DOI: https://doi.org/10.21203/rs.3.rs-2930604/v1
Background
Existing studies suggested that the efficacy and safety of tubular microdiscectomy (TMD) and percutaneous transforaminal endoscopic discectomy (TED) for lumbar disc herniation (LDH) was similar to open microdiscectomy (OMD). No head-to-head randomized controlled trials (RCTs) between TMD and TED for LDH have been reported, however, making room for indirect, integrated comparisons. Network meta-analysis (NMA) based on RCTs was used to comparing the clinical efficacy and safety of TMD and TED for LDH.
Methods
We systematically searched online databases of the Cochrane Library, PubMed, and Embase from inception through March 2023 for eligible literature. The following search terms were used: “transforaminal endoscopic discectomy,” “microdiscectomy,” “endoscopic,” “minimally invasive,” “tubular microdiscectomy,” “spinal disease,” and “randomized clinical trial”. Primary outcomes were Oswestry disability index (ODI), visual analogue scale (VAS) for leg pain, complications, and reoperation. Direct comparison meta-analyses and NMA were carried out.
Results
Eight RCTs (1391 patients) met the inclusion criteria. NMA indicated that there was no significant difference in any of the outcomes between TED and TMD. Trend analyses of rank probabilities showed that cumulative probabilities of being the most effective treatment, as measured by primary outcomes (VAS, ODI, reoperation, complications), were: TED (95%, 77%, 23%, 58%), TMD (4%, 22%, 54%, 36%), OMD (1%,1%, 23%, 6%).
Conclusion
This NMA showed no significant differences between TED and TMD in efficacy and safety for LDH.
PROSPERO registration number: CRD42020156123.
Sciatica is one of most common type of painful disease globally, affecting 1–5% of the population each year.1 It seriously affects patient quality of life, and greatly increases the burden of care placed on social caregivers and family. Sciatica can be caused by a variety of diseases, most commonly lumbar disc herniation (LDH).2 When patients with persistent pain have difficulty in conserving treatment or have progressive neurological defects, early surgery is suggested. More than 40% of patients assigned to conservative treatment undergo surgery within 2 years, according to randomized controlled trials (RCTs).3,4 Surgical treatment reports for lumbar disc herniation began in the 1930’s.5 In 1977, Caspar and Yasargil introduced a more minimally invasive LDH treatment: open microdiscectomy (OMD).6,7 Since its introduction, OMD has been considered the first choice of surgical treatment for symptomatic LDH.8,9 However, due to muscle, bone, and other structure trauma, OMD can result in complications including postoperative spinal instability and cerebrospinal fluid leakage.10,11 For these reasons, tubular microdiscectomy (TMD) and percutaneous transforaminal endoscopic discectomy (TED) were developed, and are still the most popular minimally invasive techniques today.12,13 The latest meta-analysis finds that the efficacy 1 year after TMD were broadly similar to that of OMD.14 Compared to OMD, TMD not only has a smaller incision, but also reduces muscle tissue damage, and significantly reduces the consumption of postoperative analgesics.15 TED was developed earlier than TMD. In the late 1970s, the Kambin triangle was used as an endoscopic approach for spine surgery using transforaminal approach.16 With improvement of endoscopic instruments and operative techniques, TED came to be used for symptomatic LDH. It was a more minimally invasive method that seemed to lead to fewer soft tissue injuries and more bone preservation.17–19 Compared to OMD, TED has been shown to reduce hospital length of stay, but the effectiveness of the two treatments was similar.20
Given that the indications for TMD and TED are similar to those for OMD surgery in patients with LDH,21,22 surgeons are faced with a dilemma when deciding between these two minimally invasive techniques. A recent meta-review of research showed that operative effects of TMD or TED and OMD for LDH are essentially equivalent.23 Due to the lack of head-to-head comparisons between TMD and TED, most of the studies are pairwise meta-analyses of TMD and MD, or TED and OMD. A networked meta-analyses (NMA) about this topic has been performed previously, but the focus of this study was limited to surgical complications and did not include efficacy.24 Importantly, we have identified an additional RCT which directly compares TMD and MD.25 Given in the absence of evidence regarding direct comparisons of TMD with TED, we conducted a Bayesian NMA of RCTs intending to compare effectiveness and safety between TMD with TED.
We registered the review (PROSPERO CRD42020156123) in advance and this study was prepared by the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines (Supplemental table 1).
We searched Embase, Cochrane Central Register of Controlled Trials, and PubMed through March of 2023 using the following keywords in various combinations: “transforaminal endoscopic discectomy,” “microdiscectomy,” “endoscopic,” “minimally invasive,” “tubular microdiscectomy,” “spinal disease,” and “randomized clinical trial”.
The inclusive criteria for this NMA were as follow (1) age eighteen to eighty years; (2) LDH requiring surgery; (3) RCTs comparing TMD with MD, TED with MD, or TMD with TED; (4) at least consecutively followed up 12 months.
Exclusion criteria were: (1) suffering from spinal fractures, deformities, infections or tumors; (2) studies other than RCTs.
Two investigators (S.C.L., R.W.) extracted data from eligible studies to evaluate the following outcomes: (1) visual analogue scale (VAS) for leg pain;26 (2) Oswestry disability index (ODI);27 (3) short form 36 (SF-36);28 (4) complications; (5) reoperation; (6) operative time, blood loss, and hospital stay.
Two investigators (S.C.L., R.W.) assessed bias risk using twelve criteria recommended by the Cochrane Back Review Group.29 The Grading of Recommendations Assessment, Development and Evaluation Working Group modality (GRADE) approach was used to evaluate both strength of recommendations and quality of evidence.30
We performed pair-wise meta-analysis to synthesize studies comparing the same of treatment pair. We choosed odds ratio (OR) and standardized mean difference (SMD) 95% confidence intervals (95% CI) to represent the result of dichotomous outcomes and continuous outcomes. If the 95% CI included 0 for SMD or 1 for OR, there were no significantly differences in result. Statistical heterogeneity among studies was evaluated using forest plot and the inconsistency statistic. 31 Pairwise meta-analysis was performed with RevMan (Review Manager 5.3 version.). NMA and rank probability was performed with the ADDIS software (Aggregate Data Drug Information System 1.16.5 version) to incorporate indirect comparisons. 32
Eligible studies
Our search strategy yielded 1130 studies from EMBASE (n=580), PubMed (n=331), and Cochrane Central Register of Controlled Trials (n=219). Only sixteen RCTs were included.15,21,25,33-45 Three of 16 studies included follow-up of less than 1 year,15,38,39 five were duplicate reports of the same set of patients.40-44 8 RCTs with 1391 patients were included in the meta-analysis. There were 997, 248, and 558 patients allocated to OMD, TMD, and TED, respectively (Figure 1). Characteristics of 8 studies were shown (Table 1). 21,25,33-37,45
Risk of Bias of Individual Studies
Figure 6-7 shows the graph of risk of bias. In the included studies, 7 studies indicated “randomly allocating”. Only 3 trials described methods of randomization. All trials doesn’t mentioned it use the blind method, because no studies could perform blinding. 6 studies found no significant other bias.
Pooled Weighted Outcomes and Direct Meta-Analysis
Compared with OMD, TMD is superior in ODI (SMD=-3.43 95% CrI -4.64 to -2.21, Figure 2), and there is no statistical difference in other aspects (Figure 3-5). Compared with OMD, the TED was associated with higher pain relief (SMD=-1.10 95% CrI -1.85 to -0.34, Figure 3), functional outcome (SMD=-5.17 95% CrI -8.04 to -2.31, Figure 2), and shorter hospital stays (SMD=-0.70 95% CrI -1.05 to -0.35). There is no statistical difference in other outcomes (Figure 4-5).
Network Meta-Analyses and Rank Probabilities
We established a network for comparisons of OMD, TMD, and TED. According to our results, OMD, TMD, and TED showed no statistical difference in terms of VAS, ODI, complications, reoperation, operation time, and duration of hospital stay (Table 2A-F).
Using a ranking system that indicates the best treatment probability, we developed a histogram figure (Supplemental Figure S2) to show the probability to be the best, the second-best, the third best among 3 treatments. It was found that agents with greater value in the histogram had greater probabilities for better outcomes. The cumulative probabilities of TED (95%), TMD (4%), and OMD (1%) being associated with the highest level of pain relief came from the network (Figure S2A). TED (77%), TMD (22%), and OMD(1%) were associated with the highest cumulative probabilities of disability prevention (Figure S2B). In other words, the most likely clinical efficacy was found with TED, followed by TMD, and finally OMD. TMD (54%), TED (23%), and OMD (23%) are associated with the lowest cumulative probability of reoperation ( Figure S2C). According to the cumulative probabilities, TED (58%), TMD (36%), and OMD (6%) are associated with the lowest complication rates (Figure S2D). That is to say, TED was the most likely to have the highest safety, followed by TMD, and then OMD. TED (56.3%), TMD (39.3%), and OMD (4.4%) are associated with the least cumulative probability of operation time. TED (87.7%), TMD (10.3%), and OMD (2%) are associated with the shortest cumulative probability of duration of hospital stay. By using the 12 criteria recommended by the Cochrane Back Review Group, we assessed bias risk in all original studies.29 Figure 7-8 summarizes the ratings from all included studies.
An analysis of the funnel plot (Supplemental Figure S3) revealed no apparent publication bias. As our study had a limited sample size, no sensitivity or scenario analysis was conducted.
Quality Assessment
All pooled outcomes were evaluated using GRADE quality assessment. Results are shown in Table 3.
As far as we know, this is the first systematic review that compares TMD with TED for the treatment of LDH by using a network meta-analysis. Based on data from eight RCTs, we evaluated the efficacy (in terms of VAS, ODI) and safety (in terms of complications, reoperation) of three treatment options for patients with LDH in this study. The NMA indicated that none of the outcomes were significantly different for TED and TMD. When relative values fail to reach statistical significance, rank probabilities can be used to analyze a treatment group's position among certain treatments. It can tell us which treatment would be most likely to be the best option, or if one treatment might be better than another. Our NMA concluded that TED had the greatest probability to rank the first among all three surgical options regarding VAS, ODI, complications, operation time, and intraoperative blood loss, while TMD had the greatest probability to rank best in reoperation.
The ultimate goals for LDH treatments are to eliminate or reduce pain and restore or improve limb function. Prior to this study, no direct comparison between TMD and TED in LDH populations has been available. The direct Meta-Analysis shows that TMD have no advantages over OMD in terms of pain relief. This conclusion is consistent with the results of previous meta-analyses.14 It's worth mentioning that patient-reported VAS outcome following TED were better than OMD. This is in contrast to the findings of Qin's study.46 However our findings our limited by the availability of only one suitable RCT for this analysis.25 Our NMA results showed no significant differences in VAS and ODI outcomes from TED, TMD, and OMD treatments, but the rank probabilities revealed decreasing potential advantage sequentially. One possible reason for this trend is that TED uses the anatomical space to gain access to the internal surgery site and the musculoskeletal structure is rarely damaged.47 There is also evidence that paravertebral muscle injury is associated with poor clinical outcomes.20,48 A study that compared preoperative and postoperative serum creatine phosphokinase levels with postoperative low back pain, between TED with OMD treatments, confirmed that TED can reduce muscle injury.38 A comparison of TMD and OMD found no reduction in muscle injury, and patients experienced more low-back pain a year after surgery with TMD. 41 Regarding surgical data, TMD and TED did not differ significantly in operation time and hospitalization days based on the NMA. Since most of the original studies failed to provide valid data, the intraoperative blood loss could not be included in this analysis.
In terms of safety, common complications as a result of LDH surgical repair include cerebrospinal fluid leakage, nerve root injury, and incision-related complications. When OMD is compared with TMD or TED, our NMA showed no reduced risk of complications. These results are in line with previous studies. A meta-analysis found no significant difference in the clinical efficacy of TMD and OMD for LDH in outcomes concerning the incidence of reoperation and dural tear.14 Zhang et al. reported no significant differences in the incidence of complications between TED and OMD in treating LDH.20 Our NMA found no significant differences in the rate of reoperation between TED and TMD, however rank probabilities revealed that TMD was associated with a lower incidence of complications and reoperation compared with TED. One possible reason for these trends is that limited surgical exposure increases the difficulty of surgery, making it easier to cause nerve damage and other complications.49 An RCT comparing TED and TMD efficacy is needed to confirm our conclusions.
Our study had a few potential limitations. First, although all the studies in our study were RCTs, the size of the studies was small, and the total sample size was limited. Second, since there wasn't enough available data, SF-36 scores and intraoperative blood loss hadn't been separately analyzed. Third, heterogeneity is inherent in our study as a result of the inconsistency of patient follow-up time, incomplete allocation methods, and failure to use independent blinding. Not only that, the included endoscopic studies also have heterogeneities. Researches by Mayer et al.36 and Hermantin et al.35 used the legacy endoscopic system, which is different from researches by Ruetten et al.37 and Gibson et al.25, who used a modern full endoscopic system. Ruetten's study also includes patients with an interlaminar endoscopic approach, which is a different procedure with TED. The heterogeneity of the available studies may reduce the level of evidence of this study to level II. Last, despite the fact that this study's evidence network plot appears to be star-shaped, it does not indicate a closed loop, which indicates there are no head-to-head comparisons; thus, the efficacy and safety of TED and TMD do not differ statistically significantly. Consequently, more RCTs comparing TED with TMD should be conducted to obtain more robust results.
It is the first network meta-analysis that compares the clinical efficacy and safety of TMD and TED, despite the limitations mentioned above. This NMA showed no significant differences among TMD and TED in efficacy and safety for LDH. This conclusion needs to be confirmed by additional well-designed and large-scale RCTs.
Abbreviations |
Full name |
LDH |
Lumbar disc herniation |
RCTs |
Randomized controlled trials |
OMD |
Open microdiscectomy |
TMD |
Tubular microdiscectomy |
TED |
Percutaneous transforaminal endoscopic discectomy |
MED |
Microendoscopic discectomy |
NMA |
Network meta-analyses |
VAS |
Visual analogue scale |
ODI |
Oswestry disability index |
SF-36 |
Short form 36 |
OR |
Odds ratio |
CI |
Confidence interval |
SMD |
Standardized mean difference |
ADDIS |
Aggregate data drug information system |
Author contributions: * Rui Wang is the co-first author. Shichao Liu and Rui Wang have contributed equally to this study; Shichao Liu, Rui Wang, Haodong Chen, Yuandong Zhuang, and Chunmei Chen designed and performed the experiments, collected and analyzed data, and wrote the manuscript; Shichao Liu, Rui Wang, and Chunmei Chen wrote the manuscript. All authors read and approved the final manuscript.
Funding acknowledgements: This work was funded by Startup Fund for scientific research, Fujian Medical University(Grant number:2021QH1037).
Institutional review board statement: This research did not increase the risk and economic burden of patients; the patients’ rights were fully protected; the project design was conducted in line with scientific and ethical principles. The institutional review board approved this project.
Data sharing statement: All data generated during the project will be made freely available via the Fujian Medical University Union Hospital’s Research Data Repository. DOIs to these data will be provided (as part of the DataCite programme) and cited in any published articles using these data and any other data generated in the project. There are no security, licensing, or ethical issues related to these data.
Table1. Characteristics of the included studies |
|||||||
Study |
Study type |
Preoperative diagnosis |
Surgical Intervention |
Sample size |
Mean age (year) |
Follow-up (month) |
Outcomes |
Ryang 2008 |
RCT |
Lumbar disc herniation |
OMD TMD |
30 30 159 166 48 52 30 30 20 20 87 91 70 70 |
39.1 38.2 41.6 41.3 44.0 44.0 40.0 39.0 39.8 42.7 39.0 39.0 39.0 42.0 |
16 |
VAS,ODI,SF-36,complications,OT, DHS, BL, reoperation |
Arts 2009 |
RCT |
Lumbar disc herniation |
OMD TMD |
13 |
VAS,ODI,SF-36,complications,OT, DHS, BL, reoperation |
||
Franke 2009 |
RCT |
Lumbar disc herniation |
OMD TMD |
12 |
VAS, ODI, complications, OT, DHS, reoperation |
||
Hermantin 1999 |
RCT |
Lumbar disc herniation |
OMD TED |
31 |
complications |
||
Mayer 1993 |
RCT |
Lumbar disc herniation |
OMD TED |
24 |
complications, OT, reoperation |
||
Ruetten 2008 |
RCT |
Lumbar disc herniation |
OMD TED |
24 |
VAS, ODI, complications, OT, BL, reoperation |
||
Gibson 2016 |
RCT |
Lumbar disc herniation |
OMD TED |
24 |
VAS, ODI, SF-36, complications, OT, DHS, BL, reoperation |
||
Gadjradj 2022 |
RCT |
Lumbar disc herniation |
OMD TED |
309 179 |
45.7 45.3 |
12 |
VAS,ODI,SF-36,AD,OT, LOS,BL,reoperation, complications |
OMD, open microdiscectomy; TMD, tubular microdiscectomy; TED, percutaneous transforaminal endoscopic discectomy; RCT, randomized controlled trial; VAS, visual analogue scale for back and/or leg pain; ODI, Oswestry disability index; SF-36, short form 36; OT, operation time; DHS, duration of hospital stay; BL,blood loss |
Table2A. Multiple-treatment comparisons based for ODI on the network |
||
OMD |
-5.05 (-9.93, 0.06) |
-3.08 (-7.26, 2.36) |
5.05 (-0.06, 9.93) |
TED |
-2.05 (-4.43, 9.64) |
3.08 (-2.36, 7.26) |
-2.05 (-9.64, 4.43) |
TMD |
Table2B. Multiple-treatment comparisons based for VAS on the network |
||
OMD |
-1.09 (-2.21, -0.11) |
-0.07 (-0.90, 0.86) |
1.09 (0.11, 2.21) |
TED |
1.03 (-0.25, 2.52) |
0.07 (-0.86, 0.90) |
-1.03 (-2.52, 0.25) |
TMD |
Table2C. Multiple-treatment comparisons based for complication on the network |
||
OMD |
0.54 (0.12, 2.49) |
0.72 (0.15, 3.06) |
1.86 (0.40, 8.20) |
TED |
1.36 (0.14, 11.05) |
1.38 (0.33, 6.52) |
0.73 (0.09, 7.17) |
TMD |
Table2D. Multiple-treatment comparisons based for reoperation on the network |
||
OMD |
1.09 (0.51, 2.82) |
0.87 (0.29, 2.13) |
0.92 (0.35, 1.97) |
TED |
0.80 (0.18, 2.61) |
1.15 (0.47, 3.39) |
1.24 (0.38, 5.69) |
TMD |
Table2E. Multiple-treatment comparisons based for operation time on the network |
||
OMD |
-10.69 (-35.83, 14.40) |
-7.48 (-28.29, 12.96) |
10.69 (-14.40, 35.83) |
TED |
2.98 (-29.54, 35.60) |
7.48 (-12.96, 28.29) |
-2.98 (-35.60, 29.54) |
TMD |
Table2F. Multiple-treatment comparisons based for hospital stay time on the network |
||
OMD |
-0.70 (-1.64, 0.20) |
-0.05 (-0.88, 0.64) |
0.70 (-0.20, 1.64) |
TED |
0.64 (-0.57, 1.78) |
0.05 (-0.64, 0.88) |
-0.64 (-1.78, 0.57) |
TMD |
Table3. Summary of Findings for the Main Comparison. |
|||||||
Outcomes |
Comparison of inteventions |
Direct estimate |
Indirect estimate |
Network estimate |
|||
OR/SMD (95%CI) |
Certainty direct estimate |
OR/SMD (95%CI) |
Certainty indirect estimate |
OR/SMD (95%CI) |
Certainty network estimate |
||
ODI |
TMD vs. MD |
-3.43 (-4.64, -2.21)
|
⨁⨁⨁⨁ HIGH |
Not evaluated a |
Not evaluated a |
-3.08 (-7.26, 2.36) |
⨁⨁⨁⨁ HIGH |
TED vs. MD |
-5.17 (-8.04, -2.31)
|
⨁⨁◯◯ LOW c |
Not evaluated a |
Not evaluated a |
-5.05 (-9.93, 0.06) |
⨁⨁◯◯ LOW |
|
TED vs. TMD |
Not evaluated a |
Not evaluated a |
-2.05 (-9.64, 4.43) |
⨁⨁◯◯ LOW d |
-2.05 (-9.64, 4.43) |
⨁⨁◯◯ LOW |
|
VAS |
TMD vs. MD |
-0.11 (-0.46, 0.24) |
⨁⨁⨁◯ MODERATE b |
Not evaluated a |
Not evaluated a |
-0.07 (-0.90, 0.86) |
⨁⨁⨁◯ MODERATE |
TED vs. MD |
-1.10 (-1.85, -0.34) |
⨁⨁◯◯ LOW c |
Not evaluated a |
Not evaluated a |
-1.09 (-2.21, -0.11) |
⨁⨁◯◯ LOW |
|
TED vs. TMD |
Not evaluated a |
Not evaluated a |
-1.03 (-2.52, 0.25) |
⨁⨁◯◯ LOW d |
-1.03 (-2.52, 0.25) |
⨁⨁◯◯ LOW |
|
Complications |
TMD vs. MD |
0.83 (0.29, 2.36) |
⨁⨁⨁◯ MODERATE b |
Not evaluated a |
Not evaluated a |
0.72 (0.15, 3.06) |
⨁⨁⨁◯ MODERATE |
TED vs. MD |
0.62 (0.18, 2.15) |
⨁⨁⨁◯ MODERATE b |
Not evaluated a |
Not evaluated a |
0.54 (0.12, 2.49) |
⨁⨁⨁◯ MODERATE |
|
TED vs. TMD |
Not evaluated a |
Not evaluated a |
0.73 (0.09, 7.17) |
⨁⨁⨁◯ MODERATE e |
0.73 (0.09, 7.17) |
⨁⨁⨁◯ MODERATE |
|
Reoperation |
TMD vs. MD |
0.81 (0.29, 2.23)
|
⨁⨁⨁◯ MODERATE b |
Not evaluated a |
Not evaluated a |
0.87 (0.29, 2.13) |
⨁⨁⨁◯ MODERATE |
TED vs. MD |
1.02 (0.56, 1.85)
|
⨁⨁⨁◯ MODERATE b |
Not evaluated a |
Not evaluated a |
1.09 (0.51, 2.82) |
⨁⨁⨁◯ MODERATE |
|
TED vs. TMD |
Not evaluated a |
Not evaluated a |
1.24 (0.38, 5.69) |
⨁⨁⨁◯ MODERATE e |
1.24 (0.38, 5.69) |
⨁⨁⨁◯ MODERATE |
|
Operation time |
TMD vs. MD |
-7.70 (-33.72, 18.32)
|
⨁⨁⨁◯ MODERATE b |
Not evaluated a |
Not evaluated a |
-7.48 (-28.29,12.96) |
⨁⨁⨁◯ MODERATE |
TED vs. MD |
-10.91 (-24.13, 2.32)
|
⨁⨁⨁◯ MODERATE b |
Not evaluated a |
Not evaluated a |
-10.69 (-35.83, 14.40) |
⨁⨁⨁◯ MODERATE |
|
TED vs. TMD |
Not evaluated a |
Not evaluated a |
-2.98 (-35.60, 29.54) |
⨁⨁⨁◯ MODERATE e |
-2.98 (-35.60, 29.54) |
⨁⨁⨁◯ MODERATE |
|
Duration of hospital stay |
TMD vs. MD |
-0.01 (-0.26, 0.23) |
⨁⨁⨁⨁ HIGH |
Not evaluated a |
Not evaluated a |
-0.05 (-0.88, 0.64) |
⨁⨁⨁⨁ HIGH |
TED vs. MD |
-0.70 (-1.05, -0.35) |
⨁⨁◯◯ LOW c |
Not evaluated a |
Not evaluated a |
-0.70 (-1.64, 0.20) |
⨁⨁◯◯ LOW |
|
TED vs. TMD |
Not evaluated a |
Not evaluated a |
-0.64 (-1.78, 0.57) |
⨁⨁◯◯ LOW d |
-0.64 (-1.78, 0.57) |
⨁⨁◯◯ LOW |
CI, confidence interval; OR, odds ratio; SMD, standardized mean difference; VAS, visual analogue scale; ODI, Oswestry disability index; MD, microscope discectomy; TMD, tubular microdiscectomy; TED, percutaneous transforaminal endoscopic discectomy
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
Explanations
a. Not evaluated, because there are no trials included in the network; b. Due to risk of bias; c. Only one study was available to elucidate the question; d. Low direct evidence; e. Moderate direct evidence.