Supplementary Appendix 1: Flow Chart of Selection of Studies

Table of Contents

Supplementary Appendix 1: Flow chart of selection of studies

Supplementary Appendix 2: Search Criteria

Supplementary Appendix 3: Risk of bias assessment tool

Supplementary Figure 1: A forest plot demonstrating the standardized mean difference in hot flash scores from baseline to completion of treatment in all studies

Supplementary Appendix 1: Flow chart of selection of studies

Flow of selection process of clinical trials according to PRISMA statement and flowchart showing number of references at different stages of systematic review.

Supplementary Appendix 2: Search Criteria

MEDLINE
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized controlled trial.sh.
4. random allocation.sh.
5. double blind method.sh.
6. single blind method.sh.
7. clinical trial.pt.
8. exp clinical trial/
9. (clin$ adj25 trial$).ti,ab.
10. ((singl$ OR doubl$ OR trebl$ OR tripl$) adj25 (blind$ OR mask$)).ti,ab.
11. placebos.sh.
12. placebo$.ti,ab.
13. random$.ti,ab.
14. research design.sh.
15. comparative study.sh.
16. exp evaluation studies/
17. follow up studies.sh.
18. prospective studies.sh.
19. (control$ OR prospectiv$ OR volunteer$).ti,ab.
20. or/1-19
21. venlafaxine.mp.
22. venlafaxine SR.mp.
23. effexor.mp.
24. efexor.mp.
25. venlafaxine HCL.mp.
26. or/21-25
27. exp breast neoplasm/
28. Gabapentin.mp.
29. Gabarone.mp.
30. neurontin.mp.
31. Gralise.mp.
32. or/28-31
33. exp Clonidine/
34. Catapres.mp.
35. Amitriptyline/
36. Elavil.mp.
37. Serotonin Uptake Inhibitors/
38. Fluoxetine/
39. (Rapiflux or Selfemra or Prozac or Sarafem).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
40. Paroxetine/
41. (Paxil or Paxil CR).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
42. Sertraline/
43. zoloft.mp.
44. exp Vitamin E/
45. exp Tocopherols/
46. 44 or 45
47. exp Acupuncture Therapy/
48. exp Placebos/ or exp Placebo Effect/
49. exp Hot Flashes/
50. 26 and 27
51. 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43
52. 46 or 47 or 48 or 51
53. 49 and 50 and 52
SCOPUS
1. (TITLE-ABS-KEY(hotflashes))
2. AND
3. ((TITLE-ABS-KEY(venlafaxine)ORTITLE-ABS-KEY(venlafaxinehcl)ORTITLE-ABS-KEY(efexor)ORTITLE-ABS-KEY(effexor)ORTITLE-ABS-KEY(venlafaxinesr)))
4. AND
5. ((TITLE-ABS-KEY(gabapentin)ORTITLE-ABS-KEY(gabarone)ORTITLE-ABS-KEY(neurontin)ORTITLE-ABS-KEY(gralise)
6. ORTITLE-ABS-KEY(clonidine)ORTITLE-ABS-KEY(catapres)ORTITLE-ABS-KEY(antidepressiveagents)
7. ORTITLE-ABS-KEY(amitriptyline)ORTITLE-ABS-KEY(elavril)OR
8. KEY(serotoninuptakeinhibitors)ORTITLE-ABS-KEY(fluoxetine)ORTITLE-ABS-KEY(rapiflux)ORTITLE-ABS-KEY(selfemra)ORTITLE-ABS-KEY(prozac)ORTITLE-ABS-KEY(sarafem)
9. ORTITLE-ABS-KEY(paroxetine)ORTITLE-ABS-KEY(paxil)ORTITLE-ABS-KEY(paxilcr)ORTITLE-ABS-KEY(sertraline)ORTITLE-ABS-KEY(zoloft)
10. TITLE-ABS- ORTITLE-ABS-KEY(vitamine)ORTITLE-ABS-KEY(tocopherols)ORTITLE-ABS-KEY(acupuncturetherapy)ORTITLE-ABS-KEY(placebo)ORTITLE-ABS-KEY(placeboeffect)))
11. AND
12. (TITLE-ABS-KEY(randomizedcontroltrial))
13. AND
14. (TITLE-ABS-KEY(breastcancer)ORTITLE-ABS-KEY(breastneoplasm))
CENTRAL / COCHRANE
1. MeSH descriptor: [Breast Neoplasms] explode all trees
2. MeSH descriptor: [Hot Flashes] explode all trees
3. “venlafaxine”:ti,ab,kw (Word variations have been searched)
4. “venlafaxine HCL”:ti,ab,kw (Word variations have been searched)
5. “effexor”:ti,ab,kw (Word variations have been searched)
6. “gabapentin”:ti,ab,kw (Word variations have been searched)
7. “antidepressant”:ti,ab,kw (Word variations have been searched)
8. “sertraline”:ti,ab,kw (Word variations have been searched)
9. “serotonin reuptake inhibitors”:ti,ab,kw (Word variations have been searched)
10. “paroxetine”:ti,ab,kw (Word variations have been searched)
11. “fluoxetine”:ti,ab,kw (Word variations have been searched)
12. “clonidine”:ti,ab,kw (Word variations have been searched)
13. “vitamin E”:ti,ab,kw (Word variations have been searched)
14. “acupuncture”:ti,ab,kw (Word variations have been searched)

#3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14

16. #1 AND #2 AND #15

Supplementary Appendix 3: Risk of bias assessment tool

Stradling et al. assessed risk of bias of studies within their published meta-analysis. This was adapted from the Cochrane Handbook, and the following scores were applied:

Evidence present – therefore low risk of bias

Unclear evidence – Information is unclear in publication

Not evident – High risk of bias

Allocation adequately generated?

Yes / No

Assignment to groups is randomized.
Method of randomization described i.e. generation of the sequence by computer or individual.

Allocation to group influenced by characteristic or individual within the study.

Allocation concealment?

Yes / No

Allocation of information from central site.
Information that is sealed i.e. identical containers, envelopes

Predictable allocation based on characteristic such as order, identifier or date of birth.

Blinding outcome assessment?

Yes / No

Comparators and placebo are identical in appearance.
Double blinding present.

Observer bias present.
Blinding is not possible due to study design.

Intention to treat analysis completed?

Yes / No

All participants that are randomized are included in the final analysis.

Although authors mention intention to treat analysis, discrepancy noted between the number randomized and those involved in final analysis.

Incomplete outcome data addressed?

Yes / No

Missing data is balanced across groups.
Missing data imputed as part of analysis.
Authors comment on the effect on missing data on effect size.

Missing information not accounted for in the final analysis.
There is an effect on missing data on the final analysis, and this is not addressed in publication.

Selective outcome reporting?

Yes / No

Primary outcomes are specified and reported.
Power calculation done and sample size recruited as stipulated.

Not reporting on primary outcome.
Study stopped before timeline set forth in protocol.

Adapted from Stradling et al., and Cochrane Handbook version 5.0 derived criteria.

Supplementary Figure 1: A forest plot demonstrating the standardized mean difference in hot flash scores from baseline to completion of treatment in all studies

Study by Buijs et al. was included, where hot flash scores could not be obtained from the original paper. Sensitivity analysis was performed after using extrapolated information from Boekhout et al, where the comparator was clonidine.