Surgical options for lumbar spinal stenosis

Gustavo C Machado (Corresponding Author), Paulo H Ferreira, Ian A Harris, Marina B Pinheiro, Bart W Koes, Magdalena Rzewuska, Christopher G Maher, Manuela L Ferreira

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Background
Hospital charges for lumbar spinal stenosis have increased significantly worldwide in recent times, with great variation in the costs and rates of different surgical procedures. There have also been significant increases in the rate of complex fusion and the use of spinal spacer implants compared to that of traditional decompression surgery, even though the former is known to incur costs up to three times higher. Moreover, the superiority of these new surgical procedures over traditional decompression surgery is still unclear.

Objectives
To determine the efficacy of surgery in the management of patients with symptomatic lumbar spinal stenosis and the comparative effectiveness between commonly performed surgical techniques to treat this condition on patient‐related outcomes. We also aimed to investigate the safety of these surgical interventions by including perioperative surgical data and reoperation rates.

Search methods
Review authors performed electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, Web of Science, LILACS and three trials registries from their inception to 16 June 2016. Authors also conducted citation tracking on the reference lists of included trials and relevant systematic reviews.

Selection criteria
This review included only randomised controlled trials that investigated the efficacy and safety of surgery compared with no treatment, placebo or sham surgery, or with another surgical technique in patients with lumbar spinal stenosis.

Data collection and analysis
Two reviewers independently assessed the studies for inclusion and performed the 'Risk of bias' assessment, using the Cochrane Back and Neck Review Group criteria. Reviewers also extracted demographics, surgery details, and types of outcomes to describe the characteristics of included studies. Primary outcomes were pain intensity, physical function or disability status, quality of life, and recovery. The secondary outcomes included measurements related to surgery, such as perioperative blood loss, operation time, length of hospital stay, reoperation rates, and costs. We grouped trials according to the types of surgical interventions being compared and categorised follow‐up times as short‐term when less than 12 months and long‐term when 12 months or more. Pain and disability scores were converted to a common 0 to 100 scale. We calculated mean differences for continuous outcomes and relative risks for dichotomous outcomes. We pooled data using the random‐effects model in Review Manager 5.3, and used the GRADE approach to assess the quality of the evidence.

Main results
We included a total of 24 randomised controlled trials (reported in 39 published research articles or abstracts) in this review. The trials included 2352 participants with lumbar spinal stenosis with symptoms of neurogenic claudication. None of the included trials compared surgery with no treatment, placebo or sham surgery. Therefore, all included studies compared two or more surgical techniques. We judged all trials to be at high risk of bias for the blinding of care provider domain, and most of the trials failed to adequately conceal the randomisation process, blind the participants or use intention‐to‐treat analysis. Five trials compared the effects of fusion in addition to decompression surgery. Our results showed no significant differences in pain relief at long‐term (mean difference (MD) ‐0.29, 95% confidence interval (CI) ‐7.32 to 6.74). Similarly, we found no between‐group differences in disability reduction in the long‐term (MD 3.26, 95% CI ‐6.12 to 12.63). Participants who received decompression alone had significantly less perioperative blood loss (MD ‐0.52 L, 95% CI ‐0.70 L to ‐0.34 L) and required shorter operations (MD ‐107.94 minutes, 95% CI ‐161.65 minutes to ‐54.23 minutes) compared with those treated with decompression plus fusion, though we found no difference in the number of reoperations (risk ratio (RR) 1.25, 95% CI 0.81 to 1.92). Another three trials investigated the effects of interspinous process spacer devices compared with conventional bony decompression. These spacer devices resulted in similar reductions in pain (MD ‐0.55, 95% CI ‐8.08 to 6.99) and disability (MD 1.25, 95% CI ‐4.48 to 6.98). The spacer devices required longer operation time (MD 39.11 minutes, 95% CI 19.43 minutes to 58.78 minutes) and were associated with higher risk of reoperation (RR 3.95, 95% CI 2.12 to 7.37), but we found no difference in perioperative blood loss (MD 144.00 mL, 95% CI ‐209.74 mL to 497.74 mL). Two trials compared interspinous spacer devices with decompression plus fusion. Although we found no difference in pain relief (MD 5.35, 95% CI ‐1.18 to 11.88), the spacer devices revealed a small but significant effect in disability reduction (MD 5.72, 95% CI 1.28 to 10.15). They were also superior to decompression plus fusion in terms of operation time (MD 78.91 minutes, 95% CI 30.16 minutes to 127.65 minutes) and perioperative blood loss (MD 238.90 mL, 95% CI 182.66 mL to 295.14 mL), however, there was no difference in rate of reoperation (RR 0.70, 95% CI 0.32 to 1.51). Overall there were no differences for the primary or secondary outcomes when different types of surgical decompression techniques were compared among each other. The quality of evidence varied from 'very low quality' to 'high quality'.

Authors' conclusions
The results of this Cochrane review show a paucity of evidence on the efficacy of surgery for lumbar spinal stenosis, as to date no trials have compared surgery with no treatment, placebo or sham surgery. Placebo‐controlled trials in surgery are feasible and needed in the field of lumbar spinal stenosis. Our results demonstrate that at present, decompression plus fusion and interspinous process spacers have not been shown to be superior to conventional decompression alone. More methodologically rigorous studies are needed in this field to confirm our results.
Original languageEnglish
Article numberCD012421
Number of pages133
JournalCochrane Database of Systematic Reviews
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016

Fingerprint

Spinal Stenosis
Confidence Intervals
Decompression
Reoperation
Pain
Equipment and Supplies
Odds Ratio
Placebos
Costs and Cost Analysis
Length of Stay
Randomized Controlled Trials
Safety
Surgical Decompression
Spinal Fusion
Random Allocation
MEDLINE

Keywords

  • lumbar spinal stenosis
  • systematic review
  • comparative effectiveness
  • surgery

Cite this

Machado, G. C., Ferreira, P. H., Harris, I. A., Pinheiro, M. B., Koes, B. W., Rzewuska, M., ... Ferreira, M. L. (2016). Surgical options for lumbar spinal stenosis. Cochrane Database of Systematic Reviews, (11), [CD012421]. https://doi.org/10.1002/14651858.CD012421

Surgical options for lumbar spinal stenosis. / Machado, Gustavo C (Corresponding Author); Ferreira, Paulo H; Harris, Ian A; Pinheiro, Marina B; Koes, Bart W; Rzewuska, Magdalena; Maher, Christopher G; Ferreira, Manuela L.

In: Cochrane Database of Systematic Reviews, No. 11, CD012421, 01.11.2016.

Research output: Contribution to journalArticle

Machado, GC, Ferreira, PH, Harris, IA, Pinheiro, MB, Koes, BW, Rzewuska, M, Maher, CG & Ferreira, ML 2016, 'Surgical options for lumbar spinal stenosis', Cochrane Database of Systematic Reviews, no. 11, CD012421. https://doi.org/10.1002/14651858.CD012421
Machado GC, Ferreira PH, Harris IA, Pinheiro MB, Koes BW, Rzewuska M et al. Surgical options for lumbar spinal stenosis. Cochrane Database of Systematic Reviews. 2016 Nov 1;(11). CD012421. https://doi.org/10.1002/14651858.CD012421
Machado, Gustavo C ; Ferreira, Paulo H ; Harris, Ian A ; Pinheiro, Marina B ; Koes, Bart W ; Rzewuska, Magdalena ; Maher, Christopher G ; Ferreira, Manuela L. / Surgical options for lumbar spinal stenosis. In: Cochrane Database of Systematic Reviews. 2016 ; No. 11.
@article{7d63ec70485446a7b199b896934722fd,
title = "Surgical options for lumbar spinal stenosis",
abstract = "BackgroundHospital charges for lumbar spinal stenosis have increased significantly worldwide in recent times, with great variation in the costs and rates of different surgical procedures. There have also been significant increases in the rate of complex fusion and the use of spinal spacer implants compared to that of traditional decompression surgery, even though the former is known to incur costs up to three times higher. Moreover, the superiority of these new surgical procedures over traditional decompression surgery is still unclear.ObjectivesTo determine the efficacy of surgery in the management of patients with symptomatic lumbar spinal stenosis and the comparative effectiveness between commonly performed surgical techniques to treat this condition on patient‐related outcomes. We also aimed to investigate the safety of these surgical interventions by including perioperative surgical data and reoperation rates.Search methodsReview authors performed electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, Web of Science, LILACS and three trials registries from their inception to 16 June 2016. Authors also conducted citation tracking on the reference lists of included trials and relevant systematic reviews.Selection criteriaThis review included only randomised controlled trials that investigated the efficacy and safety of surgery compared with no treatment, placebo or sham surgery, or with another surgical technique in patients with lumbar spinal stenosis.Data collection and analysisTwo reviewers independently assessed the studies for inclusion and performed the 'Risk of bias' assessment, using the Cochrane Back and Neck Review Group criteria. Reviewers also extracted demographics, surgery details, and types of outcomes to describe the characteristics of included studies. Primary outcomes were pain intensity, physical function or disability status, quality of life, and recovery. The secondary outcomes included measurements related to surgery, such as perioperative blood loss, operation time, length of hospital stay, reoperation rates, and costs. We grouped trials according to the types of surgical interventions being compared and categorised follow‐up times as short‐term when less than 12 months and long‐term when 12 months or more. Pain and disability scores were converted to a common 0 to 100 scale. We calculated mean differences for continuous outcomes and relative risks for dichotomous outcomes. We pooled data using the random‐effects model in Review Manager 5.3, and used the GRADE approach to assess the quality of the evidence.Main resultsWe included a total of 24 randomised controlled trials (reported in 39 published research articles or abstracts) in this review. The trials included 2352 participants with lumbar spinal stenosis with symptoms of neurogenic claudication. None of the included trials compared surgery with no treatment, placebo or sham surgery. Therefore, all included studies compared two or more surgical techniques. We judged all trials to be at high risk of bias for the blinding of care provider domain, and most of the trials failed to adequately conceal the randomisation process, blind the participants or use intention‐to‐treat analysis. Five trials compared the effects of fusion in addition to decompression surgery. Our results showed no significant differences in pain relief at long‐term (mean difference (MD) ‐0.29, 95{\%} confidence interval (CI) ‐7.32 to 6.74). Similarly, we found no between‐group differences in disability reduction in the long‐term (MD 3.26, 95{\%} CI ‐6.12 to 12.63). Participants who received decompression alone had significantly less perioperative blood loss (MD ‐0.52 L, 95{\%} CI ‐0.70 L to ‐0.34 L) and required shorter operations (MD ‐107.94 minutes, 95{\%} CI ‐161.65 minutes to ‐54.23 minutes) compared with those treated with decompression plus fusion, though we found no difference in the number of reoperations (risk ratio (RR) 1.25, 95{\%} CI 0.81 to 1.92). Another three trials investigated the effects of interspinous process spacer devices compared with conventional bony decompression. These spacer devices resulted in similar reductions in pain (MD ‐0.55, 95{\%} CI ‐8.08 to 6.99) and disability (MD 1.25, 95{\%} CI ‐4.48 to 6.98). The spacer devices required longer operation time (MD 39.11 minutes, 95{\%} CI 19.43 minutes to 58.78 minutes) and were associated with higher risk of reoperation (RR 3.95, 95{\%} CI 2.12 to 7.37), but we found no difference in perioperative blood loss (MD 144.00 mL, 95{\%} CI ‐209.74 mL to 497.74 mL). Two trials compared interspinous spacer devices with decompression plus fusion. Although we found no difference in pain relief (MD 5.35, 95{\%} CI ‐1.18 to 11.88), the spacer devices revealed a small but significant effect in disability reduction (MD 5.72, 95{\%} CI 1.28 to 10.15). They were also superior to decompression plus fusion in terms of operation time (MD 78.91 minutes, 95{\%} CI 30.16 minutes to 127.65 minutes) and perioperative blood loss (MD 238.90 mL, 95{\%} CI 182.66 mL to 295.14 mL), however, there was no difference in rate of reoperation (RR 0.70, 95{\%} CI 0.32 to 1.51). Overall there were no differences for the primary or secondary outcomes when different types of surgical decompression techniques were compared among each other. The quality of evidence varied from 'very low quality' to 'high quality'.Authors' conclusionsThe results of this Cochrane review show a paucity of evidence on the efficacy of surgery for lumbar spinal stenosis, as to date no trials have compared surgery with no treatment, placebo or sham surgery. Placebo‐controlled trials in surgery are feasible and needed in the field of lumbar spinal stenosis. Our results demonstrate that at present, decompression plus fusion and interspinous process spacers have not been shown to be superior to conventional decompression alone. More methodologically rigorous studies are needed in this field to confirm our results.",
keywords = "lumbar spinal stenosis, systematic review, comparative effectiveness, surgery",
author = "Machado, {Gustavo C} and Ferreira, {Paulo H} and Harris, {Ian A} and Pinheiro, {Marina B} and Koes, {Bart W} and Magdalena Rzewuska and Maher, {Christopher G} and Ferreira, {Manuela L}",
note = "This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors. GCM and MBP are supported by an international postgraduate research scholarship/postgraduate award from the Australian Department of Education and Training. CGM is supported by a principal research fellowship from the National Health and Medical Research Council. MLF is supported by a Sydney Medical Foundation Fellowship from the Sydney Medical School, The University of Sydney.",
year = "2016",
month = "11",
day = "1",
doi = "10.1002/14651858.CD012421",
language = "English",
journal = "Cochrane Database of Systematic Reviews",
issn = "1469-493X",
publisher = "Wiley",
number = "11",

}

TY - JOUR

T1 - Surgical options for lumbar spinal stenosis

AU - Machado, Gustavo C

AU - Ferreira, Paulo H

AU - Harris, Ian A

AU - Pinheiro, Marina B

AU - Koes, Bart W

AU - Rzewuska, Magdalena

AU - Maher, Christopher G

AU - Ferreira, Manuela L

N1 - This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors. GCM and MBP are supported by an international postgraduate research scholarship/postgraduate award from the Australian Department of Education and Training. CGM is supported by a principal research fellowship from the National Health and Medical Research Council. MLF is supported by a Sydney Medical Foundation Fellowship from the Sydney Medical School, The University of Sydney.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - BackgroundHospital charges for lumbar spinal stenosis have increased significantly worldwide in recent times, with great variation in the costs and rates of different surgical procedures. There have also been significant increases in the rate of complex fusion and the use of spinal spacer implants compared to that of traditional decompression surgery, even though the former is known to incur costs up to three times higher. Moreover, the superiority of these new surgical procedures over traditional decompression surgery is still unclear.ObjectivesTo determine the efficacy of surgery in the management of patients with symptomatic lumbar spinal stenosis and the comparative effectiveness between commonly performed surgical techniques to treat this condition on patient‐related outcomes. We also aimed to investigate the safety of these surgical interventions by including perioperative surgical data and reoperation rates.Search methodsReview authors performed electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, Web of Science, LILACS and three trials registries from their inception to 16 June 2016. Authors also conducted citation tracking on the reference lists of included trials and relevant systematic reviews.Selection criteriaThis review included only randomised controlled trials that investigated the efficacy and safety of surgery compared with no treatment, placebo or sham surgery, or with another surgical technique in patients with lumbar spinal stenosis.Data collection and analysisTwo reviewers independently assessed the studies for inclusion and performed the 'Risk of bias' assessment, using the Cochrane Back and Neck Review Group criteria. Reviewers also extracted demographics, surgery details, and types of outcomes to describe the characteristics of included studies. Primary outcomes were pain intensity, physical function or disability status, quality of life, and recovery. The secondary outcomes included measurements related to surgery, such as perioperative blood loss, operation time, length of hospital stay, reoperation rates, and costs. We grouped trials according to the types of surgical interventions being compared and categorised follow‐up times as short‐term when less than 12 months and long‐term when 12 months or more. Pain and disability scores were converted to a common 0 to 100 scale. We calculated mean differences for continuous outcomes and relative risks for dichotomous outcomes. We pooled data using the random‐effects model in Review Manager 5.3, and used the GRADE approach to assess the quality of the evidence.Main resultsWe included a total of 24 randomised controlled trials (reported in 39 published research articles or abstracts) in this review. The trials included 2352 participants with lumbar spinal stenosis with symptoms of neurogenic claudication. None of the included trials compared surgery with no treatment, placebo or sham surgery. Therefore, all included studies compared two or more surgical techniques. We judged all trials to be at high risk of bias for the blinding of care provider domain, and most of the trials failed to adequately conceal the randomisation process, blind the participants or use intention‐to‐treat analysis. Five trials compared the effects of fusion in addition to decompression surgery. Our results showed no significant differences in pain relief at long‐term (mean difference (MD) ‐0.29, 95% confidence interval (CI) ‐7.32 to 6.74). Similarly, we found no between‐group differences in disability reduction in the long‐term (MD 3.26, 95% CI ‐6.12 to 12.63). Participants who received decompression alone had significantly less perioperative blood loss (MD ‐0.52 L, 95% CI ‐0.70 L to ‐0.34 L) and required shorter operations (MD ‐107.94 minutes, 95% CI ‐161.65 minutes to ‐54.23 minutes) compared with those treated with decompression plus fusion, though we found no difference in the number of reoperations (risk ratio (RR) 1.25, 95% CI 0.81 to 1.92). Another three trials investigated the effects of interspinous process spacer devices compared with conventional bony decompression. These spacer devices resulted in similar reductions in pain (MD ‐0.55, 95% CI ‐8.08 to 6.99) and disability (MD 1.25, 95% CI ‐4.48 to 6.98). The spacer devices required longer operation time (MD 39.11 minutes, 95% CI 19.43 minutes to 58.78 minutes) and were associated with higher risk of reoperation (RR 3.95, 95% CI 2.12 to 7.37), but we found no difference in perioperative blood loss (MD 144.00 mL, 95% CI ‐209.74 mL to 497.74 mL). Two trials compared interspinous spacer devices with decompression plus fusion. Although we found no difference in pain relief (MD 5.35, 95% CI ‐1.18 to 11.88), the spacer devices revealed a small but significant effect in disability reduction (MD 5.72, 95% CI 1.28 to 10.15). They were also superior to decompression plus fusion in terms of operation time (MD 78.91 minutes, 95% CI 30.16 minutes to 127.65 minutes) and perioperative blood loss (MD 238.90 mL, 95% CI 182.66 mL to 295.14 mL), however, there was no difference in rate of reoperation (RR 0.70, 95% CI 0.32 to 1.51). Overall there were no differences for the primary or secondary outcomes when different types of surgical decompression techniques were compared among each other. The quality of evidence varied from 'very low quality' to 'high quality'.Authors' conclusionsThe results of this Cochrane review show a paucity of evidence on the efficacy of surgery for lumbar spinal stenosis, as to date no trials have compared surgery with no treatment, placebo or sham surgery. Placebo‐controlled trials in surgery are feasible and needed in the field of lumbar spinal stenosis. Our results demonstrate that at present, decompression plus fusion and interspinous process spacers have not been shown to be superior to conventional decompression alone. More methodologically rigorous studies are needed in this field to confirm our results.

AB - BackgroundHospital charges for lumbar spinal stenosis have increased significantly worldwide in recent times, with great variation in the costs and rates of different surgical procedures. There have also been significant increases in the rate of complex fusion and the use of spinal spacer implants compared to that of traditional decompression surgery, even though the former is known to incur costs up to three times higher. Moreover, the superiority of these new surgical procedures over traditional decompression surgery is still unclear.ObjectivesTo determine the efficacy of surgery in the management of patients with symptomatic lumbar spinal stenosis and the comparative effectiveness between commonly performed surgical techniques to treat this condition on patient‐related outcomes. We also aimed to investigate the safety of these surgical interventions by including perioperative surgical data and reoperation rates.Search methodsReview authors performed electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, Web of Science, LILACS and three trials registries from their inception to 16 June 2016. Authors also conducted citation tracking on the reference lists of included trials and relevant systematic reviews.Selection criteriaThis review included only randomised controlled trials that investigated the efficacy and safety of surgery compared with no treatment, placebo or sham surgery, or with another surgical technique in patients with lumbar spinal stenosis.Data collection and analysisTwo reviewers independently assessed the studies for inclusion and performed the 'Risk of bias' assessment, using the Cochrane Back and Neck Review Group criteria. Reviewers also extracted demographics, surgery details, and types of outcomes to describe the characteristics of included studies. Primary outcomes were pain intensity, physical function or disability status, quality of life, and recovery. The secondary outcomes included measurements related to surgery, such as perioperative blood loss, operation time, length of hospital stay, reoperation rates, and costs. We grouped trials according to the types of surgical interventions being compared and categorised follow‐up times as short‐term when less than 12 months and long‐term when 12 months or more. Pain and disability scores were converted to a common 0 to 100 scale. We calculated mean differences for continuous outcomes and relative risks for dichotomous outcomes. We pooled data using the random‐effects model in Review Manager 5.3, and used the GRADE approach to assess the quality of the evidence.Main resultsWe included a total of 24 randomised controlled trials (reported in 39 published research articles or abstracts) in this review. The trials included 2352 participants with lumbar spinal stenosis with symptoms of neurogenic claudication. None of the included trials compared surgery with no treatment, placebo or sham surgery. Therefore, all included studies compared two or more surgical techniques. We judged all trials to be at high risk of bias for the blinding of care provider domain, and most of the trials failed to adequately conceal the randomisation process, blind the participants or use intention‐to‐treat analysis. Five trials compared the effects of fusion in addition to decompression surgery. Our results showed no significant differences in pain relief at long‐term (mean difference (MD) ‐0.29, 95% confidence interval (CI) ‐7.32 to 6.74). Similarly, we found no between‐group differences in disability reduction in the long‐term (MD 3.26, 95% CI ‐6.12 to 12.63). Participants who received decompression alone had significantly less perioperative blood loss (MD ‐0.52 L, 95% CI ‐0.70 L to ‐0.34 L) and required shorter operations (MD ‐107.94 minutes, 95% CI ‐161.65 minutes to ‐54.23 minutes) compared with those treated with decompression plus fusion, though we found no difference in the number of reoperations (risk ratio (RR) 1.25, 95% CI 0.81 to 1.92). Another three trials investigated the effects of interspinous process spacer devices compared with conventional bony decompression. These spacer devices resulted in similar reductions in pain (MD ‐0.55, 95% CI ‐8.08 to 6.99) and disability (MD 1.25, 95% CI ‐4.48 to 6.98). The spacer devices required longer operation time (MD 39.11 minutes, 95% CI 19.43 minutes to 58.78 minutes) and were associated with higher risk of reoperation (RR 3.95, 95% CI 2.12 to 7.37), but we found no difference in perioperative blood loss (MD 144.00 mL, 95% CI ‐209.74 mL to 497.74 mL). Two trials compared interspinous spacer devices with decompression plus fusion. Although we found no difference in pain relief (MD 5.35, 95% CI ‐1.18 to 11.88), the spacer devices revealed a small but significant effect in disability reduction (MD 5.72, 95% CI 1.28 to 10.15). They were also superior to decompression plus fusion in terms of operation time (MD 78.91 minutes, 95% CI 30.16 minutes to 127.65 minutes) and perioperative blood loss (MD 238.90 mL, 95% CI 182.66 mL to 295.14 mL), however, there was no difference in rate of reoperation (RR 0.70, 95% CI 0.32 to 1.51). Overall there were no differences for the primary or secondary outcomes when different types of surgical decompression techniques were compared among each other. The quality of evidence varied from 'very low quality' to 'high quality'.Authors' conclusionsThe results of this Cochrane review show a paucity of evidence on the efficacy of surgery for lumbar spinal stenosis, as to date no trials have compared surgery with no treatment, placebo or sham surgery. Placebo‐controlled trials in surgery are feasible and needed in the field of lumbar spinal stenosis. Our results demonstrate that at present, decompression plus fusion and interspinous process spacers have not been shown to be superior to conventional decompression alone. More methodologically rigorous studies are needed in this field to confirm our results.

KW - lumbar spinal stenosis

KW - systematic review

KW - comparative effectiveness

KW - surgery

U2 - 10.1002/14651858.CD012421

DO - 10.1002/14651858.CD012421

M3 - Article

JO - Cochrane Database of Systematic Reviews

JF - Cochrane Database of Systematic Reviews

SN - 1469-493X

IS - 11

M1 - CD012421

ER -