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Interventions for great saphenous vein reflux: network meta-analysis of randomized clinical trials

Background: A variety of endovascular and open surgical interventions exist to treat great saphenous vein reﬂux. However, compari- sons of treatment outcomes have been inconsistent. Methods: A systematic review and network meta-analysis of RCTs was performed to compare rates of incomplete stripping or non-occlusion of the great saphenous vein with or without reﬂux (anatomical failure) at early, mid- and long-term follow-up; and secondary outcomes (reintervention and clinical recurrence) among intervention groups. The surface under the cumulative ranking curve (SUCRA) method was used to estimate the probability of the intervention with the lowest anatomical failure rates. Results: Some 72 RCTs were included. Comparisons of endothermal techniques with open surgery were mostly not signiﬁcantly different, except for endovenous laser ablation (EVLA), which had higher long-term anatomical failure rates (pooled risk ratio (RR) 1.87, 95 per cent c.i. 1.14 to 3.07). Mechanochemical ablation had higher anatomical failure rates than radiofrequency ablation (RFA) (pooled RR 2.77, 1.38 to 5.53), and cyanoacrylate closure (CAC) had a RR 0.56 (0.34 to 0.93) times lower than either RFA or EVLA at the early term. Ultrasound-guided foam sclerotherapy had a higher risk of anatomical failure and reintervention than open surgery, with the lowest SUCRA value, and CAC was ranked ﬁrst, third and ﬁrst for best intervention for anatomical failure at early, mid and long term respectively. However, clinical recurrence rates were not signiﬁcantly different between all comparisons. Conclusion: Mechanochemical ablation and ultrasound-guided foam sclerotherapy performed poorly, with higher anatomical failure rates in the long term. The other treatment modalities had similar rates of anatomical failure in the short and mid term.


Introduction
Endovenous thermal ablation methods, including radiofrequency ablation (RFA) and endovenous laser ablation (EVLA), have been recommended instead of open surgery for the treatment of great saphenous vein reflux 1,2 . Other non-invasive modalities are available, including ultrasound-guided foam sclerotherapy (UGFS) and non-thermal non-tumescent (NTNT) techniques, such as mechanochemical ablation (MOCA) and cyanoacrylate closure (CAC).
A meta-analysis 3 in 2012 demonstrated similar efficacies in the mid term (1-3 years) for rates of incomplete stripping or non-occlusion of the great saphenous vein (GSV) with or without reflux (anatomical failure) following RFA and EVLA, but poorer outcomes for UGFS, compared with open surgery. However, findings from two recent meta-analyses 4,5 of RCTs that assessed long-term outcomes (more than 5 years) reached conflicting conclusions, with one 4 reporting similar rates of anatomical failure between open surgery and EVLA, and the other 5 demonstrating significantly greater anatomical failure after EVLA at long-term follow-up compared with open surgery.
The primary aim of this systematic review and network meta-analysis was to quantify the rates of anatomical failure between the treatment techniques. In addition, a variety of secondary outcomes were assessed.

Methods
The study was conducted according to the PRISMA guidelines 15 and extension statement for network meta-analysis of healthcare interventions 16 . The published protocol was registered at PROSPERO (number CRD42018096794) 17 .
Search strategy and study selection MEDLINE and Scopus were searched from 2011 to March 2020. Search terms were based on patients and interventions 17 . Two reviewers independently selected studies according to predefined inclusion criteria: RCTs of GSV reflux; comparison of defined interventions as outlined below; and reporting any of the primary or secondary outcomes of interest. Data from multiple publications involving the same cohort were combined.

Interventions
Interventions of interest included open surgery, endothermal ablation (EVLA, RFA), UGFS, CAC, and MOCA. In addition, EVLA and UGFS procedures that were combined with HL were also considered.

Outcomes
Anatomical failure (incomplete stripping or GSV non-occlusion with or without reflux, as defined in the original study 3 ) was regarded as the primary outcome of interest. Secondary outcomes included postoperative complications (wound infection, haematoma, paraesthesia and venous thromboembolism), postoperative pain, time to recovery, Venous Clinical Severity Score (VCSS), AASV reflux, neovascularization, clinical recurrence, reintervention, and quality of life as measured by the Aberdeen Varicose Vein Questionnaire (AVVQ). Outcomes including anatomical failure, neovascularization, AASV reflux, VCSS and AVVQ scores were measured and stratified according to followup time as periprocedural (less than 30 days), early term (30 days to 1 year), mid term (1-3 years) and long term (more than 3 years) 1 .

Data extraction
Data, including characteristics of studies and patients, such as setting, interventions, outcomes, mean age, severity, GSV diameter, co-intervention (compression, concomitant phlebectomy), were extracted independently by two of three reviewers. In addition, data for pooling (frequency data among interventions and dichotomous outcomes; mean(s.d.) values of continuous outcomes by intervention group) were extracted. Corresponding authors were contacted twice to request unreported data for pooling. Discrepancies between reviewers were resolved by consensus.

Risk-of-bias assessment and grading of evidence
The Cochrane Collaboration tool 18 was used by two independent reviewers to assess sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome reports, selective outcome reports, and other sources of potential bias. In addition, the quality of evidence was graded using the GRADE working group tool 19 to consider study limitations, consistency, indirectness, imprecision and publication bias.

Statistical analysis
Direct meta-analysis was applied for direct comparison of intervention and comparator when at least three studies reported the same comparisons and outcomes. Effect sizes (risk ratio (RR) and risk difference for dichotomous outcomes, mean difference (MD) or standardized mean difference (SMD) for continuous outcomes) with 95 per cent c.i. were estimated. A fixed-effect model was used when effect sizes demonstrated low levels of heterogeneity across studies; otherwise a random-effects model was used. When studies did not report mean(s.d.) values, these were estimated from median (range/i.q.r.) values 20 . Number needed to treat (NNT) and harm (NNH) along with 95 per cent c.i. were estimated by inverse of pooled risk differences.
The Q test and I 2 values were used to assess heterogeneity. Outcomes with either a significant Q test results (P < 0.100) or I 2 value of 25 per cent or more were considered heterogeneous 21 . Possible sources of heterogeneity (such as wavelength and perprotocol analysis) were explored by means of meta-regression. Subgroup or sensitivity analyses were performed accordingly. Publication bias was assessed with Egger's test and funnel plots. Contour-enhanced funnel plots were assessed to determine whether asymmetry was likely due to heterogeneity or publication bias.
Network meta-analysis 22 was performed by borrowing information from the common comparators where direct comparisons were not available to compare outcomes indirectly among interventions (RFA, EVLA, EVLA with HL, UGFS, UGFS with HL, MOCA, CAC and open surgery). Effect sizes and variance-covariance were estimated for individual studies and pooled in a multivariable consistency model meta-analysis. Mixed intervention comparisons were also estimated. A surface under the cumulative ranking curve (SUCRA) based on the frequentist method was used to estimate the probability of the best intervention. The SUCRA method used cumulative posterior probability with 1000 simulations to estimate the probability of each intervention being the best ranked; values range from 0 to 100 per cent, where the higher value demonstrates high likelihood of being the best intervention.
The inconsistency assumption was tested using a design-bytreatment interaction model; if this was unmet, inconsistency factors were estimated and tested. Comparison-adjusted funnel plots were explored for evidence of small study effects across the whole network. A cluster rank plot of SUCRA for anatomical failure on the y-axis and postoperative pain on the x-axis was constructed 23 . Analysis was performed using STATA V R version 16.0 (StataCorp, College Station, TX, USA) with a threshold of P < 0.050 for the two-sided test considered statistically significant 25 .

Results
Seventy-four RCTs 6,7,9-14,24-89 met the study inclusion criteria (Fig. S1). Of them, 26 studies were the same as other RCTs but reported outcomes measured at different times, leaving 48 original RCTs for qualitative and risk-of-bias assessment (Table S1). A total of 49 RCTs 7,9-14,24-56,79-87 from 30 studies compared endovenous ablation with open surgery, and the remainder included comparisons between endovenous ablation methods only ( Table S1). Duration of follow-up ranged from 0.5 months to 8 years, with 18 of the 48 studies (38 per cent) reporting long-term outcomes (more than 3 years). Most studies included participants with a mean GSV diameter below 10 mm, with the exception of a single study 39 that reported a mean GSV diameter above 10 mm.

Risk-of-bias assessment
Results from the risk-of-bias assessment are presented in Table S2. Blinding domains represented the highest risk, with 85 and 75 per cent of RCTs unblinded for personnel and outcome assessors respectively. Approximately 30 per cent of RCTs had randomizations that were unclear or had a high risk of bias. However, most studies (95 per cent) had a low risk of bias for incomplete and selective outcome reports.

Direct meta-analysis
For EVLA versus open surgery, there were between 5 and 12 comparisons of anatomical failure at periprocedural, early, mid-term and long-term follow-up ( Table 1). Anatomical failure rates were not significantly different for EVLA in relation to open surgery at periprocedural to mid-term follow-up (Fig. S2). However, anatomical failure at long-term follow-up after EVLA was significantly higher than after surgery, with a pooled RR of 1.87 (95 per cent c.i. 1.14 to 3.07) and NNH of 20 (12 to 59). Sources of heterogeneity (I 2 ¼53.5 per cent) were explored by fitting different types of wavelength in a meta-regression and sensitivity analysis with study exclusion according to protocol 36,37 ; however, the source of heterogeneity could not be determined (data not shown). The contour-enhanced funnel plots suggested publication bias at early-term follow-up (Fig. S3).
Comparisons of RFA and open surgery outcomes were reported in five or six RCTs at periprocedural, early and mid-term follow-up, ( Table 1 and Fig. S4). Anatomical failure risk was 1.26 (95 per cent c.i. 0.20 to 7.99), 1.99 (0.92 to 4.31) and 1.45 (0.75 to 2.80) times greater for RFA than for open surgery at periprocedural, early and mid-term follow-up respectively, although none was significant and I 2 values were 0 per cent for early and midterm follow-up. Evidence of publication bias was not identified for any pooled comparisons (Fig. S4).
Comparisons of UGFS and open surgery outcomes were reported in three to nine RCTs at periprocedural, early, mid-term and long-term follow-up (Fig. S5). The anatomical failure risk was significantly higher at early, mid-term and long-term follow-up with corresponding RRs of 2.47 (95 per cent c.i. 1.78 to 3.43; NNH 6 (4 to 14), 2.14 (1.42 to 3.23; NNH 6 (5 to 10) and 3.06 (1.74 to 5.36; NNH 4 (2 to 9), with moderate to high levels of heterogeneity detected (I 2 values between 37.3 and 84.5 per cent). Sensitivity analyses through the exclusion of a study 11 that reported combined outcomes of UGFS with HL did not reduce the heterogeneity. Contour-enhanced funnel plots suggested missing studies from mid-term to long-term follow-up (Fig. S6).
The pooling of 10 RCTs of EVLA and RFA outcomes at early term identified significantly lower rates of anatomical failure for EVLA compared with RFA (RR 0.75, 95 per cent c.i. 0.58 to 0.97;  S7).
Three RCTs compared CAC with endothermal ablation (RFA and EVLA). The risk of anatomical failure was significantly lower after CAC compared with endothermal ablation at early term, with a pooled RR of 0.56 (95 per cent c.i. 0.34 to 0.93) and NNT of 30 (17 to 200). In contrast, the anatomical failure risk at early term was higher after MOCA than RFA (pooled RR 2.77, 1.38 to 5.53; NNH 12, 8 to 29). Both results were homogeneous (I 2 ¼0 per cent) with no publication bias (Fig. S8).

Network meta-analysis
Network meta-analyses of anatomical failure were generated from 26, 37, 17 and 15 RCTs for periprocedural, early-term, midterm and long-term outcomes respectively ( CAC comparisons with open surgery showed a lower risk of anatomical failure at periprocedural, early and long-term followup (RR 0.21 (95 per cent c.i. 0.01 to 6.84), 0.65 (0.36 to 1.17) and 0.62 (0.08 to 4.60) respectively), but none was significant ( Table 2). Comparisons of CAC with RFA and EVLA showed that RFA had a significantly higher anatomical failure rate than CAC at early term (RR 1.98, 1.17 to 3.35); EVLA and EVLA with HL also had a higher risk than CAC, but this was not significant. MOCA and UGFS had significantly greater risks of anatomical failure compared with CAC, RFA and EVLA at early term ( Table 2).
Consideration of the additional effect of HL on anatomical failure identified a significantly higher failure rate following UGFS compared with UGFS with HL at early follow-up (RR 2.48, 95 per cent c.i. 1.30 to 4.73); this was also reflected at mid-term and long-term follow-up, but was not significant ( Table 2). EVLA also showed an increased risk of failure between 1.61 and 1.92 times higher than EVLA with HL at both mid-term and long-term follow-up, but neither was significant.
SUCRA values associated with the lowest risk of anatomical failure were calculated for each follow-up period (Table S4). CAC was the top ranked intervention in lowering anatomical failure risk at the periprocedural, early and long-term follow-up. Open surgery and endothermal ablation were largely ranked next, followed by MOCA and UGFS with HL, whereas UGFS alone was ranked lowest across most of the follow-up periods. Adjusted funnel plots indicated no evidence of publication bias (Fig. S10).

Secondary outcomes
Secondary outcomes, including neovascularization, AASV reflux, clinical recurrence and reintervention, were considered (  (Fig. S12). Similarly, VCSS and AVVQ showed no significant differences at early, mid-term and long-term follow-up for EVLA comparisons with open surgery, and at early follow-up for UGFS versus open surgery (Figs S13-S15).
A network meta-analysis of postoperative pain showed consistent global test results between direct and network metaanalyses (Tables S3 and S5). Ranking indicated that CAC was ranked top in lowering postoperative pain, followed by MOCA, RFA, UGFS, EVLA and open surgery (Table S4). A cluster rank plot was constructed based on SUCRA values for lowering anatomical failure at mid-term and long-term follow-up on the y-axis and lowering postoperative pain on the x-axis (Fig. 1). The plot was divided into four quadrants at the SUCRA value of 0.5: interventions that fell in the right upper and lower quadrant had low pain with low and high anatomical failure respectively, whereas those in the left upper and lower quadrants had high pain with low and high anatomical failure. Therefore, the best intervention should fall in the right upper quadrant, with values for CAC indicating low anatomical failure and low postoperative pain for both midterm and long-term follow-up. EVLA, RFA and UGFS were associated with 3-4 and 4-8 days shorter return to normal activities and work compared with open surgery, with high levels of heterogeneity. NTNT had significantly reduced time to normal activities compared with endothermal ablation (pooled MD À0.9, 95 per cent c.i. À1.5 to À0.3; I 2 ¼92 per cent), but this was not significantly different for time to work.

Quality of evidence
The quality of the body of evidence for direct meta-analysis was graded according to each outcome across studies (Tables S6-S9). The most common reason for a reduction in the quality of evidence was serious imprecision as a result of inadequate sample size.

Discussion
This study failed to identify any significant differences in anatomical failure from comparisons between open surgery and RFA and EVLA at early and mid-term follow-up. The network meta-analysis did, however, identify significantly higher levels of anatomical failure with EVLA at long-term follow-up, although no data were available for assessment of RFA in the longer term. At early-term follow-up, CAC resulted in lower levels of anatomical failure than endothermal ablation, supported by a moderate quality of evidence. MOCA was associated with higher levels of anatomical failure compared with RFA, with a NNH value of 12 (95 per cent c.i. 8 to 29). Network meta-analysis also showed higher levels of anatomical failure following MOCA compared with open surgery, CAC, RFA, UGFS with HL, and EVLA at early follow-up. UGFS was associated with a higher risk of anatomical failure than open surgery in both direct and network meta-analyses, with NNH values ranging between 2 and 14 across all periods of follow-up with the lowest SUCRA value.
The data also demonstrated greater anatomical failure for EVLA at long-term follow-up compared with open surgery, with findings of moderate quality due to heterogeneity. These findings contrast with the previous meta-analysis 4 , which found no evidence of difference in anatomical failure rates between EVLA and open surgery. However, the present study supports the conclusions from the meta-analysis by Kheirelseid  In early-term follow-up, direct meta-analysis identified reduced anatomical failure after CAC compared with endothermal ablation, with moderate levels of quality associated with imprecision (the upper boundary of NNT was as high as 200 and with a suboptimal sample size). In addition, CAC ranked better than RFA for having the lowest anatomical failure rate in the network meta-analysis, scoring first, third and first rank for early, midterm and long-term follow-up respectively. The findings of this study are consistent with a recent network meta-analysis of early-term follow-up 90 . Only longer-term RCT data (5-year follow-up) also detected non-significant differences in the rate of GSV recanalization following CAC (8.6 per cent) and RFA (14.8 per cent) 74 . AASV reflux was significantly greater following EVLA, whereas neovascularization was greater after open surgery, with little difference in NNT/NNH values. However, anatomical failure, AASV reflux and neovascularization were surrogate outcomes of clinical recurrence that were not significantly different in the present analyses. In addition, other important patient outcomes, such as VCSS, AVVQ scores and reintervention, were also not significantly different beyond the higher reintervention rate observed after UGFS in relation to open surgery, although these outcomes should be considered further. Other likely sources of recurrence include perforator insufficiency, saphenopopliteal reflux and primary varicosities, which should be considered across different types of intervention. More detailed classification of clinical recurrence associated with specific interventions would facilitate comparisons of efficacies between interventions.
Paraesthesia was reduced after NTNT compared with endothermal ablation, which may result from lower levels of thermal injury to the adjacent nerve during the procedure, whereas superficial thrombophlebitis was not significantly different across the comparisons assessed. Postprocedure phlebitis was the most common complication following CAC 91 , and comparisons of superficial thrombophlebitis with endothermal ablation and NTNT were not significantly different (RR 0.99 (95 per cent c.i. 0.63 to 1.54).
The data in this study confirmed the benefit of endovenous ablation in terms of postoperative pain and recovery time following RFA and UGFS compared with open surgery. Although the benefits of EVLA relative to open surgery were reduced, the effect observed failed to reach significance. This may be explained through variation in the wavelength of EVLA considered within the analysis. Variation from lower to higher wavelength EVLA (1470 nm), which targets the vein wall instead of blood within, could reduce pain and complications. The subgroup analysis by wavelength reduced the I 2 value to zero, resulting in significantly higher pain recorded at wavelength thresholds below 1470 nm and lower pain levels at thresholds of 1470 nm for EVLA comparisons with RFA. Two RCTs 92,93 also reported significantly lower levels of pain and complications at EVLA wavelengths of 1470 nm.
CAC was also associated with lower postoperative pain compared with endothermal ablation, possibly as a consequence of non-thermal mechanisms of ablation or perhaps due to unnecessary use of tumescent anaesthesia. Although MOCA does not need tumescent anaesthesia, its mechanical injury of vein during the procedure may cause discomfort. The quality of evidence was graded as moderate, owing to inconsistency 70,89 .
The efficacies, benefits and harms, together with measures on the quality of evidence according to outcomes, were reported in the present study to support physician decisions when choosing the most appropriate intervention for individual patients. For instance, if anatomical failure is the main concern in the mid and long term, open surgery might be best, given its associated complications are similar to those of other techniques. If patient outcome such as postoperative pain is of more concern, CAC might be preferred over open surgery and other interventions, given that anatomical failure is not much different to that for open surgery. However, this should be interpreted with caution because data for other important outcomes (neovascularization, AASV reflux, clinical recurrence and quality of life) were not available for CAC comparisons.
There are some limitations to this study. Although comparisons of many relevant clinical outcomes were included, important patient outcomes such as symptomatic improvement were not considered owing to lack of available data. Quality of life, measured by the AVVQ, was available for a small number of studies of endothermal ablation, but not for CAC or MOCA. Cost is also an important consideration, but was not part of the present analysis.

Supplementary material
Supplementary material is available at BJS online.

Acknowledgements
This work was supported by the Centre of Excellence in Applied Epidemiology, Thammasat University, and the Department of Clinical Epidemiology and Biostatistics, Ramathibodi Hospital,