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Editor's Choice – Relationship Between Global Limb Anatomic Staging System (GLASS) and Clinical Outcomes Following Revascularisation for Chronic Limb Threatening Ischaemia in the Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 Trial

Open ArchivePublished:August 07, 2020DOI:https://doi.org/10.1016/j.ejvs.2020.06.042

      Objective

      The Global Vascular Guideline on chronic limb threatening ischaemia (CLTI) has introduced the Global Limb Anatomic Staging System (GLASS) as a new angiographic scoring system. However, the relationship between GLASS and outcomes following revascularisation has not previously been studied.

      Methods

      Using pre-intervention angiograms the relationship between GLASS and immediate technical failure (ITF), amputation free survival (AFS), limb salvage (LS), overall survival (OS), and freedom from major adverse limb events (FF-MALE) was examined in 377 patients undergoing endovascular therapy (EVT, n = 213) or bypass surgery (BS, n = 164) in the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 trial (randomised 1999–2004).

      Results

      There was no significant difference in GLASS between cohorts. There was a significant relationship between ITF and GLASS in EVT (I 14%, II 15%, III 28%, p = .049). GLASS was significantly related to AFS (hazard ratio [HR], 1.37; 95% CI 1.01–1.85; p = .042), LS (HR 1.96; 95 % CI 1.12–3.43; p = .018), and FF-MALE (HR 1.49; 95% CI 1.04–1.87; p = .028) in the EVT cohort. In BS patients, there was no relationship between GLASS and these outcomes. FF-MALE was significantly worse after EVT than BS in GLASS II (p = .038) and III (p = .001). Among the subgroup of patients with femoropopliteal (FP) disease (BS, n = 109 or EVT, n = 159), FF-MALE was significantly higher after BS than EVT (p < .001). The superiority of BS over EVT with increasing GLASS FP grade was greater in the analysis of patients using vein grafts.

      Conclusion

      In the BASIL-1 cohort, GLASS is associated with outcomes following EVT but not BS. Although further validation in contemporary CLTI cohorts is required, GLASS seems likely be useful in shared decision making and for stratifying patients in future trials.

      Keywords

      The Global Vascular Guidelines on chronic limb threatening ischaemia (CLTI) have introduced the Global Limb Anatomic Staging System (GLASS) as a new method for quantifying angiographic disease severity. However, the relationship between GLASS and outcomes following revascularisation has not previously been studied. This paper is, therefore, the first attempt at evaluating GLASS in CLTI patients and is based upon pre-intervention angiograms and outcome data gathered in the Bypass versus Angioplasty in Severe Ischaemia of the Leg-1 trial. The study suggests that GLASS may be used to predict both immediate and long term outcomes after undergoing endovascular therapy (EVT) but not bypass surgery (BS). Outcomes were better following BS than EVT in patients with more advanced GLASS stage. Although further validation and refinement of GLASS is clearly required in contemporary series, this new limb integrated system seems likely to facilitate both shared decision making and the stratification of CLTI patients within future clinical trials.

      Introduction

      The Global Limb Anatomic Staging System (GLASS) is a newly proposed method for defining the angiographic complexity and severity of infra-inguinal disease that has recently been introduced within the Global Vascular Guidelines on Chronic Limb Threatening Ischaemia (CLTI).
      • Conte M.S.
      • Bradbury A.W.
      • Kolh P.
      • White J.V.
      • Dick F.
      • Fitridge R.
      • et al.
      Global Vascular Guidelines on the management of chronic limb-threatening ischemia.
      ,
      • Conte M.S.
      • Bradbury A.W.
      • Kolh P.
      • White J.V.
      • Dick F.
      • Fitridge R.
      • et al.
      Global vascular guidelines on the management of chronic limb-threatening ischemia.
      GLASS I, II, III stages are derived by combining femoropopliteal (FP) and infrapopliteal (IP) GLASS grades (1–4) that represent increasing severity and complexity of disease along the target arterial path (TAP). The TAP is defined as the physician preferred route for endovascular therapy (EVT) that is most likely to establish continuous in line flow from the origin of the superficial femoral artery to the foot. In the Global Vascular Guidelines (GVG) and in GLASS, the common and deep femoral arteries are considered inflow vessels and it is assumed that inflow disease is corrected prior to, or at the same time as, the infra-inguinal revascularisation. The TAP will normally include the least diseased IP artery unless an angiosome specific revascularisation is planned. GLASS stages are designed to correspond to low, intermediate, and high complexity disease for EVT and to correlate with both immediate technical failure (ITF) and one year limb based patency of the TAP. GLASS grades and stages were derived by expert consensus within the GVG writing group and based on existing available data. However, to date, the utility of GLASS has not been examined in a cohort of CLTI patients undergoing EVT or bypass surgery (BS). The UK National Institute of Health Research (NIHR) Health Technology Assessment (HTA) funded Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 trial remains the only published randomised control trial to have compared (vein and prosthetic) BS with EVT, comprising plain balloon angioplasty with or without bare metal stent, in patients with CLTI due to infra-inguinal disease.
      • Bradbury A.W.A.D.
      • Bell J.
      • Forbes J.F.
      • Fowkes F.G.
      • Gillespie I.
      • Raab G.
      • et al.
      Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infra-inguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.
      The aim of this study was to use the BASIL-1 trial patient cohort to examine the relationship between GLASS grade and stage of disease and immediate and long term clinical outcomes following BS or EVT for CLTI.

      Materials and methods

      The BASIL-1 trial randomised 452 patients presenting with CLTI resulting from infra-inguinal disease to either a BS first or EVT first revascularisation strategy. The recruitment period was from 1999 to 2004, and follow up ended on 1 July 2007.
      • Bradbury A.W.A.D.
      • Bell J.
      • Forbes J.F.
      • Fowkes F.G.
      • Gillespie I.
      • Raab G.
      • et al.
      Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infra-inguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.
      In the present study an expert panel of three vascular surgeons (A.K., L.M., and A.B.), blind to the revascularisation method and clinical outcomes, GLASS graded and staged pre-intervention digital subtraction angiograms (DSA) in 377 CLTI patients undergoing BS (n = 164) or EVT (n = 213) as their first intervention in the BASIL-1 trial (Fig. 1). The TAP used for GLASS grading and staging included the actual FP and IP arteries undergoing EVT or BS, or, where there was no IP EVT or BS, the least diseased IP artery. As it was not possible to reliably quantify calcification on the DSA, and not all DSAs included adequate biplanar foot views, the GLASS calcification and inframalleolar (IM) (pedal) modifiers were not used in this study. The GLASS grade and stage were determined by consensus by the expert panel. The relationship between GLASS stage and grade and ITF rate, amputation free survival (AFS), limb salvage (LS), overall survival (OS), and freedom from major adverse limb events (FF-MALE) (defined as freedom from major limb amputation or any major vascular re-intervention) was examined. These relationships were examined within the cohort as a whole and also in a subgroup of patients who only underwent a FP EVT or BS. There were too few patients in the BASIL-1 cohort who only underwent an IP intervention to allow a meaningful analysis of this subgroup. BASIL-1 case record forms were interrogated for baseline age, gender, ambulatory status, body mass index (BMI), comorbidities, serum creatinine, medication, presence of tissue loss, and for the above clinical outcome data. The availability of follow up haemodynamic data and imaging studies within the trial was not adequate to allow reliable calculation of limb based patency. The median duration of follow up was 4.1 (interquartile range [IQR] 1.5, 5.5) years.
      Figure 1
      Figure 1Flow diagram of patient inclusions and exclusions to study relationship between Global Anatomic Staging System (GLASS) and clinical outcomes following revascularisation by endovascular therapy (EVT) and bypass surgery (BS) for chronic limb threatening ischaemia in the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 trial.
      Unless otherwise stated, data are expressed as mean and standard deviation for continuous, and as percentages for dichotomous, variables. When comparing BS and EVT, the unpaired t test or the Wilcoxon rank sum tests were used for univariable analysis of continuous data depending on the distribution of the data. The chi square test was used for univariable analysis of categorical data. Long term clinical outcomes were analysed using Kaplan–Meier life tables and curves and then compared statistically using the log rank test. Univariable analysis was used to identify potential predictors of long term clinical outcomes and covariates with p < .050 were entered into a Cox multivariable regression analysis. A p value < .05 was considered statistically significant. Statistical analyses were performed using the Statistical Package for Social Sciences software (SPSS version 24, SPSS Inc., Chicago, IL, USA).

      Results

      Considering the cohort of 377 CLTI patients as a whole, there were no significant differences prior to revascularisation between those undergoing EVT or BS except for a higher proportion of men in the BS group (Table 1). Patients in both groups had typical risk factors for CLTI. Use of antiplatelet agents and statins prior to intervention was suboptimal by current standards; 75% of patients presented with tissue loss; and the median ABPI was just under 0.5. There was no significant difference in GLASS FP or IP grade or overall stage between the groups. There were no significant differences in the TAP between the EVT and BS cohorts, including regarding the selected crural vessel.
      Table 1Comparison of baseline characteristics of 377 patients undergoing bypass surgery (BS) and endovascular therapy (EVT) for chronic limb threatening ischaemia (CLTI) in the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 trial
      Overall (n = 377)EVT (n = 213)BS (n = 164)p value
      Age – years73 ± 974 ± 872 ± 10.11
      Male223 (59)113 (53)110 (67)<.006
      Non-ambulatory status30 (8)16 (8)14 (9).71
      BMI – kg/m224 (22, 28)25 (22, 28)24 (22, 27).80
      Comorbidities
       Hypertension239 (63)140 (66)99 (60).33
       Diabetes159 (42)91 (43)68 (41).83
       CAD102 (27)63 (30)39 (24).24
       CVD72 (19)37 (17)35 (21).36
      Smoking status.077
       Current smoker139 (37)68 (32)71 (43)
       Ex-smoker159 (42)97 (46)62 (38)
       Never smoker79 (21)48 (23)31 (19)
      Creatinine – μmol/L99 (84, 125)98 (84, 124)100 (84, 126).39
      Pre-intervention medication
       Antiplatelet agent225 (60)118 (55)107 (65).057
       Statin130 (35)77 (36)53 (32).45
      Limb status
       Tissue loss286 (76)161 (76)125 (76).90
       ABPI0.49 ± 0.160.49 ± 0.160.49 ± 0.17.95
      Location of disease
       FP/FP+IP/IP218/97/12159/49/5109/49/6.21
      GLASS
       FP grade (0/1/2/3/4)13/43/61/65/1955/23/37/42/1068/20/24/23/89.35
       IP grade (0/1/2/3/4)254/41/36/14/32149/23/18/8/15105/18/18/6/17.68
       Selected TAP (AT/PE/PT)168/124/8593/75/4575/49/40.52
       GLASS stage (I/II/III)76/87/21443/54/11633/33/98.46
      Data are presented as n (%) or mean ± standard deviation, or median (interquartile range). ABPI = ankle brachial pressure index; BMI = body mass index; CAD = coronary artery disease; CVD = cerebrovascular disease; GLASS = Global Anatomic Staging System; FP = femoropopliteal; IP = infrapopliteal; TAP = target artery path; AT = anterior tibial artery; PE = peroneal artery; PT = posterior tibial artery.

      Multivariable analysis of the endovascular therapy and bypass cohort

      In patients undergoing EVT, male sex, BMI, history of cerebrovascular disease, presentation with tissue loss, and GLASS stage were independently related to AFS (Table 2). In patients undergoing EVT, male sex, a history of coronary artery disease, and presentation with tissue loss were independently related to OS, but there was no relationship between OS and GLASS stage. Diabetes, presentation with tissue loss and GLASS stage were independently related to LS, and diabetes and GLASS stage were independently related to MALE. In patients undergoing BS, diabetes was independently related to AFS, and a history of cerebrovascular disease was independently related to OS. However, there was no significant relationship between GLASS stage and AFS, OS, LS, or FF-MALE.
      Table 2Relationship between baseline patient characteristics and long term clinical outcomes of 377 patients following endovascular therapy (n = 213) and bypass surgery (n = 164) for chronic limb threatening ischaemia (CLTI) in the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 trial
      Outcome measuren
      Number of observed events.
      Univariable analysisMultivariable analysis
      HR95% CIp valueHR95% CIp value
      Endovascular therapy
      Major amputation or all cause death100
      Male1.661.11–2.48.0141.961.20–3.21.008
      Non-ambulatory status2.171.13–4.17.0211.240.51–3.04.638
      BMI – kg/m2, +10.950.90–0.99.0290.940.89–0.99.022
      Coronary artery disease1.701.13–2.54.0101.390.85–2.28.186
      Cerebrovascular disease1.661.03–2.66.0372.231.23–4.06.009
      Tissue loss3.441.84–6.44<.0013.221.63–6.37.001
      GLASS stage – stage, +11.281.00–1.68.0491.371.01–1.85.042
      Overall mortality83
      Body mass index – kg/m2, +10.930.89–0.99.0130.940.89–0.99.020
      Coronary artery disease2.301.49–3.55<.0012.751.58–4.80<.001
      Serum creatinine – μmol/L, +11.001.00–1.01.0461.0020.999–1.01.20
      Statin0.600.37–0.97.0380.570.31–1.06.074
      Tissue loss3.241.62–6.47.0012,501.08–5.75.032
      Major amputation31
      Diabetes3.181.50–6.76.0032.881.35–6.13.006
      Tissue loss5.601.34–23.50.0185.101.21–21.45.026
      GLASS – stage, +11.901.09–3.33.0251.961.12–3.43.018
      MALE81
      Diabetes2.221.41–3.50.0012.111.34–3.27.001
      Tissue loss1.831.01–3.33.0481.510.96–3.19.069
      GLASS – stage, +11.491.09–2.03.0121.491.04–1.87.028
      Bypass surgery
      Major amputation or death71
      Diabetes1.921.20–3.06.0061.771.10–2.85.019
      Cerebrovascular disease1.881.14–3.11.0141.670.998–2.78.051
      Overall mortality57
      Diabetes1.670.99–2.80.0541.600.95–2.72.080
      Cerebrovascular disease1.971.13–3.45.0171.901.08–3.35.027
       Statin0.590.32–1.10.0960.540.29–1.004.052
      Major amputation28
      Diabetes2.080.98–4.40.055
      MALE35
      Diabetes1.780.91–3.49.095
      HR = hazard ratio; BMI = body mass index; CI = confidence interval; GLASS = Global Anatomic Staging System; MALE = major adverse limb event.
      Number of observed events.

      GLASS stage and immediate technical failure

      In the EVT cohort, the ITF rate for GLASS stages I, II, and III was 14% (6/43), 15% (8/54), and 28% (33/116) respectively (p = .049, chi squared test). On multivariable analysis, GLASS stage was significantly associated with ITF rate (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.08–2.78, p = .023) as was the presence of diabetes (OR 2.74, 95% CI 1.39–5.42, p = .004). However, there was no significant relationship between ITF and GLASS stage in patients undergoing BS.

      GLASS and long term clinical outcomes

      In patients undergoing EVT, GLASS stage III disease was associated with significantly worse AFS (p = .035), LS (p = .047), and FF-MALE (p = .045), but not OS compared with GLASS stage I disease (Fig. 2). In patients undergoing BS, there was no significant relationship between GLASS stage and any of the long term clinical outcomes studied (Fig. 3). Two year clinical outcomes are summarised in Table 3. Long term outcomes in patients undergoing EVT tended to become progressively worse with increasing GLASS stage. In particular, FF-MALE was significantly worse after EVT than after BS in patients with GLASS stage II (p = .038) and III (p = .001), but not GLASS stage I, disease (Fig. 4).
      Figure 2
      Figure 2Relationship between Global Limb Anatomic Staging System (GLASS) stage and long term clinical outcomes following endovascular therapy for chronic limb threatening ischaemia (CLTI) in the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 trial for (A) amputation free survival, (B) overall survival, (C) limb salvage, and (D) freedom from major adverse limb event (MALE). SE = standard error.
      Figure 3
      Figure 3Relationship between Global Limb Anatomic Staging System (GLASS) stage and long term clinical outcomes following bypass surgery for chronic limb threatening ischaemia (CLTI) in the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 trial for (A) amputation free survival, (B) overall survival, (C) limb salvage, and (D) freedom from major adverse limb event (MALE).
      Table 3Summary of two year clinical outcomes as amputation free survival (AFS), overall survival (OS), limb salvage (LS), and freedom from major adverse limb events (FF-MALE) of 377 patients following endovascular therapy (EVT) and bypass surgery (BS) for chronic limb threatening ischaemia (CLTI) by Global Anatomic Staging System (GLASS) stage in the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 trial
      GLASS stageOutcomesEVT (n = 213)

      % (SE)
      BS (n = 164)

      % (SE)
      p value
      IAFS79 (0.06)64 (0.08).23
      OS86 (0.05)70 (0.08).40
      LS93 (0.04)84 (0.07).13
      FF-MALE71 (0.07)78 (0.08).99
      IIAFS61 (0.07)64 (0.08).38
      OS65 (0.07)73 (0.08).23
      LS90 (0.04)90 (0.06).94
      FF-MALE65 (0.07)90 (0.06).038
      IIIAFS60 (0.05)60 (0.05).46
      OS72 (0.04)67 (0.05).67
      LS80 (0.04)81 (0.04).91
      FF-MALE56 (0.05)78 (0.05).001
      Data are provided as % (SE). SE = standard error.
      Figure 4
      Figure 4Comparison of freedom from major adverse limb event (MALE) following endovascular therapy (EVT) and bypass surgery (BS) for chronic limb threatening ischaemia (CLTI) in the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-1 trial by Global Anatomic Staging System (GLASS) stage I (A), II (B), and III (C).

      Subanalysis of femoropopliteal revascularisation

      There were 268 patients who underwent only FP EVT (n = 159) or BS (n = 109). There were no significant differences between these two groups at baseline except for a higher proportion of men in the BS group (Table S1). In particular, there were no significant differences in the FP vs. IP distribution of disease, GLASS stage, or GLASS FP or IP grades between the FP EVT and BS cohorts. Clinical outcomes following FP EVT and FP BS in patients with advancing GLASS FP grade are shown in Fig. S1. As observed in the cohort as a whole, there was a trend for clinical outcomes following FP EVT to be adversely affected by increasing GLASS stage. In particular, in patients with FP GLASS grade 4 disease undergoing FP only intervention, FF-MALE was highly significantly better after BS than after EVT (p < .001). The superiority of FP BS over FP EVT with increasing GLASS FP grade was more pronounced when the 33 prosthetic BS patients were removed, so restricting the analysis to patients who had undergone FP vein BS (Table S2, Fig. S2).

      Discussion

      When the BASIL-1 trial was designed it was always intended to explore the relationship between clinical outcomes and severity of the baseline arterial disease and so this analysis was included in the trial protocol and statistical analysis plan. To this end, pre-intervention angiograms were collected and stored centrally in the trial office for later scoring. At the time, the available angiographic scoring tools, Bollinger and TASC, were not found to be especially helpful in predicting clinical outcomes with regard to the leg. However, the Bollinger score was found to be an independent predictor for survival and a better predictor of outcomes than TASC II.
      • Lo Z.J.
      • Lin Z.
      • Pua U.
      • Quek L.H.H.
      • Tan B.P.
      • Punamiya S.
      • et al.
      Diabetic foot limb salvage – a series of 809 attempts and predictors for endovascular limb salvage failure.
      ,
      • Darling J.D.
      • McCallum J.C.
      • Soden P.A.
      • Korepta L.
      • Guzman R.J.
      • Wyers M.C.
      • et al.
      Results for primary bypass versus primary angioplasty/stent for lower extremity chronic limb-threatening ischemia.
      This shortcoming of previous scoring systems with regard to limb based outcomes was the main reason that GLASS was developed as part of the GVG. Having developed GLASS, examining its utility using the BASIL-1 angiograms and clinical outcome seemed an obvious and logical place to begin the evaluation of this novel tool. In the present study, considering the cohort as a whole, increasing GLASS stage of disease was significantly associated with increasing ITF rate in patients undergoing EVT but not BS. In patients undergoing EVT, when compared with GLASS stage I, GLASS stage III disease was associated with significantly worse AFS, LS, and FF-MALE. However, in the BS cohort, GLASS was not associated with ITF or any of the long term outcomes examined. Furthermore, on multivariable analysis, in the EVT but not in the BS cohort, increasing GLASS stage was significantly related to worse AFS, LS and MALE.
      Clinical outcomes, especially FF-MALE, were significantly better after BS than after EVT in patients with GLASS II and III stage disease. In the subgroup of patients who only underwent a FP intervention, GLASS FP grade 4 disease was associated with a highly significantly better FF-MALE after BS than after EVT. The superiority of BS over EVT with increasing GLASS FP grade was more pronounced when the analysis was restricted to vein bypass grafts.
      The present study also provides information regarding the relationship between FP grade and outcome in the subgroup of patents who only underwent an FP revascularisation. In patients with extensive FP (grade 4) disease, FF-MALE in the patients who underwent BS, especially vein BS, was significantly better than in those treated by EVT. Furthermore, there was a trend towards better AFS and LS in patients with FP grade 4 disease undergoing vein BS compared with EVT.
      The definition of FP grade 4 in GLASS is similar to that of TASC D lesions. Single centre retrospective analyses have indicated that TASC C or D lesions are a negative predictor for LS after EVT.
      • Lo Z.J.
      • Lin Z.
      • Pua U.
      • Quek L.H.H.
      • Tan B.P.
      • Punamiya S.
      • et al.
      Diabetic foot limb salvage – a series of 809 attempts and predictors for endovascular limb salvage failure.
      Thus, Darling et al. reported that TASC C and D lesions were associated with more re-intervention, and TASC D was associated with worse LS in a CLTI cohort undergoing EVT or BS.
      • Darling J.D.
      • McCallum J.C.
      • Soden P.A.
      • Korepta L.
      • Guzman R.J.
      • Wyers M.C.
      • et al.
      Results for primary bypass versus primary angioplasty/stent for lower extremity chronic limb-threatening ischemia.
      These and current data suggest the descriptors for FP grade 4 in GLASS are clinically appropriate.
      The relationship between outcomes and GLASS IP grade could not be examined in the same way as FP grade because there were too few patients in BASIL-1 who underwent an IP intervention to allow this, and so further studies are needed. The ongoing UK NIHR HTA funded BASIL-2 and BASIL-3 trials will permit the relationship between GLASS staging, and FP and IP grading, to be examined in two further large randomised cohorts of CLTI patients.
      • Popplewell M.A.
      • Davies H.
      • Jarrett H.
      • Bate G.
      • Grant M.
      • Patel S.
      • et al.
      Bypass versus angio plasty in severe ischaemia of the leg – 2 (BASIL-2) trial: study protocol for a randomised controlled trial.
      ,
      • Hunt B.D.
      • Popplewell M.A.
      • Davies H.
      • Meecham L.
      • Jarrett H.
      • Bate G.
      • et al.
      BAlloon versus Stenting in severe Ischaemia of the Leg-3 (BASIL-3): study protocol for a randomised controlled trial.
      Although further validation work is required, this first evaluation of GLASS suggests that it is likely to be a useful tool for shared decision making regarding revascularisation options in patients presenting with CLTI, and for risk stratifying such patients in future clinical trials. A weakness of the FP TASC classification was its lack of repeatability.
      • Kukkonen T.
      • Korhonen M.
      • Halmesmaki K.
      • Lehti L.
      • Tiitola M.
      • Aho P.
      • et al.
      Poor inter-observer agreement on the TASC II classification of femoropopliteal lesions.
      Further studies looking at inter- and intra-observer variability with regard to GLASS scoring would be valuable and are currently ongoing within the group. In particular, whether a GLASS ‘App’, developed by the European Society for Vascular Surgery, aids the utility and repeatability of GLASS is being explored, so encouraging the use of GLASS in everyday practice.
      It is important to discuss the strengths and weaknesses of using the BASIL-1 dataset. Its key, indeed unique, strength is that it remains the only randomised dataset and so avoids selection bias with regard to treatment allocation that so bedevils the rest of the published literature. Thus, as expected due to the randomisation, there was no difference in GLASS stage or grade between the two groups studied. The other unique strengths of BASIL-1 are the length and completeness (less than 1% lost to follow up) of follow up.
      The BASIL-1 interventions were performed between 1999 and 2004, and it has been suggested that clinical outcomes for the same angiographic severity of disease would be significantly better in current practice. However, unfortunately, there is little or no evidence to support that view. The sample size calculation for ongoing BASIL-2 and BASIL-3 trials were based upon BASIL-1 outcomes, as they were considered by the investigators, the sponsor, and the funder to be the best data available.
      • Popplewell M.A.
      • Davies H.
      • Jarrett H.
      • Bate G.
      • Grant M.
      • Patel S.
      • et al.
      Bypass versus angio plasty in severe ischaemia of the leg – 2 (BASIL-2) trial: study protocol for a randomised controlled trial.
      ,
      • Hunt B.D.
      • Popplewell M.A.
      • Davies H.
      • Meecham L.
      • Jarrett H.
      • Bate G.
      • et al.
      BAlloon versus Stenting in severe Ischaemia of the Leg-3 (BASIL-3): study protocol for a randomised controlled trial.
      That decision has turned out to be correct as aggregate outcomes in BASIL-2 (predominantly IP disease) and BASIL3 (predominantly FP disease) are virtually identical to, and indeed if anything somewhat worse than, those observed in BASIL-1. Other published data from this group and other groups also suggest that the results of revascularisation have not, in fact, improved since BASIL-1.
      • Meecham L.
      • Popplewell M.
      • Bate G.
      • Patel S.
      • Bradbury A.W.
      Contemporary (2009-2014) clinical outcomes after femoropopliteal bypass surgery for chronic limb threatening ischemia are inferior to those reported in the UK Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL) trial (1999-2004).
      ,
      • Popplewell M.A.
      • Davies H.O.B.
      • Renton M.
      • Bate G.
      • Patel S.
      • Deeks J.J.
      • et al.
      Comparison of outcomes following infrapopliteal plain balloon angioplasty in the BASIL Trial (1999–2004) and in a contemporary series (2009-2013).
      The previously widely expressed confidence that better patency rates following the use of paclitaxel based drug coated balloons (DCB) and drug eluting stents (DES) would translate into better clinical outcomes has now been shown to be seriously misplaced. So, although BASIL-1 interventions were performed some time ago, the weight of current evidence strongly indicate that BASIL-1 outcomes remain relevant to current practice.
      • Meecham L.
      • Popplewell M.
      • Bate G.
      • Patel S.
      • Bradbury A.W.
      Contemporary (2009-2014) clinical outcomes after femoropopliteal bypass surgery for chronic limb threatening ischemia are inferior to those reported in the UK Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL) trial (1999-2004).
      • Popplewell M.A.
      • Davies H.O.B.
      • Renton M.
      • Bate G.
      • Patel S.
      • Deeks J.J.
      • et al.
      Comparison of outcomes following infrapopliteal plain balloon angioplasty in the BASIL Trial (1999–2004) and in a contemporary series (2009-2013).
      • Popplewell M.A.
      • Davies H.O.B.
      • Narayanswami J.
      • Renton M.
      • Sharp A.
      • Bate G.
      • et al.
      A comparison of outcomes in patients with infrapopliteal disease randomised to vein bypass or plain balloon angioplasty in the Bypass vs. Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.
      • Meecham L.
      • Patel S.
      • Bate G.R.
      • Bradbury A.W.
      Editor's Choice – a comparison of clinical outcomes between primary bypass and secondary bypass after failed plain balloon angioplasty in the Bypass versus Angioplasty for Severe Ischaemia of the Limb (BASIL) trial.
      • Benson R.A.
      • Meecham L.A.
      • Hewitt C.A.
      • Bradbury A.W.
      Comparison of immediate and long-term outcomes in men and women undergoing revascularisation for chronic limb threatening ischaemia in the Bypass vs. Angioplasty in Severe Ischaemia of the Leg (BASIL-1) trial.
      • Meecham L.
      • Bate G.
      • Patel S.
      • Bradbury A.W.
      A comparison of clinical outcomes following femoropopliteal bypass or plain balloon angioplasty with selective bare metal stenting in the Bypass versus Angioplasty in Severe Ischaemia of the Limb (BASIL) trial.
      Leaving aside the age of the BASIL-1 dataset, the current study has a number of methodological limitations. (1) Only 86% of the BASIL-1 pre-intervention DSA were available for evaluation. Therefore, only a relatively small number of patients was included in each GLASS stage, especially in FP only subanalysis. (2) Only static DSA images were available. (3) It was not possible to independently examine GLASS IP grade due to small numbers. (4) The impact on outcomes of the severity of calcification and of IM disease, both modifiers in GLASS, could not be evaluated.
      • Iida O.
      • Soga Y.
      • Yamauchi Y.
      • Hirano K.
      • Kawasaki D.
      • Tazaki J.
      • et al.
      Anatomical predictors of major adverse limb events after infrapopliteal angioplasty for patients with critical limb ischaemia due to pure isolated infrapopliteal lesions.
      ,
      • Stoner M.C.
      • Calligaro K.D.
      • Chaer R.A.
      • Dietzek A.M.
      • Farber A.
      • Guzman R.J.
      • et al.
      Reporting standards of the Society for Vascular Surgery for endovascular treatment of chronic lower extremity peripheral artery disease.
      (5) Stent use was rare in the EVT arm of BASIL (six patients received a bare metal stent in the superficial femoral artery). Recent evidence suggests that the use of self expanding stents or stent grafts (as well as drug eluting devices) is associated with superior patency and freedom from re-intervention compared with PBA in more advanced FP disease (e.g., GLASS FP stages 2/3).
      • Conte M.S.
      • Bradbury A.W.
      • Kolh P.
      • White J.V.
      • Dick F.
      • Fitridge R.
      • et al.
      Global Vascular Guidelines on the management of chronic limb-threatening ischemia.
      However, these studies were conducted primarily in patients with claudication and it is widely accepted, and indeed explicitly stated in the GVG, that trial data in patients with intermittent claudication and with CLTI should not be conflated and are not transferrable in either direction. Furthermore, while DCB and DES are no longer recommended for routine use in patients with intermittent claudication due to excess all cause mortality associated with their use, the clinical and cost effectiveness of these devices in CLTI will remain unknown until BASIL-3 publishes it results.
      • Hunt B.D.
      • Popplewell M.A.
      • Davies H.
      • Meecham L.
      • Jarrett H.
      • Bate G.
      • et al.
      BAlloon versus Stenting in severe Ischaemia of the Leg-3 (BASIL-3): study protocol for a randomised controlled trial.
      ,
      • Katsanos K.
      • Spiliopoulos S.
      • Kitrou P.
      • Krokidis M.
      • Karnabatidis D.
      Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials.
      ,
      • Katsanos K.
      • Spiliopoulos S.
      • Kitrou P.
      • Krokidis M.
      • Paraskevopoulos I.
      • Karnabatidis D.
      Risk of death and amputation with use of paclitaxel-coated balloons in the infrapopliteal arteries for treatment of critical limb ischemia: a systematic review and meta-analysis of randomized controlled trials.
      In the meantime, it would seem appropriate to use these devices with great caution in CLTI patients outside registered trials. In contrast, PBA remains the standard approach for EVT in the IP arteries. The observations regarding EVT outcomes and GLASS FP grade in BASIL should thus be taken within this context and require further examination in a contemporary cohort.
      In conclusion, these data from BASIL-1 suggest that, with the exception of OS, GLASS is likely to be a useful predictor of immediate and long term clinical outcomes in patients undergoing EVT but not BS. The study also shows that, as GLASS stage and grade increase, immediate and long term clinical outcomes, in particular FF-MALE, become increasingly favourable after (especially vein) BS than after EVT. As described above, there are several limitations in the current study. Further research in the form of prospective cohort studies and randomised controlled trials such as the BASIL-2, and -3 trials and the BEST-CLI is required to determine if the results of this study are generalisable to current CLTI patients.
      • Popplewell M.A.
      • Davies H.
      • Jarrett H.
      • Bate G.
      • Grant M.
      • Patel S.
      • et al.
      Bypass versus angio plasty in severe ischaemia of the leg – 2 (BASIL-2) trial: study protocol for a randomised controlled trial.
      ,
      • Hunt B.D.
      • Popplewell M.A.
      • Davies H.
      • Meecham L.
      • Jarrett H.
      • Bate G.
      • et al.
      BAlloon versus Stenting in severe Ischaemia of the Leg-3 (BASIL-3): study protocol for a randomised controlled trial.
      ,
      • Menard M.T.
      • Farber A.
      • Assmann S.F.
      • Choudhry N.K.
      • Conte M.S.
      • Creager M.A.
      • et al.
      Design and rationale of the best endovascular versus best surgical therapy for patients with critical limb ischemia (BEST-CLI) trial.
      Although further validation and refinement of the GLASS is clearly required in contemporary series, GLASS seems likely to facilitate shared decision making regarding revascularisation options and the stratification of patients within clinical trials.

      Conflict of interest

      None

      Funding

      The BASIL trial was funded by the UK NIHR, HTA Programme.

      Appendix A. Supplementary data

      Supplementary Figure 1
      Supplementary Figure 1Comparison of clinical outcomes in patients having only femoropopliteal (FP) endovascular therapy or bypass surgery for CLTI in the BASIL-1 trial (A) Amputation free survival (FP grade 1) (B) Amputation free survival (FP grade 2) (C) Limb salvage (FP grade 1) (D) Limb salvage (FP grade 2) (E) Freedom from MALE (FP grade 3) (F) Freedom from MALE (FP grade 4).
      Supplementary Figure 2
      Supplementary Figure 2Comparison of clinical outcomes following femoropopliteal endovascular therapy or vein bypass surgery for CLTI in the BASIL-1 trial (A) Amputation free survival (FP grade 4) (B) Limb salvage (FP grade 4) (C) Freedom from MALE (FP grade 3) (D) Freedom from MALE (FP grade 4).
      Supplementary Figure 3
      Supplementary Figure 3Comparison of (A) amputation free survival, (B) overall survival, and (C) limb salvage following endovascular therapy and bypass surgery for CLTI in the BASIL-1 trial by GLASS stage I, II and III.

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