Graft nephrectomy for people with a failed kidney transplant(protocol)

Transcription

1 Cochrane Database of Systematic Reviews Graft nephrectomy for people with a failed kidney transplant (Protocol) AungNN,IrishA,SwaminathanR,BurrowsS,FidlerS,D OrsognaL AungNN,IrishA,SwaminathanR,BurrowsS,FidlerS,D OrsognaL. Graft nephrectomy for people with a failed kidney transplant. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No.: CD DOI: / CD Graft nephrectomy for people with a failed kidney transplant(protocol) Copyright 2016 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT BACKGROUND OBJECTIVES METHODS ACKNOWLEDGEMENTS REFERENCES APPENDICES CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST i

3 [Intervention Protocol] Graft nephrectomy for people with a failed kidney transplant Nyi Nyi Aung 1, Ashley Irish 1, Ramyasuda Swaminathan 1, Sally Burrows 2, Samantha Fidler 3, Lloyd D Orsogna 4 1 Nephrology and Renal Transplantation, Fiona Stanley Hospital, Murdoch, Australia. 2 Medicine and Pharmacology RPH Unit, University of Western Australia, Crawley, Australia. 3 Department of Immunology, Fiona Stanley Hospital, Murdoch, Australia. 4 Fiona Stanley Hospital, Murdoch, Australia Contact address: Nyi Nyi Aung, Nephrology and Renal Transplantation, Fiona Stanley Hospital, Murdoch Drive, Murdoch, WA, 6150, Australia. Nyi.Aung@health.wa.gov.au. Editorial group: Cochrane Kidney and Transplant Group. Publication status and date: New, published in Issue 10, Citation: Aung NN, Irish A, Swaminathan R, Burrows S, Fidler S, D Orsogna L. Graft nephrectomy for people with a failed kidney transplant. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No.: CD DOI: / CD A B S T R A C T This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The review aims to look at the immunological and clinical benefits and harms of graft nephrectomy for people with a failed kidney transplant. B A C K G R O U N D Description of the condition The US Renal Data System 2104 Annual Data Report showed that recent advances in immunosuppression improve the early stages of kidney transplant survival but actual kidney allograft half-life showed only a marginal improvement (Saran 2015). The report also showed that the number of patients returning to dialysis after kidney allograft failure has remained stable at around 5200 patients annually or around 5% of the new incidental dialysis population. Kidney allograft failure is classified as early allograft failure (a return to dialysis within one year of transplantation), and late allograft failure (those required dialysis after one year of transplantation). The most common indications for nephrectomy after transplant failure are the onset of symptoms or complications or both related to rejection, after withdrawal of immunosuppression, and those with an early allograft failure. Andrews 2014 described the surgical technique used for graft nephrectomy as dependent on timing after transplantation and operator preference; there is no compelling evidence favouring the intracapsular or extracapsular approach in the late phase post-transplantation. Graft nephrectomy has become a safer procedure with almost no mortality and a low incidence of major morbidity (Akoh 2011; Hansen 1987; Khamis 1996); however, there is no clear consensus concerning its timing, benefits and harms when compared with leaving the failed allograft in situ. Description of the intervention Kidney allograft nephropathy is associated with higher mortality and morbidity during the return to dialysis. Kaplan 2002 described crude death rates of US dialysis patients after kidney allograft loss exceed that of patients on the kidney transplantation waiting list. Early acute allograft failure (less than one year) is usually associated with nephrectomy due to clinical indications, However following a period of established graft function, late decline of graft func- 1

4 tion and return to dialysis requires a decision as to the risks and benefits of graft nephrectomy and withdrawal versus continuation (tapering) of immunosuppression. Allosensitization due to early sensitising events may worsen or be induced by allograft nephrectomy and impact retransplantation. Withdrawal of immunosuppression with an in-situ allograft is also associated with enhanced allosensitization and acts as a source of inflammation that may contribute to morbidity and mortality. Retention of some level of immunosuppression to mitigate this risk is common practice although it may itself increase complications: increased risk of infection, malignancy and complication associated with long-term corticosteroids. How the intervention might work Ayus 2010 described receiving an allograft nephrectomy was associated with a 32% lower adjusted relative risk for all-cause death (adjusted HR 0.68, 95% CI 0.63 to 0.74) and they concluded that within a large, nationally representative sample of high-risk patients returning to long-term dialysis after failed kidney transplant, receipt of allograft nephrectomy was independently associated with improved survival. On the other hand, Del Bello 2012a described development of donor-specific alloantibodies (DSA) was significant greater in patients with a failed kidney transplant who had undergone an allograft nephrectomy compared with those patients who had not undergone allograft nephrectomy. Del Bello 2012b confirmed in another study that even after a short transplantation period, DSA and non-dsa anti-hla antibodies may develop in more than 50% of patients whose immunosuppression has been stopped after an allograft nephrectomy and this suggests that a short transplantation period is sufficient to stimulate the immune system and to induce alloantibody production. Del Bello 2012b postulated the reasons of allosensitization are due to cessation of immunosuppressive medications, the removal of the allograft which could absorb the alloantibodies and the persistence of antigen-presenting cells after allograft removal. Almond 1994 described that the highest erythropoietin requirements were those with a retained kidney transplant because of chronic rejection and inflammation in the graft, but no known data to support that transplant nephrectomy would reduce erythropoietin requirement. Withdrawal of immunosuppression means total cessation of all immunosuppressive medications and continuation (tapering) of immunosuppression means maintaining some sort of immunosuppressive medications by tapering the dose or cessation of some class of immunosuppressive medications but not all. review will aim to investigate and find out what is the best evidence-based practice concerning removal versus leaving the failed allograft in situ in people with a failed kidney transplant. O B J E C T I V E S The review aims to look at the immunological and clinical benefits and harms of graft nephrectomy for people with a failed kidney transplant. M E T H O D S Criteria for considering studies for this review Types of studies RCTs or quasi-rcts (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) will be included. If no relevant RCTs are identified, relevant non-randomised studies will be included (e.g. prospective and retrospective longitudinal cohort studies). Types of participants Inclusion criteria All (adults and children) kidney transplant recipients with acute and late allograft failure who have received grafts from either adults or children. These grafts can be from living related or unrelated donors, from cadaveric donors of DBD (deceased brain death), DCB (deceased cardiac death), or ECD (extended criteria donor). Exclusion criteria People who received a pre-emptive repeat kidney transplant Types of interventions Nephrectomy versus non-nephrectomy Why it is important to do this review Graft nephrectomy is considered a low risk procedure; however there is no clear consensus concerning its timing, benefits and harms when compared with leaving the failed allograft in situ. This Types of outcome measures Primary outcomes Patient survival and outcomes post kidney allograft failure 2

5 Secondary outcomes Alloantibody sensitization (breadth, strength and durability) Time to retransplantation Markers and measures of inflammation: C-reactive protein (CRP) and albumin level Anaemia: haemoglobin (Hb) level and erythropoietin dose Other determinants: quality of life and hospitalisations The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable; however studies and reviews that might include relevant data or information on studies will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria. Search methods for identification of studies Electronic searches We will search the Cochrane Kidney and Transplant Specialised Register through contact with the Information Specialist using search terms relevant to this review. The Specialised Register contains studies identified from several sources. 1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) 2. Weekly searches of MEDLINE OVID SP 3. Handsearching of kidney-related journals and the proceedings of major kidney conferences 4. Searching of the current year of EMBASE OVID SP 5. Weekly current awareness alerts for selected kidney and transplant journals 6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about Cochrane Kidney and Transplant. See Appendix 1 for search terms used in strategies for this review. We will also search MEDLINE (OVID) and EMBASE (OVID) for non-randomised studies suitable for inclusion in this review. Searching other resources 1. Reference lists of review articles, relevant studies and clinical practice guidelines. 2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies. Data collection and analysis Selection of studies Data extraction and management Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non- English language journals will be translated before assessment. Where more than one publication of one study exists, these will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted. Assessment of risk of bias in included studies Randomised studies The following items will be independently assessed by two authors using the risk of bias assessment tool for RCTs (Higgins 2011) (see Appendix 2). Was there adequate sequence generation (selection bias)? Was allocation adequately concealed (selection bias)? Was knowledge of the allocated interventions adequately prevented during the study? Participants and personnel (performance bias) Outcome assessors (detection bias) Were incomplete outcome data adequately addressed (attrition bias)? Are reports of the study free of suggestion of selective outcome reporting (reporting bias)? Was the study apparently free of other problems that could put it at a risk of bias? Non-randomised studies The risk of bias in observational studies will be assessed using assessment forms adapted from the Newcastle-Ottawa Quality Assessment Scale (NOS) for cohort and case-control studies (Wells 2015). The NOS form for cohort studies will be used for all included observational studies, and the NOS case-control form will be used for nested case-control studies. The NOS uses a star system in which studies are judged on key domains pertaining to the selection and comparability of study groups, the ascertainment of exposure and outcome, and the duration of follow-up. For each 3

6 domain, either a star or no star is assigned, with a star indicating that study design element was considered adequate and less likely to introduce bias. A study could receive a maximum of nine stars in the cohort assessment (Appendix 3) and nine stars in the assessment of the case-control portion (Appendix 4). Measures of treatment effect For dichotomous outcomes (quality of life, hospitalisation, outcomes post kidney allograft failure) results will be expressed as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (survival in years, alloantibody sensitisation shown in breadth, length and durability, panel reactive antibody (PRA) level, time to retransplantation in years, Hb level, marker and measures of inflammation, CRP, albumin level), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. For observational studies, we will use the odds ratio (OR) or the RR and its 95% CI as measures of the association between [A] and [B]. When adjusted ORs are reported, we will use the OR with the most extensive covariate adjustment reported in the publication. Resche-Region 2012 showed two statistical analyses can be performed using the propensity score matching approach and the inverse probability weighting approach in estimating the treatment effect from non-randomised studies. Evaluating risk of bias in a systemic review of non-randomised studies requires both methodological and content expertise. Unit of analysis issues We will include only data from the first period of treatment in cross-over studies (Higgins 2011). Data expressed in different metrics will be analysed using SMD. Dealing with missing data Any further information required from the original author will be requested by written correspondence (e.g. ing corresponding authors) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intentionto-treat, as-treated and per-protocol population will be carefully performed. Attrition rates, for example drop-outs, losses to followup and withdrawals will be investigated. Issues of missing data and imputation methods (for example, last-observation-carriedforward) will be critically appraised (Higgins 2011). Assessment of heterogeneity We will first assess the heterogeneity by visual inspection of the forest plot. Heterogeneity will then be analysed using a Chi 2 test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I 2 test (Higgins 2003). A guide to the interpretation of I 2 values will be as follows. 0% to 40%: might not be important 30% to 60%: may represent moderate heterogeneity 50% to 90%: may represent substantial heterogeneity 75% to 100%: considerable heterogeneity The importance of the observed value of I 2 depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P-value from the Chi 2 test, or a CI for I 2 ) (Higgins 2011). Assessment of reporting biases If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011). Data synthesis Data will be pooled using the random-effects model but the fixedeffect model will also be used to ensure robustness of the model chosen and susceptibility to outliers. Subgroup analysis and investigation of heterogeneity Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, interventions and study quality): time of kidney allograft failure (immediate < 90 days, early > 90 days but < 1 year, late > 1 year); time of transplant nephrectomy post kidney allograft failure ((immediate versus delayed), urgent (symptomatic) versus elective (asymptomatic)); immunosuppression (intensity and duration) (maintenance versus withdrawal); age (adults versus children); unsensitised versus sensitised; first transplant versus re-transplant. Heterogeneity among participants could be related to age, baseline immunological risk, immunosuppression used, transplant type, previous sensitisation history, timing and clinical reasons for kidney allograft failure. Heterogeneity in treatments could be related to timing of allograft nephrectomy, reasons of allograft nephrectomy and withdrawal or continuation of immunosuppressive medications. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent. Sensitivity analysis We will perform sensitivity analyses in order to explore the influence of the following factors on effect size. Repeating the analysis excluding unpublished studies Repeating the analysis taking account of risk of bias, as specified 4

7 Repeating the analysis excluding any very long or large studies to establish how much they dominate the results Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country. Summary of findings tables We will present the main results of the review in Summary of findings tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schünemann 2011a). The Summary of findings tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within-trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We plan to present the following outcomes in the Summary of findings tables. 1. Patient s survival and outcomes post kidney allograft failure 2. Alloantibody sensitization (breadth, strength and durability) 3. Time to retransplantation 4. Markers and measures of inflammation: CRP and albumin level 5. Anaemia: Hb level and erythropoietin dose 6. Other determinants: quality of life and hospitalisations A C K N O W L E D G E M E N T S We acknowledge the assistance of the Cochrane Kidney and Transplant editorial office for their assistance with this protocol. We would also like to thank the referees for their comments and feedback during the preparation of this protocol. R E F E R E N C E S Additional references Akoh 2011 Akoh JA. Transplant nephrectomy. World Journal of Transplantation 2011;1(1):4 12. [MEDLINE: ] Almond 1994 Almond MK, Tailor D, Marsh FP, Raftery MJ, Cunningham J. Increased erythropoietin requirements in patients with failed renal transplants returning to a dialysis programme. Nephrology Dialysis Transplantation 1994;9(3): [MEDLINE: ] Andrews 2014 Andrews PA, Standards Committee of the British Transplantation Society. Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant. Transplantation 2014;98(11): [MEDLINE: ] Ayus 2010 Ayus JC, Achinger SG, Lee S, Sayegh MH, Go AS. Transplant nephrectomy improves survival following a failed renal allograft. Journal of the American Society of Nephrology 2010;21(2): [MEDLINE: ] Del Bello 2012a Del Bello A, Congy-Jolivet N, Sallusto F, Guilbeau-Frugier C, Cardeau-Desangles I, Fort M, et al. Donor-specific antibodies after ceasing immunosuppressive therapy, with or without an allograft nephrectomy. Clinical Journal of the American Society of Nephrology 2012;7(8): [MEDLINE: ] Del Bello 2012b Del Bello A, Congy N, Sallusto F, Cardeau-Desangles I, Fort M, Esposito L, et al. Anti-human leukocyte antigen immunization after early allograft nephrectomy. Transplantation 2012;93(9): [MEDLINE: ] GRADE 2008 Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650): [MEDLINE: ] Hansen 1987 Hansen BL, Rohr N, Svendsen V, Birkeland SA. Graft failure and graft nephrectomy without severe complications. Nephrology Dialysis Transplantation 1987;2(3): [MEDLINE: ] Higgins 2003 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414): [MEDLINE: ] Higgins 2011 Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011]. The Cochrane Collaboration, Available from Kaplan 2002 Kaplan B, Meier-Kriesche HU. Death after graft loss: an important late study endpoint in kidney transplantation. 5

8 American Journal of Transplantation 2002;2(10): [MEDLINE: ] Khamis 1996 Vanrenterghem Y, Khamis S. The management of the failed renal allograft. Nephrology Dialysis Transplantation 1996;11 (6): [MEDLINE: ] Resche-Region 2012 Resche-Rigon M, Pirracchio R, Robin M, De Latour RP, Sibon D, Ades L, et al. Estimating the treatment effect from non-randomized studies: the example of reduced intensity conditioning allogeneic stem cell transplantation in hematological diseases. BMC Blood Disorders 2012;12: 10. [MEDLINE: ] Saran 2015 Saran R, Li Y, Robinson B, Ayanian J, Balkrishnan R, Bragg-Gresham J, et al. US Renal Data System 2014 Annual Data Report: Epidemiology of Kidney Disease in the United States. [Erratum appears in Am J Kidney Dis Sep;66(3):545]. American Journal Of Kidney Diseases 2015;66(1 Suppl 1):S [MEDLINE: ] Schunemann 2011b Schünemann HJ, Oxman AD, Higgins JP, Deeks JJ, Glasziou P, Guyatt GH. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011]. The Cochrane Collaboration, Available from Schünemann 2011a Schünemann HJ, Oxman AD, Higgins JP, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and Summary of findings tables. In: Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011]. The Cochrane Collaboration, Available from Wells 2015 Wells GA, Shea B, O Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses. oxford.asp (accessed 5 September 2016). Indicates the major publication for the study A P P E N D I C E S Appendix 1. Electronic search strategies Database CENTRAL MEDLINE Search terms 1. MeSH descriptor: [Graft Rejection] this term only 2. graft failure or graft rejection:ti,ab,kw (Word variations have been searched) 3. transplant failure:ti,ab,kw (Word variations have been searched) 4. {or #1-#3} 5. MeSH descriptor: [Nephrectomy] this term only 6. ((transplant* or graft*) and nephrectom*):ti,ab,kw (Word variations have been searched) 7. {or #5-#6} 8. {and #4, #7} 1. Graft Rejection/ 2. (graft failure or graft rejection).tw. 3. transplant failure.tw. 4. or/ Nephrectomy/ 6. ((transplant$ or graft$) and nephrectom$).tw. 7. or/ and/4,7 6

9 (Continued) EMBASE 1. graft rejection/ 2. acute graft rejection/ 3. chronic graft rejection/ 4. exp renal graft dysfunction/ 5. (graft failure or graft rejection).tw. 6. transplant failure.tw. 7. or/ exp nephrectomy/ 9. ((transplant$ or graft$) and nephrectom$).tw. 10. or/ and/7,10 Appendix 2. Risk of bias assessment tool Potential source of bias Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence Assessment criteria Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be implemented without a random element, and this is considered to be equivalent to being random) High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention Unclear: Insufficient information about the sequence generation process to permit judgement Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes) High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or nonopaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure 7

10 (Continued) Unclear: Randomisation stated but no information on method used is available Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding Unclear: Insufficient information to permit judgement Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding Unclear: Insufficient information to permit judgement Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plau- 8

11 (Continued) sible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; as-treated analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation Unclear: Insufficient information to permit judgement Selective reporting Reporting bias due to selective outcome reporting Low risk of bias: The study protocol is available and all of the study s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon) High risk of bias: Not all of the study s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub-scales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a metaanalysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study Unclear: Insufficient information to permit judgement Other bias Bias due to problems not covered elsewhere in the table Low risk of bias: The study appears to be free of other sources of bias. High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias 9

12 Appendix 3. Risk of bias assessment - Newcastle Ottawa Scale Form Note: A study can be awarded a maximum of one star ( maximum of two stars can be given for Comparability ) for each numbered item within the Selection and Outcome categories. A Selection 1. Representativeness of the exposed cohort i) Truly representative of the average (describe) in the community ii) Somewhat representative of the average in the community iii) Selected group of users (e.g. nurses, volunteers) iv) No description of the derivation of the cohort 2. Selection of the non exposed cohort i) Drawn from the same community as the exposed cohort ii) Drawn from a different source iii) No description of the derivation of the non exposed cohort 3. Ascertainment of exposure i) Secure record (e.g. surgical records) ii) Structured interview iii) Written self-report iv) No description 4. Demonstration that outcome of interest was not present at start of study i) Yes ii) No Comparability 1. Comparability of cohorts on the basis of the design or analysis i) Study controls for (select the most important factor) ii) Study controls for any additional factor important factor) (this criteria could be modified to indicate specific control for a second Outcome 1. Assessment of outcome i) Independent blind assessment ii) Record linkage iii) Self-report iv) No description 2. Was follow-up long enough for outcomes to occur i) Yes (select an adequate follow up period for outcome of interest) ii) No 3. Adequacy of follow-up of cohorts i) Complete follow-up - all subjects accounted for ii) Subjects lost to follow-up unlikely to introduce bias - small number lost - < 15 % follow-up or description provided of those lost iii) Follow-up rate < 85% and no description of those lost 10

13 iv) No statement Appendix 4. Risk of bias assessment - Newcastle Ottawa Scale Coding manual for cohort studies Selection 1. Representativeness of the exposed cohort Item is assessing the representativeness of exposed individuals in the community, not the representativeness of the sample of women from some general population. For example, subjects derived from groups likely to contain middle class, better educated, health oriented women are likely to be representative of postmenopausal oestrogen users while they are not representative of all women (e.g. members of a health maintenance organisation (HMO) will be a representative sample of oestrogen users. While the HMO may have an under-representation of ethnic groups, the poor, and poorly educated, these excluded groups are not the predominant users of oestrogen). Allocation of stars as per rating sheet 2. Selection of the non-exposed cohort Allocation of stars as per rating sheet 3. Ascertainment of exposure Allocation of stars as per rating sheet 4. Demonstration that outcome of interest was not present at start of study In the case of mortality studies, outcome of interest is still the presence of a disease/incident, rather than death. That is to say that a statement of no history of disease or incident earns a star Comparability 1. Comparability of cohorts on the basis of the design or analysis A maximum of 2 stars can be allotted in this category. Either exposed and non-exposed individuals must be matched in the design and/or confounders must be adjusted for in the analysis. Statements of no differences between groups or that differences were not statistically significant are not sufficient for establishing comparability. Note; If the relative risk for the exposure of interest is adjusted for the confounders listed, then the groups will be considered to be comparable on each variable used in the adjustment. There may be multiple ratings for this item for different categories of exposure (e.g. ever versus never, current versus previous or never) Outcome 1. Assessment of outcome For some outcomes (e.g. fractured hip), reference to the medical record is sufficient to satisfy the requirement for confirmation of the fracture. This would not be adequate for vertebral fracture outcomes where reference to x-rays would be required. i) Independent or blind assessment stated in the paper, or confirmation of the outcome by reference to secure records (e.g. X- rays, medical records) ii) Record linkage (e.g. identified through ICD codes on database records) iii) Self-report (i.e. no reference to original medical records or X-rays to confirm the outcome) iv) No description. 2. Was follow-up long enough for outcomes to occur An acceptable length of time should be decided before quality assessment begins (e.g. 5 yrs. for exposure to breast implants) 3. Adequacy of follow-up of cohorts This item assesses the follow-up of the exposed and non-exposed cohorts to ensure that losses are not related to either the exposure or the outcome. Allocation of stars as per rating sheet 11

14 C O N T R I B U T I O N S O F A U T H O R S 1. Draft the protocol: NA, AI, RS 2. Study selection: AI, NA, RS 3. Extract data from studies: AI, NA 4. Enter data into RevMan: NA 5. Carry out the analysis: NA 6. Interpret the analysis: NA, AI, RS 7. Draft the final review: NA, AI, RS, SB, SF, LD 8. Disagreement resolution: NA, AI, RS, SB, SF, LD 9. Update the review: NA D E C L A R A T I O N S O F None known. I N T E R E S T 12