/min; max, 36 hours)Operative (ALI symptoms ≤14 days)670 at 6 months90 at 6 months62.5 at 6 months
      CDT (ALI symptoms ≤14 days)688.9 at 6 months; P = .0294.4 at 6 months; P = NS84.7 at 6 months; P = .01
      Operative (ALI symptoms >14 days)697 at 6 months92.1 at 6 months90.1 at 6 months
      CDT (ALI symptoms >14 days)687.9 at 6 months; P = .0193.1 at 6 months; P = NS82.2 at 6 months; P = NS
      Weaver et al
      • Weaver F.A.
      • Comerota A.J.
      • Youngblood M.
      • Froehlich J.
      • Hosking J.D.
      • Papanicolaou G.
      Surgical revascularization versus thrombolysis for nonembolic lower extremity native artery occlusions: results of a prospective randomized trial. The STILE Investigators. Surgery versus Thrombolysis for Ischemia of the Lower Extremity.


      STILE trial, 1996
      Lower extremity ischemic symptoms <6 months (mean, 59 days; 20% <14 days) caused by native artery occlusions at IF or FPOperative (bypass 86%) vs CDT with rt-PA (mean, 8 hours) or UK (mean, 24 hours)Operative (ALI symptoms ≤14 days; n = 16)12100 at 12 months81.2 at 12 months81.2 at 12 months
      CDT (ALI symptoms ≤14 days; n = 32)1293.7 at 12 months93.7 at 12 months87.5 at 12 months
      Operative (ALI symptoms >14 days; n = 69)12100 at 12 months85.5 at 12 months85.5 at 12 months
      CDT (ALI symptoms >14 days; n = 118)1289 at 12 months88.1 at 12 months80.5 at 12 months
      Han et al
      • Han S.M.
      • Weaver F.A.
      • Comerota A.J.
      • Perler B.A.
      • Joing M.
      Efficacy and safety of alfimeprase in patients with acute peripheral arterial occlusion (PAO).


      HA004 and HA007 trial, 2010
      Rutherford class I or IIa ALI with symptoms <14 days (average, 8 days) caused by occlusion of native artery or bypass graftIT or PT alfimeprase or placebo at 1 mL/min infusion pulsed boluses × 4 hours; followed by endovascular or open surgeryHA004 (n = 300)
      • IT alfimeprase (n = 149)
      46.3 at 4 hours10634.9 at 30 days
      • IT placebo (n = 113)
      37.2 at 4 hours; P = .13819637.2 at 30 days; P = .7045
      • PT placebo (n = 38)
      15.8% at 4 hours10618.4 at 30 days
      HA007 (n = 102)
      • IT alfimeprase (n = 51)
      35.3% at 4 hours629.4 at 30 days
      • IT placebo (n = 51)
      23.5% at 4 hours; P = .1923617.6 at 30 days; P = .1613
      AFS, Amputation-free survival; ALI, acute limb ischemia; CDT, catheter-directed thrombolysis; FP, femoral-popliteal; IF, iliac-common femoral; IT, intrathrombus; LOS, length of stay; LS, limb salvage; NS, not significant; OS, overall survival; PT, perithrombus; rt-PA, recombinant tissue plasminogen activator; rUK, recombinant urokinase; STILE, Surgery vs Thrombolysis for Ischemia of the Lower Extremity; TOPAS, Thrombolysis or Peripheral Arterial Surgery; UK, urokinase; —, not available.
      Table IIReported complications from each study
      AuthorInterventionComplications (% patients)
      Ouriel et al
      • Ouriel K.
      • Shortell C.K.
      • DeWeese J.A.
      • Green R.M.
      • Francis C.W.
      • Azodo M.V.
      • et al.
      A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.


      Rochester 1994
      SurgeryMajor bleeding (2)

      Cardiopulmonary (49; MI, 16)
      Thrombolytic therapy UKMajor bleeding (11; P = .06)

      Cardiopulmonary (16 [P = .001]; MI, 5 [P = .02])
      Ouriel et al
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.


      TOPAS trial phase II, 1998
      SurgeryMajor bleeding (5.5)
      rUK at initial rate of 4000 IU/minMajor bleeding (12.5; P = .05)

      CVA (1.6)
      STILE trial
      Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.


      1994
      SurgeryNot available
      ThrombolyticBleeding (intracranial hemorrhage; 1-2)
      Han et al
      • Han S.M.
      • Weaver F.A.
      • Comerota A.J.
      • Perler B.A.
      • Joing M.
      Efficacy and safety of alfimeprase in patients with acute peripheral arterial occlusion (PAO).


      HA004 and HA007 trial, 2010
      Alfimeprase(Combined adverse events in HA004 and HA007)

      All hypotension (19.1; placebo, 2.5; P < .002)

      All peripheral embolism (10.0; placebo, 2.5; P = .0038)

      All cardiac events (13.6; placebo, 5; P = .005)

      Significant infections (10.6; placebo, 4.5; P = .037)
      Thrombolysis Study Group
      • Earnshaw J.J.
      • Whitman B.
      • Foy C.
      National Audit of Thrombolysis for Acute Leg Ischemia (NATALI): clinical factors associated with early outcome.


      NATALI study, 2004
      CDTMajor bleeding (7.85% of episodes)

      Minor bleeding (6.3% of episodes)

      Stroke (2.3% of episodes)

      Pericatheter thrombosis (0.8% of episodes)

      Distal embolization (2.4% of episodes)
      Kashyap et al
      • Kashyap V.S.
      • Gilani R.
      • Bena J.F.
      • Bannazadeh M.
      • Sarac T.P.
      Endovascular therapy for acute limb ischemia.


      Cleveland Clinic Foundation, 2011
      CDTMajor bleeding requiring transfusion (8)

      Access site hematoma (11)

      Hemorrhagic stroke (0.76)

      Leg compartment syndrome (4)
      Taha et al
      • Taha A.G.
      • Byrne R.M.
      • Avgerinos E.D.
      • Marone L.K.
      • Makaroun M.S.
      • Chaer R.A.
      Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia.


      UPMC, 2014
      SurgeryBleeding (0)

      Reversible acute renal failure (12)

      New-onset hemodialysis (4)

      Fasciotomy (29.1)

      Wound infection (9)

      Rethrombosis (14.7)

      Unplanned return to operating room (25.5)
      CDTBleeding (5.8; P < .001)

      Reversible acute renal failure (4; P = .005)

      New-onset hemodialysis (0.7; P = .04)

      Fasciotomy (7.3; P < .001)

      Wound infection (0.7; P < .001)

      Rethrombosis (1.3; P < .001)

      Unplanned return operating room (1.3; P < .001)
      Kempe et al
      • Kempe K.
      • Starr B.
      • Stafford J.M.
      • Islam A.
      • Mooney A.
      • Lagergren E.
      • et al.
      Results of surgical management of acute thromboembolic lower extremity ischemia.


      Wake Forest, 2014
      Embolectomy (16% also had intraoperative thrombolysis)Hemorrhage (17)

      Noninfectious pulmonary failure (12)

      Pneumonia (9)

      MI (6)

      Acute renal failure (8)

      Fasciotomy (4)

      Recurrent embolization (14)

      Wound infection (21)

      Unplanned return to operating room (24)
      CDT, Catheter-directed thrombolysis; CVA, cerebrovascular accident; MI, myocardial infarction; NATALI, National Audit of Thrombolysis for Acute Leg Ischemia; rUK, recombinant urokinase; STILE, Surgery vs Thrombolysis for Ischemia of the Lower Extremity; TOPAS, Thrombolysis or Peripheral Arterial Surgery; UK, urokinase; UPMC, University of Pittsburgh Medical Center.

       TOPAS (Thrombolysis or Peripheral Arterial Surgery)

      In this multicenter trial, phase I demonstrated maximal lytic effect (71%) and lowest bleeding rate (2%) with recombinant UK dosed at 4000 IU/min.
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      Thrombolysis or peripheral arterial surgery: phase I results. TOPAS Investigators.
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
      Phase II compared surgery with recombinant UK CDT for ALI. The 6-month AFS was not significantly different between the two arms. The 1-year AFS and mortality rates were similar (Table I). The thrombolysis group experienced more major hemorrhagic complications (ie, intracranial hemorrhage), especially with systemic heparin coadministration (Table II). The investigators concluded that a thrombolysis-first approach reduced the need for subsequent surgery with no significant increase in limb amputation or death, despite the higher bleeding risk.

       STILE (Surgery vs Thrombolysis for Ischemia of the Lower Extremity) trial

      This multicenter trial compared open revascularization vs UK CDT vs recombinant tissue plasminogen activator (rt-PA) CDT for nonembolic leg ischemia. CDT with rt-PA and CDT with UK were equally effective and safe, but rt-PA thrombolysis duration was shorter.
      Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
      • Weaver F.A.
      • Comerota A.J.
      • Youngblood M.
      • Froehlich J.
      • Hosking J.D.
      • Papanicolaou G.
      Surgical revascularization versus thrombolysis for nonembolic lower extremity native artery occlusions: results of a prospective randomized trial. The STILE Investigators. Surgery versus Thrombolysis for Ischemia of the Lower Extremity.
      Importantly, only 30% of patients in STILE had ischemic symptoms <14 days. Post hoc analysis stratifying symptoms ≤14 days or >14 days is noteworthy (Table I). Patients with ischemic deterioration ≤14 days had better LS and AFS at 6 months and shorter LOS with thrombolysis than with initial open revascularization or those with ischemia >14 days treated with thrombolysis. Another subset analysis reported on patients with native artery occlusions, of which 20% fulfilled the criteria for ALI.
      • Weaver F.A.
      • Comerota A.J.
      • Youngblood M.
      • Froehlich J.
      • Hosking J.D.
      • Papanicolaou G.
      Surgical revascularization versus thrombolysis for nonembolic lower extremity native artery occlusions: results of a prospective randomized trial. The STILE Investigators. Surgery versus Thrombolysis for Ischemia of the Lower Extremity.
      Pretreatment with thrombolysis reduced the need for surgery in both native femoropopliteal and iliofemoral arterial disease. However, the operative group had less ongoing or recurrent ischemia and major limb amputations at 1 year. Femoropopliteal occlusion, diabetes, and chronic ischemia were associated with overall poorer outcomes after CDT.

       Alfimeprase HA004 and HA007 trial

      HA004 and HA007 trials compared a new direct fibrinolytic agent, alfimeprase, with placebo in ALI (Rutherford class I or IIa).
      • Han S.M.
      • Weaver F.A.
      • Comerota A.J.
      • Perler B.A.
      • Joing M.
      Efficacy and safety of alfimeprase in patients with acute peripheral arterial occlusion (PAO).
      Pilot studies showed a shorter onset of action than t-PA (median half-life of 15 minutes) with fewer bleeding complications. Overall adverse events with alfimeprase were low and equal to placebo (Table II). Alfimeprase did not significantly reduce the need for open revascularization at 30 days. The investigators observed a trend toward higher arterial flow restoration rates at 4 hours and improved 30-day ankle-brachial index, postulating inadequate drug dosing as one possible reason for this nonsignificant result. HA004 trial suggested a benefit in graft occlusions treated with alfimeprase but none for native arteries.

       Retrospective studies

       NATALI (National Audit of Thrombolysis for Acute Leg Ischemia)

      NATALI contains 1133 ALI patient episodes treated with CDT, >75% of whom presented within 1 week of symptoms.
      • Earnshaw J.J.
      • Whitman B.
      • Foy C.
      National Audit of Thrombolysis for Acute Leg Ischemia (NATALI): clinical factors associated with early outcome.
      At 30 days, AFS was 75.2%, amputation rate was 12.4%, and mortality was 12.4% (Table III). Poor prognostic features for AFS included diabetes, age, short-duration ischemia, Fontaine grade, and limb neurosensory deficit. Amputation risk was highest in younger men and with more severe ischemia, bypass graft occlusion, or native/outflow vessel thrombosis. AFS improved in patients receiving warfarin at the time of intervention. Mortality was worse in women and with increased age, native vessel occlusion, thromboembolism, and coronary artery disease (CAD). The most common causes of death were MI or cardiac failure, stroke, pneumonia, and renal failure.
      Table IIISummary of major outcomes of five retrospective studies
      AuthorStudy designInclusion criteriaAimTreatmentPatientsLOS, daysFollow-up, monthsPatencyLS, % patientsOS, % patientsAFS, % patients
      Thrombolysis Study Group
      • Earnshaw J.J.
      • Whitman B.
      • Foy C.
      National Audit of Thrombolysis for Acute Leg Ischemia (NATALI): clinical factors associated with early outcome.


      NATALI study, 2004
      Registry, collected from 11 centers 1990-2000Symptoms of acute leg ischemia; symptom duration was not specifiedTo assess 30-day outcomes of patients who received tPA for ALICDT

      Most received rt-PA and 59 patients received streptokinase
      Total 1133 events

      Symptom duration:

      <8 hours (n = 288, 25.4%)

      8-48 hours (n = 336, 29.6%)

      48 hours to 1 week (n = 231, 20.4%)

      >1 week (n = 277, 24.4%)

      Disease severity:

      Fontaine II (n = 214, 19.8%)

      Fontaine III (n = 746, 69.2%)

      Fontaine IV (n = 104, 9.6%)
      87.6 at 30 days87.6 at 30 days75.2 at 30 days
      Kashyap et al
      • Kashyap V.S.
      • Gilani R.
      • Bena J.F.
      • Bannazadeh M.
      • Sarac T.P.
      Endovascular therapy for acute limb ischemia.


      Cleveland Clinic Foundation, 2011
      Single-center, retrospective review 2005-2007All patients who had symptoms of ALI due to embolism or thrombosis and were treated with endovascular technique; symptom duration was not specifiedTo assess outcomes of patients with ALI treated by endovascular techniqueCDT using rt-PA; 47% had additional PMT with rt-PA

      Thrombolysis days:

      0-1 day: 49%

      1-2 days: 39%

      ≥3 days: 12%
      Total 119 patients; 129 limbs, of which 72% were bypass graft thrombosis

      Disease severity:

      Rutherford I (n = 88, 68%)

      Rutherford IIa (n = 30, 23%)

      Rutherford IIb (n = 10, 9%)
      16.8

      (0-43)
      Primary patency:

      50.1 at 1 year, 37.7 at 2 years

      Secondary patency:

      74.0 at 1 year, 65.3 at 2 years
      74.6 at 1 year

      68.8 at 2 years
      84.5 at 3 years82 at 30 days
      Taha et al
      • Taha A.G.
      • Byrne R.M.
      • Avgerinos E.D.
      • Marone L.K.
      • Makaroun M.S.
      • Chaer R.A.
      Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia.


      UPMC, 2014
      Single-center, retrospective review 2005-2011All patients who had symptoms of ALI due to embolism or thrombosis of native artery, bypass graft, previous stent; symptom duration was not specifiedTo compare effectiveness of surgery vs CDT ± PMT as treatment for ALISurgery:

      Thromboembolectomy, 44%

      Bypass, 33%

      Endarterectomy, 21%

      Hybrid, 17%
      Total N = 296 (326 limbs)

      Disease severity:

      Rutherford IIa (41%)

      Rutherford IIb (42%)
      Surgery

      11.5 ± 12
      Surgery

      14 ± 18.5
      57 at 1 year86.5 at 30 days

      80.4 at 1 year
      86.8 at 30 days

      66.2 at 1 year

      59.5 at 2 years
      Endovascular/tPA:

      CDT, 54%

      PMT, 10%

      CDT and PMT, 36%
      Total N = 147 (154 limbs)

      Disease severity:

      Rutherford IIa (70%), P < .001

      Rutherford IIb (20%), P < .001
      Endovascular

      8.7 ± 7

      (P = .002)
      Endovascular/t-PA

      14 ± 18.5
      51 at 1 year; P = NS93.5 at 30 days; P = .023

      87 at 1 year; P = NS
      94.6 at 30 days; P = .012

      87.1 at 1 year; P < .001

      81.3 at 2 years; P < .001
      Kempe et al
      • Kempe K.
      • Starr B.
      • Stafford J.M.
      • Islam A.
      • Mooney A.
      • Lagergren E.
      • et al.
      Results of surgical management of acute thromboembolic lower extremity ischemia.


      Forest, 2014
      Single-center, retrospective review 2002-2012All ALI patients who underwent lower extremity embolectomy of aorta, iliac, or infrainguinal arteries; excluded patients with ALI symptoms >7 days or cases due to trauma, iatrogenesis, and occlusion of prior bypass graft or stentTo assess outcomes of surgical management in treatment of ALISurgery:

      Femoral embolectomy, 86%

      Popliteal embolectomy, 9%

      Femoral-popliteal embolectomy, 4%

      (intraoperative thrombolysis, 16%)
      Total N = 170

      Symptom duration:

      1.7 ± 1.4 days

      Severity:

      Rutherford I (<1%)

      Rutherford IIa (29%)

      Rutherford IIb (52%)

      Rutherford III (18%)
      885 at 90 days82 at 30 days;

      est 41 at 5 years
      est 80 at 5 years
      Baril et al
      • Baril D.T.
      • Ghosh K.
      • Rosen A.B.
      Trends in the incidence, treatment, and outcomes of acute lower extremity ischemia in the United States Medicare population.


      Medicare trends, 2014
      Observational 1998-2009All patients 65 years or older who had a principal diagnosis of lower extremity embolism or thrombosis and admitted urgently/emergentlyTo trend incidence of ALI and use of open and endovascular treatmentSurgery

      57.1% in 1998 vs 51.6% in 2009

      Endovascular

      15.0% in 1998 vs 33.1% in 2009
      Total N = 99,982In-hospital
      Analysis did not differentiate between surgery and CDT.
      :

      91.9 in 1998 vs 93.6 in 2009; P = NS

      30 days:

      89.6 in 1998 vs 91.9 in 2009; P < .001

      1 year:

      85.2 in 1998 vs 89.0 in 2009; P < .001
      In-hospital
      Analysis did not differentiate between surgery and CDT.
      :

      87.9 in 1998 vs 91.0 in 2009; P < .001

      30 days:

      81.7 in 1998 vs 80.8 in 2008; P = NS

      1 year:

      59.0 in 1998 vs 58 in 2008; P = NS
      In-hospital
      Analysis did not differentiate between surgery and CDT.
      :

      81.2 in 1998 vs 85.4 in 2009; P < .001

      30 days:

      73.5 in 1998 vs 74.5 in 2008; P = NS

      1 year:

      51.8 in 1998 vs 52.3 in 2009; P = NS
      AFS, Amputation-free survival; ALI, acute limb ischemia; CDT, catheter-directed thrombolysis; est, estimated; LOS, length of stay; LS, limb salvage; NATALI, National Audit of Thrombolysis for Acute Leg Ischemia; NS, not significant; OS, overall survival; PMT, pharmacomechanical thrombectomy; rt-PA, recombinant tissue plasminogen activator; t-PA, tissue plasminogen activator; UPMC, University of Pittsburgh Medical Center; —, not available.
      a Analysis did not differentiate between surgery and CDT.

       Cleveland Clinic experience

      In a single-institution review of ALI treated with CDT, PMT was used 47% of the time.
      • Kashyap V.S.
      • Gilani R.
      • Bena J.F.
      • Bannazadeh M.
      • Sarac T.P.
      Endovascular therapy for acute limb ischemia.
      Primary and secondary patency rates are listed in Table III. Factors associated with poorer primary patency rate included femoropopliteal or tibial artery thrombosis, bypass graft thrombosis, and chronic hemodialysis. LS rate at 24 months was 68.8%. Female gender and thrombolysis duration of >3 days were associated with higher risk of amputation. Complications included bleeding requiring transfusion, access site hematoma, and leg compartment syndrome (Table II).

       University of Pittsburgh Medical Center experience

      In comparing rt-PA CDT ± PMT with open revascularization, there was better technical success with surgery than with ET in ALI (Rutherford II) patients with bypass graft or stent failure.
      • Taha A.G.
      • Byrne R.M.
      • Avgerinos E.D.
      • Marone L.K.
      • Makaroun M.S.
      • Chaer R.A.
      Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia.
      Yet this did not translate to improved patency or LS rate. Overall 1-year primary patency and amputation rates between cohorts did not differ. Overall mortality was worse in the surgery group at 30 days, 1 year, and 2 years (Table III). Surgery had longer LOS and higher complication rates (Table II), whereas ET experienced more bleeding. Predictors of limb loss included Rutherford III and CAD. Predictors of death included age, end-stage renal disease, cancer, and chronic pulmonary disease.

       Wake Forest experience

      This is a single-center retrospective review of thromboembolic ALI management and outcomes during one decade.
      • Kempe K.
      • Starr B.
      • Stafford J.M.
      • Islam A.
      • Mooney A.
      • Lagergren E.
      • et al.
      Results of surgical management of acute thromboembolic lower extremity ischemia.
      Interventions included surgical embolectomy with selective angiography ± intraoperative CDT. The 90-day LS rate was 85%. The 5-year AFS was estimated at 80% (Tables III and IV). Predictors of amputation included prior vascular surgery, gangrene, and need for fasciotomy. Recurrent extremity embolization was 14%. The 30-day mortality was 18%, and estimated 5-year OS was 41%. Predictors of mortality included age, CAD, prior vascular surgery, and concurrent stroke. A high Rutherford classification was significantly associated with amputation and death.
      Table IVLimb salvage (LS), amputation-free survival (AFS), and overall survival (OS) rates of each study
      Study30-day6-month1-year2-year5-year
      SurgeryEndovascularSurgeryEndovascularSurgeryEndovascularSurgeryEndovascularSurgeryEndovascular
      LS rate (%) after surgical vs ET for ALI
       Rochester
      • Ouriel K.
      • Shortell C.K.
      • DeWeese J.A.
      • Green R.M.
      • Francis C.W.
      • Azodo M.V.
      • et al.
      A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
      8691; P = NS8282
       TOPAS trial, phase II
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
      87.187.886.985
       STILE trial
      Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
      STILE 1994 post-hoc analysis.
      ALI symptoms ≤14 days7088.9; P = .02
      ALI symptoms >14 days9787.9; P = .01
       NATALI study
      • Earnshaw J.J.
      • Whitman B.
      • Foy C.
      National Audit of Thrombolysis for Acute Leg Ischemia (NATALI): clinical factors associated with early outcome.
      87.6
       Cleveland Clinic Foundation
      • Kashyap V.S.
      • Gilani R.
      • Bena J.F.
      • Bannazadeh M.
      • Sarac T.P.
      Endovascular therapy for acute limb ischemia.
      74.668.8
       UPMC
      • Taha A.G.
      • Byrne R.M.
      • Avgerinos E.D.
      • Marone L.K.
      • Makaroun M.S.
      • Chaer R.A.
      Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia.
      86.593.5; P = .02380.487; P = NS
       Wake Forest
      • Kempe K.
      • Starr B.
      • Stafford J.M.
      • Islam A.
      • Mooney A.
      • Lagergren E.
      • et al.
      Results of surgical management of acute thromboembolic lower extremity ischemia.
      An 85% LS rate at 90 days.
      AFS rate (%) after surgical vs ET for ALI
       Rochester
      • Ouriel K.
      • Shortell C.K.
      • DeWeese J.A.
      • Green R.M.
      • Francis C.W.
      • Azodo M.V.
      • et al.
      A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
      3014; P = .045275; P = .02
       TOPAS trial, phase II
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
      74.871.8; P = NS69.965; P = NS
       STILE trial
      Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
      STILE 1994 post-hoc analysis.
      ALI symptoms ≤14 days62.584.7; P = .01
      ALI symptoms >14 days90.182.2; P = NS
       NATALI study
      • Earnshaw J.J.
      • Whitman B.
      • Foy C.
      National Audit of Thrombolysis for Acute Leg Ischemia (NATALI): clinical factors associated with early outcome.
      75.2
       Cleveland Clinic Foundation
      • Kashyap V.S.
      • Gilani R.
      • Bena J.F.
      • Bannazadeh M.
      • Sarac T.P.
      Endovascular therapy for acute limb ischemia.
      82
       UPMC
      • Taha A.G.
      • Byrne R.M.
      • Avgerinos E.D.
      • Marone L.K.
      • Makaroun M.S.
      • Chaer R.A.
      Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia.
       Wake Forest
      • Kempe K.
      • Starr B.
      • Stafford J.M.
      • Islam A.
      • Mooney A.
      • Lagergren E.
      • et al.
      Results of surgical management of acute thromboembolic lower extremity ischemia.
      est 80
      OS rate (%) after surgical vs ET for ALI
       Rochester
      • Ouriel K.
      • Shortell C.K.
      • DeWeese J.A.
      • Green R.M.
      • Francis C.W.
      • Azodo M.V.
      • et al.
      A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
      8288; P = NS5884; P = .01
       TOPAS trial, phase II
      • Ouriel K.
      • Veith F.J.
      • Sasahara A.A.
      A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
      87.784; P = NS8380; P = NS
       STILE trial
      Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
      STILE 1994 post-hoc analysis.
      ALI symptoms ≤14 days9094.4; P = NS
      ALI symptoms >14 days92.193.1; P = NS
       NATALI study
      • Earnshaw J.J.
      • Whitman B.
      • Foy C.
      National Audit of Thrombolysis for Acute Leg Ischemia (NATALI): clinical factors associated with early outcome.
      87.6
       Cleveland Clinic Foundation
      • Kashyap V.S.
      • Gilani R.
      • Bena J.F.
      • Bannazadeh M.
      • Sarac T.P.
      Endovascular therapy for acute limb ischemia.
      An 84.5% OS at 3 years.
       UPMC
      • Taha A.G.
      • Byrne R.M.
      • Avgerinos E.D.
      • Marone L.K.
      • Makaroun M.S.
      • Chaer R.A.
      Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia.
      86.894.6; P = .01266.287.1; P < .00159.581.3; P < .001
       Wake Forest
      • Kempe K.
      • Starr B.
      • Stafford J.M.
      • Islam A.
      • Mooney A.
      • Lagergren E.
      • et al.
      Results of surgical management of acute thromboembolic lower extremity ischemia.
      8241
      ALI, Acute limb ischemia; est, estimated; ET, endovascular therapy; NATALI, National Audit of Thrombolysis for Acute Leg Ischemia; NS, not significant; STILE, Surgery vs Thrombolysis for Ischemia of the Lower Extremity; TOPAS, Thrombolysis or Peripheral Arterial Surgery; UPMC, University of Pittsburgh Medical Center; —, not available.
      a STILE 1994 post-hoc analysis.
      b An 85% LS rate at 90 days.
      c An 84.5% OS at 3 years.

       Endovascular trends in Medicare patients

      The Medicare Provider Analysis and Review (MedPAR) database was queried to evaluate trends in ALI between 1998 and 2009.
      • Baril D.T.
      • Ghosh K.
      • Rosen A.B.
      Trends in the incidence, treatment, and outcomes of acute lower extremity ischemia in the United States Medicare population.
      ALI incidence decreased in the last decade, but interventions for LS, particularly with ET, have increased (15.0% to 33.1%). Overall LS rates have improved, but 30-day mortality and AFS remained unchanged after hospitalization (Table III). This is likely related to the older age at which patients are treated. Octogenarians composed 50.5% of patients in 1998 vs 58.5% in 2009. Predictors of amputation included black race, advanced age, male gender, diabetes, and history of peripheral arterial disease. Predictors of mortality encompassed advanced age, black race, male gender, heart failure, dementia, renal failure, and atrial fibrillation.

      Discussion

      Perioperative mortality for ALI was prohibitively high during the 1970s (20%-40%) such that Blaisdell et al
      • Blaisdell F.W.
      • Steele M.
      • Allen R.E.
      Management of acute lower extremity arterial ischemia due to embolism and thrombosis.
      recommended initial treatment with anticoagulation and surgical revascularization only after stabilization of the patient. The 1980s
      • Jivegard L.
      • Holm J.
      • Schersten T.
      Acute limb ischemia due to arterial embolism or thrombosis: influence of limb ischemia versus pre-existing cardiac disease on postoperative mortality rate.
      and early 1990s
      • Yeager R.A.
      • Moneta G.L.
      • Taylor Jr., L.M.
      • Hamre D.W.
      • McConnell D.B.
      • Porter J.M.
      Surgical management of severe acute lower extremity ischemia.
      experienced similar mortality rates. With contemporary refinements in revascularization techniques and critical care, mortality for critical limb ischemia ranges from 2% to 6% after surgery
      • Conte M.S.
      • Belkin M.
      • Upchurch G.R.
      • Mannick J.A.
      • Whittemore A.D.
      • Donaldson M.C.
      Impact of increasing comorbidity on infrainguinal reconstruction: a 20-year perspective.
      • Albers M.
      • Romiti M.
      • Brochado-Neto F.C.
      • De Luccia N.
      • Pereira C.A.
      Meta-analysis of popliteal-to-distal vein bypass grafts for critical ischemia.
      • Feinglass J.
      • Pearce W.H.
      • Martin G.J.
      • Gibbs J.
      • Cowper D.
      • Sorensen M.
      • et al.
      Postoperative and amputation-free survival outcomes after femorodistal bypass grafting surgery: findings from the Department of Veterans Affairs National Surgical Quality Improvement Program.
      • Adam D.J.
      • Beard J.D.
      • Cleveland T.
      • Bell J.
      • Bradbury A.W.
      • Forbes J.F.
      • et al.
      Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial.
      • Conte M.S.
      • Bandyk D.F.
      • Clowes A.W.
      • Moneta G.L.
      • Seely L.
      • Lorenz T.J.
      • et al.
      Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery.
      and 2% to 8% after ET.
      • Giles K.A.
      • Pomposelli F.B.
      • Spence T.L.
      • Hamdan A.D.
      • Blattman S.B.
      • Panossian H.
      • et al.
      Infrapopliteal angioplasty for critical limb ischemia: relation of TransAtlantic InterSociety Consensus class to outcome in 176 limbs.
      • Vogel T.R.
      • Dombrovskiy V.Y.
      • Carson J.L.
      • Graham A.M.
      In-hospital and 30-day outcomes after tibioperoneal interventions in the US Medicare population with critical limb ischemia.
      • Conrad M.F.
      • Crawford R.S.
      • Hackney L.A.
      • Paruchuri V.
      • Abularrage C.J.
      • Patel V.I.
      • et al.
      Endovascular management of patients with critical limb ischemia.
      In contradistinction, mortality after primary amputation is 6% to 12%. For the above-mentioned studies, comparable outcome measures for ALI have been difficult to extract because of heterogeneity in areas of ischemic degree and duration, patient selection, disease extent, treatment options, and outcome measures.
      Current data for ALI (Table IV) are scant but suggest no difference in LOS or 1-year LS rate between surgery and ET. The 1-year AFS and short-term OS rates are also similar in most studies. In favor of ET, the Rochester and STILE trials showed better 1-year AFS, and the University of Pittsburgh Medical Center and Rochester trials demonstrated lower mortality. Composite average 30-day mortality rates were higher for surgery than for ET (12.1% vs 6.7%). However, the STILE trial proposed other factors for consideration in treating ALI. ET may reduce the need for subsequent surgery in select patients but is associated with a higher reintervention rate than initial open revascularization. ET has higher bleeding complications; surgery has increased morbidity related to cardiopulmonary complications, blood loss, wound infections, and fasciotomy (Table II). CDT requires some duration of therapy to be effective and may not be appropriate for advanced ALI requiring immediate revascularization (Rutherford IIb progressing to III).
      There are numerous limitations to this evidence summary. Streptokinase and UK were used in older studies, whereas t-PA is currently used widely. Different agents used may affect outcomes differently. Endovascular skills, options, and hybrid approaches to treatment were not as developed in earlier studies. Patients with ALI presented with different Rutherford class severity, implying inherent varied prognoses. Most presented with Rutherford II, but not all studies identified them as IIa or IIb, nor was symptom duration always defined. Two studies included Rutherford I patients,
      • Kashyap V.S.
      • Gilani R.
      • Bena J.F.
      • Bannazadeh M.
      • Sarac T.P.
      Endovascular therapy for acute limb ischemia.
      • Han S.M.
      • Weaver F.A.
      • Comerota A.J.
      • Perler B.A.
      • Joing M.
      Efficacy and safety of alfimeprase in patients with acute peripheral arterial occlusion (PAO).
      and the number of Rutherford III patients overall was small. Those who presented with systemic emboli or autogenous graft thrombosis have poorer prognoses, but both subgroups are likely not to be evenly represented in comparative study cohorts. Whereas retrospective study findings are noteworthy, potential inaccurate interpretation due to selection bias is acknowledged. This review, pertaining to lower extremities, does not imply similar treatment strategies for upper extremities, in which embolic ALI can often be treated with local anesthesia and thromboembolectomy with minimal morbidity.
      The authors therefore recommend initial treatment of ALI with ET, if it is not contraindicated, because of its equivalence in short-term outcomes (LS, AFS, OS) and lower morbidity and mortality rates while acknowledging a higher need for future intervention. Contraindications to ET include recent neurosurgery, recent bleeding including hemorrhagic stroke, and ongoing bleeding diathesis. Once ALI is resolved and patients are systemically optimized, they may be better candidates for definitive surgical revascularization with improved longer term outcomes.

      Conclusions

      ALI remains a morbid condition with high risk for limb loss and death. Based on the current evidence, ET is effective for LS and safer in the short term than urgent open revascularization in the studied patients. Still, individual patient factors need to be carefully considered for further generalization. ET and surgery are complementary rather than competing strategies for treating ALI. Further good-quality clinical trial data are required to define longer term outcomes.

      Author contributions

      Conception and design: JW
      Analysis and interpretation: JW, VK
      Data collection: JW, AK
      Writing the article: JW, AK, VK
      Critical revision of the article: JW, VK
      Final approval of the article: JW, AK, VK
      Statistical analysis: Not applicable
      Obtained funding: Not applicable
      Overall responsibility: JW

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