Published randomized controlled trials of drug therapy for dementia often lack complete data on harm

Journal of Clinical Epidemiology 61 (2008) 1152e1160

Published randomized controlled trials of drug therapy for dementia often lack complete data on harm P.E. Leea,*, H.D. Fischerb, P.A. Rochonb,c,d,e, S.S. Gillb,f, N. Herrmanng, C.M. Bellb,d,e, K. Sykorab, G.M. Andersonb,d a

Division of Geriatric Medicine, University of British Columbia, St. Paul’s Hospital, Providence Building, Ward 9B, 1081 Burrard Street, Vancouver, British Columbia, Canada b Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada c Kunin-Lunenfeld Applied Research Unit, Baycrest, Toronto, Ontario, Canada d Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada e Department of Medicine, University of Toronto, Toronto, Ontario, Canada f Department of Medicine, Queen’s University, Kingston, Ontario, Canada g Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Accepted 10 September 2007

Abstract Objective: The objective of the study was to determine the extent to which published randomized controlled trials (RCTs) report data on harm. Study Design and Setting: A systematic search strategy was used to identify RCTs published between 1996 and 2005 on the use of cholinesterase inhibitors or atypical antipsychotics in patients with dementia. A structured abstraction form was used to determine if data on mortality or serious adverse events were reported and if the articles followed Consolidated Standards of Reporting Trials format for reporting harm. Results: Thirty-three RCTs were identified (27 on cholinesterase inhibitors and 6 on atypical antipsychotics). Nineteen trials (58%) had explicit data on mortality and only four (12%) reported regulatory-agency-defined serious adverse events. Most abstracts (31, 94%) stated that harm was studied but few studies (9, 27%) provided a clear definition of the measures of harm. Conclusions: Although most published RCTs state that they examine harm, many failed to provide data on mortality and most lacked clear definitions or detailed analyses of harm. Better reporting of harm would provide timely and important information that could help physicians and the public to make more informed decisions. Ó 2008 Elsevier Inc. All rights reserved. Keywords: Alzheimer’s disease; Dementia; Randomized controlled trials; Cholinesterase inhibitors; Atypical antipsychotics; Adverse events

1. Introduction ‘‘Primum non nocere’’ (Do no harm) is one of the basic tenets of medicine [1]. To be properly aware of potential harm associated with a medical therapy, physicians often rely on the published literature, particularly randomized control trials (RCTs). If crucial harm data are missing, physicians may not have the information necessary to make an informed decision about prescribing a medication. The public and health care professionals should have access to the data that they need and authors and editors should make an effort to provide that information [2,3].

* Corresponding author. Tel.: þ604-806-8029; fax: þ604-806-8390. E-mail address: [email protected] (P.E. Lee). 0895-4356/08/$ e see front matter Ó 2008 Elsevier Inc. All rights reserved. doi: 10.1016/j.jclinepi.2007.09.012

The published literature on RCTs of all prescription drugs is enormous and not amenable to a comprehensive systematic review. However, two representative classes of drugs are of specific interest to the elderly with dementiadcholinesterase inhibitors (ChEI) and atypical antipsychotics. The first published RCT examining the use of newer ChEI to treat memory loss in patients with dementia appeared in 1996 [4] and the first published RCT of atypical antipsychotics to manage psychological and behavioral problems in patients with dementia appeared in 1999 [5,6]. Both drug classes were actively marketed and widely used prior to the safety warnings. For example, in Ontario by 2002, 2.6% of older adults in the community were prescribed an atypical antipsychotic and 1.9% were prescribed a ChEI [7]. Use of these drugs was even higher in the nursing home populations where 15% of residents

P.E. Lee et al. / Journal of Clinical Epidemiology 61 (2008) 1152e1160

What is new?  Despite frequently stating that they examined harms, representative randomized clinical trials of medications to treat older adults with dementia often failed to report information on well-defined serious adverse events and deaths.  Closer attention to definitions of harm, analyses, and better reporting of serious adverse events would provide information that could help make informed decisions regarding harm-benefit tradeoffs.  Randomized clinical trials should state if they have collected data on serious adverse events using regulatory agency definitions, and they should make the data on serious adverse events readily available.

were prescribed an atypical antipsychotic within one year of admission [8]. Both drug classes have been subject to regulatory agency warnings related to safety issues. In 2005, based on two previously unpublished RCTs [9,10], public warnings were issued by Health Canada [11] and the United States Federal Drug Administration (FDA) [12] linking galantamine, a ChEI, to death in patients with mild cognitive impairment. In March 2006, the manufacturers of donepezil reported a potential increased risk of death in one trial assessing patients with vascular dementia on treatment [13]. In 2005, Health Canada and the FDA issued public warnings based on data from RCT showing increased mortality in patients with dementia receiving atypical antipsychotics [14,15] and a subsequent meta-analysis of published and unpublished clinical trials showed an increased risk of death in older adults with dementia treated with atypical antipsychotics [16]. The problem of widespread use of drugs that are subsequently found to be harmful may be due in part to the difficulty of obtaining public access to the safety information that drug manufacturers must submit to regulators for prelicensure assessment. Information submitted to regulators prior to drug approval is deemed to be proprietary. A full discussion of the balance between intellectual property and public safety that must be struck by regulators is beyond the scope of this paper; however, another issue related to protecting the public is the failure of published RCTs to adequately report harm [2]. The purpose of this paper is to systematically identify all published RCTs of ChEI and atypical antipsychotics in patients with dementia published prior to the safety warnings and to describe the content and format of harm reporting in these studies. By limiting the analysis to RCTs published before the regulatory agency safety warnings for these two drug classes, the study focus is on what information

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on harm was available in journals prior to the warnings not how the literature may have responded to regulatory concerns over harm. This will help increase our understanding of how well harm is reported in published RCTs and will provide a useful guide to authors and journals as they try to ensure that providers and patients have full information on the effects of drugs. 2. Methods 2.1. Literature search strategy Electronic searches of MEDLINE (1966 to May Week 4, 2005), EMBASE (1980e2005 Week 6) and the Cochrane Databases (inception to fourth quarter 2004) were performed. We didn’t want to include studies that were released after the FDA/Health Canada safety warnings had already been made public. For our search, the keywords included: dementia; Alzheimer’s disease (AD); dementia, vascular. For drug groups, we used the keywords cholinesterase inhibitors and antipsychotics. Cholinesterase inhibitors, donepezil, galantamine, and rivastigmine and their CAS registry numbers were identified. Trials assessing tacrine, another cholinesterase inhibitor, were not included. Although tacrine showed a modest degree of efficacy among a small proportion of patients with mild to moderate AD, it has important adverse effects, which limits its clinical usefulness [17]. For the atypical antipsychotics, we included aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Reference lists from the identified articles were manually searched and cross-referenced. Clinical experts were contacted to identify additional trials. 2.2. Selection of eligible trials Published, RCTs with a placebo arm that assessed medication efficacy or tolerability for ChEI or atypical antipsychotics for symptomatic treatment of patients with AD or vascular dementia were included. Studies that evaluated a mixed population of patients with dementia were included if AD was the most common dementia in the trial. Open-label extensions of RCTs, post hoc analyses, subgroup analyses of previously published data, editorials, and commentaries were excluded. For ChEI, 54 abstracts identified through a search of MEDLINE were reviewed in detail. From these abstracts, 24 clinical trials were selected. The remaining abstracts did not meet our inclusion criteria (letters, review articles, nonrandomized clinical trials, or assessment of the use of ChEIs such as physostigmine, velnacrine, metrifonate, eptastigmine, or tacrine). Seventeen abstracts were identified through EMBASE and three of these trials met inclusion criteria and were included. An additional trial assessing donepezil was not accessible for detailed review [18]. In total, there were 27 randomized placebo controlled trials: 15 donepezil [4,19e32], 6 rivastigmine [33e38] and 6 galantamine [39e44] trials.

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A Medline search provided 16 abstracts evaluating atypical antipsychotic therapy from which six randomized, placebo control clinical trials were identified: three risperidone [5,6,45], two olanzapine [46,47], and one quetiapine [48] trial. No published clinical trials that fulfilled inclusion criteria assessed the use of clozapine, aripiprazole, or ziprasidone in older adults with dementia. A search of EMBASE did not identify any additional studies for review. 2.3. Content of harm reporting: serious adverse events and death The International Conference on Harmonization (ICH) defines serious adverse events (SAE) as any untoward medical occurrence that at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect [49]. This definition of SAE forms the basis of prelicensure safety reporting by drug manufacturers required by many national drug regulatory agencies [50e52]. An abstraction form was developed to determine if information on SAE that was clearly based on the ICH definition was available in the paper and if there was clear and complete reporting on mortality in the paper. 2.4. Harm reporting in relation to CONSORT recommendations The format of harm reporting was evaluated in relation to recommendations made by the Consolidated Standards of Reporting Trials (CONSORT) group on reporting harm in RCTs [3]. CONSORT provided a checklist outlining the location in the paper (i.e., abstract and title, introduction, methods, results, and discussion) where specific topics (e.g., intent to address harm, definition of harm, analysis of harm data) related to harm should be reported. An abstraction form was developed to collect data from each paper on the extent to which the paper provided the information recommended by CONSORT. This abstraction form identified 10 specific topics on harm (one from the title or abstract, one from the introduction, three from the methods, four from the results, and one from the discussion) that should be included in published RCTs (Appendix). If the paper met any one of the criteria that CONSORT defined for a topic, then it was counted as fulfilled for that topic. 2.5. Data abstraction process Each paper was independently reviewed using the standard data abstraction form by two study investigators (PEL and HF). They indicated on the form if there was explicit reporting of the number of death and if ICH-defined-SAE were reported. They also indicated on the form if the paper fulfilled the CONSORT harm reporting suggestions for each of the ten defined topic areas. If the two reviewers

did not agree on the initial rating, they discussed the scoring and rescored the paper based on that discussion. 3. Results 3.1. Selection of eligible trials Thirty-three RCTs were identified: 27 assessed cholinesterase inhibitors and 6 assessed atypical antipsychotics (see Table 1). All trials were published from 1996 to 2005 prior to the release of regulatory agency safety warnings. The sample size of subjects ranged from 50 to 978 participants. The duration of the trials varied from 6 to 60 weeks. Twenty-nine (88%) of the studies indicated that they were supported by pharmaceutical manufacturers, three indicated that they were funded by nonindustry sources [21,28,48], and the source of funding could not be determined for one study [38]. 3.2. Reporting of mortality and ICH-defined SAE Nineteen trials (58%) explicitly reported on mortality in each arm of the trial. The fourteen trials without explicit data on deaths contained a total of 3,120 patients or about one-quarter of the total patient population. Only 4 of the 33 trials (three assessing ChEI [24,25,30] and one assessing atypical antipsychotics [45]) even roughly followed ICH guidelines for the definition of reported SAEs. These four trials included a total of only 1,653 patients or about 12% of the total of 13,311 patients in 33 studies. 3.3. Harm reporting in relation to CONSORT recommendations Table 2 provides a summary of the data on the location of information on harm and harm topics covered in the 33 studies. The vast majority of papersd94% (31/33)d indicated in the title or abstract that the study specifically looked at harm by referring to the safety or tolerability of the study medication, although a smaller proportion 76% (25/33) explicitly mentioned the intention to assess harm in the introduction. Most studiesd85% (28/33)dhad some description of the collection of data on harm but only nine (27%) defined specific harm with attention to grading, expected vs. unexpected events with reference to standardized and validated definitions or clear description of new definitions. As noted above, these nine trials included four that used a version of the ICH definition of SAE. One-third of the trials did not have a clear description of the methods used to analyze the harm data. All the trials provided information on withdrawals and contained information that could be used to provide denominators for rates calculation. Information about the absolute risk of some measure of harm could be found in 29 (88%) of the trials, although subgroup analyses or exploratory analyses for harm were performed in only five (15%) of the trials. In 30 trials (91%), there was some exploration of harm as part of their

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Table 1 Reporting of ICH-defined serious adverse events (SAE), adverse events and deaths experienced by participants in clinical trials evaluating the use of cholinesterase inhibitors or atypical antipsychotics for the symptomatic treatment of patients with AD Trial

Treatment

Number of subjects

ICH Defined SAE Reported (Y/N)

Any AE Reported (Y/N)

Holmes et al. [19]

Placebo Donepezil (10 mg) Placebo Donepezil (10 mg) Placebo Donepezil (5 & 10 mg) Placebo Donepezil (5mg) Donepezil (10 mg) Placebo Donepezil (5 mg) Donepezil (10 mg) Placebo Donepezil (10 mg) Placebo Donepezil (10 mg) Placebo Donepezil (10 mg) Placebo Donepezil (10 mg) Placebo-donepezil Donepezil-placebo Placebo Donepezil (5 mg) Placebo Donepezil (5 mg) Donepezil(10 mg) Placebo Donepezil (5 mg) Donepezil (10 mg) Placebo Donepezil (5 mg) Donepezil (10 mg) Placebo Donepezil (1 mg) Donepezil (3 mg) Donepezil (5 mg) Placebo Rivastigmine (12 mg) Placebo Rivastigmine (1-4 mg) Rivastigmine (6-8 mg) Placebo Rivastigmine BID (12 mg) Rivastigmine TID (12 mg) Placebo Rivastigmine (4 mg) Rivastigmine (6 mg) Placebo Rivastigmine (1-4 mg) Rivastigmine (6-12 mg) Placebo Rivastigmine BID (12 mg) Rivastigmine TID (12 mg) Placebo Galantamine (24-36 mg) Placebo Galantamine (24mg)

55 41 57 96 283 282 199 198 206 193 208 215 146 144 105 103 144 142 217 214 30 30 131 136 274 271 273 162 154 157 153 157 158 40 42 40 39 20 24 239 242 242 24 45 45 133 136 133 235 233 231 10 20 20 125 261 196 396

No

No

No

Yes

No

Yes

No

Yes

No

Yes

Yes

Yes

Yes

Yes

No

Yes

No

Yes

No

Yes

No

No

Yes

Yes

No

Yes

No

Yes

No

No

No

No

No

No

No

No

No

Yes

No

No

No

No

No

Yes

No

No

Seltzer et al. [20] Courtney et al. [21] Black S et al. [22]

Wilkinson et al. [23]

Feldman et al. [24] Tariot et al. [25] Winblad et al. [26] Mohs et al. [27] Greenberg et al. [28] Homma et al. [29] Burns et al. [30]

Rogers et al. [32]

Rogers et al. [31]

Rogers et al. [4]

Karaman et al. [33] Rosler et al. [34]

Forette et al. [35]

Agid et al. [36]

Corey-Bloom et al. [37]

Sramek et al. [38]

Rockwood et al. [39] Erkinjuntti et al. [40]

Deaths N (%) Not reported Not reported Not reported Not reported 50 (18) 63 (22) 7 (4) 2 (1) 6 (3) 1 (1) 3 (1) 2 (1) 0 (0) 1 (1) 7 (7) 3 (3) 3 (2) 4 (3) 4 (2) 3 (1) Not reported Not reported Not reported Not reported 2 (1) 1 (0) 2 (1) 1 (1) 0 (0) 1 (1) 1 (1) Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported 0 (0) 0 (0) 1 (0) Not reported Not reported Not reported Not reported Not reported Not reported 0 (0) 0 (0) 1 (0) Not reported Not reported Not reported 2 (2) 0 (0) 7 (4) 9 (2) (Continued )

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Table 1 Continued Trial

Treatment

Number of subjects

ICH Defined SAE Reported (Y/N)

Any AE Reported (Y/N)

Wilkinson et al. [41]

Placebo Galantamine (18mg) Galantamine (24mg) Galantamine (36mg) Placebo Galantamine (24mg) Galantamine (32mg) Placebo Galantamine (24mg) Galantamine (32mg) Placebo Galantamine (8mg) Galantamine (16mg) Galantamine (24mg) Placebo Risperidone (2mg) Placebo Risperidone (2mg) Haloperidol Placebo Risperidone (0.5mg) Risperidone (1 mg) Risperidone (2 mg) Placebo Olanzapine (1mg) Olanzapine (2.5mg) Olanzapine (5mg) Olanzapine (7.5mg) Placebo Olanzapine (5mg) Olanzapine (10mg) Olanzapine (15mg) Placebo Rivastigmine Quetiapine

87 88 56 54 215 220 218 213 212 211 286 140 279 273 170 167 114 115 115 163 149 148 165 129 129 134 125 132 47 56 50 53 31 31 31

No

Yes

No

No

No

No

No

Yes

Yes

Yes

No

No

No

Yes

No

No

No

No

No

No

Wilcock et al. [42]

Raskind et al. [43]

Tariot et al. [44]

Brodaty et al. [45] De Deyn et al. [6]

Katz et al. [5]

De Deyn et al. [47]

Street et al. [46]

Ballard et al. [48]

discussion; however, it was often limited to one or two sentences. 4. Discussion 4.1. Reporting of deaths and SAE Our analysis shows that in about 40% of the studies, there was no explicit data on deaths. In some of the publications, it might be possible for the reader to calculate or infer death rates. However, clear information on mortality should be a minimum requirement for any published trial and readers should not be required to infer or estimate mortality rates. In the event that there are no deaths encountered during the course of the trial, this should be clearly stated. Our analysis suggests that reporting of SAE in published RCTs is inadequate. Only four trials used clear ICH definitions of SAE that are routinely required by regulators. This meant that for almost 90% of study participants there was no clear definition of SAE provided. This lack of a clear and consistent definition of SAE makes it difficult if not impossible for readers to compare and aggregate data on harm

Deaths N (%) Not reported Not reported Not reported Not reported Not reported Not reported Not reported 1 (1) 1 (1) 1 (1) 4 (1) 1 (1) 3 (1) 3 (1) 4 (2) 6 (4) Not reported Not reported Not reported 5 (3) 6 (4) 13 (9) 6 (4) 2 (2) 4 (3) 3 (2) 5 (4) 3 (2) Not reported Not reported Not reported Not reported 0 (0) 0 (0) 1 (3)

across studies. Pharmaceutical companies sponsored the vast majority of trials (88%). These companies are familiar with the standard definitions of SAE used by regulators and should be able to collect data on these events. Reporting of SAE is particularly important in situations where the benefits of therapy are not substantial and the population receiving the drugs is at high risk for adverse eventsdclearly the case in the use of cholinesterase inhibitors and atypical antipsychotics in elderly patients with dementia [53,54]. The regulatory warnings about deaths and the use of atypical antipsychotics were issued six years after the initial trials were published. The signal for the potential increased risk of death only became apparent after unpublished and published RCTs data were analyzed. Our analysis shows that there was no mortality data on about one-quarter of the patients in published RCTs of atypical antipsychotics. More complete data on mortality could have helped to lead to the earlier identification of concerns. Recent studies [55] show that atypical antipsychotic drugs increase mortality soon after exposure suggesting that even short-term RCT could have provided important information on mortality.

P.E. Lee et al. / Journal of Clinical Epidemiology 61 (2008) 1152e1160 Table 2 Format of harm reporting in relation to CONSORT recommendations for 33 RCT of drug treatments for older patients with dementia Location and topic of harm reporting

Number and (%) of trials fulfilling recommendation

Title or Abstractdindication that harm examined Introductiondstatement that measuring harm is part of study Methodsdspecific harm and adverse events well defined Methodsddescription of harm collection Methodsdplan for analysis of harm Resultsddata on withdrawals from study Resultsddata on denominators for calculating harm rates Resultsddata on absolute rates of harm or adverse events per arm and by type of harm Resultsdsubgroup or exploratory analysis for harm Discussiondbalanced discussion of harm including study limitations

31 (94) 25 (76)

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Perhaps as a result of well-established criteria for judging the validity of RCTs, all the studies reviewed provided detailed information on withdrawals and provided clear data on denominators for the calculation of rates of adverse events. However, basic methodological criteria related to the accurate assessment of harm including clear definitions of the harm outcomes, details of the analysis plan and exploratory or subgroup analyses were often not met.

9 (27)

5. Limitations 28 (85) 22 (67) 33 (100) 33 (100)

29 (88)

5 (15)

30 (91)

Some authors have suggested that thinking about efficacy and harm as separate outcomes should cease, and using total SAE rates may be a better way to evaluate clinical trials [56]. This approach has drawn some criticism from others who suggest that readers of published trials are interested in all adverse events, not just those defined as serious [57]. We suggest that it is important that all trials report any effects of medications accurately with equal emphasis and detail on harm and benefits, so that others can weigh risks and benefits as they choose. In many cases, individual RCTs may not be large enough to detect statistically significant effects on mortality or SAE. However, this does not mean that data from individual trials is not useful. The ultimate detection of significant adverse effects may require meta-analysis of information from several RCTs and this type of analysis is only possible if individual trials consistently report mortality and commonly defined SAE data. Although reports of SAE submitted to regulators may be proprietary, if the RCT collects SAE data and if the results of that RCT are submitted for publication in a journal then it would not be unreasonable to expect the SAE data to be made available for publication. 4.2. Reporting in relation to CONSORT recommendations The analysis shows that the vast majority of published RCTs indicate they plan to address the issue of harm.

This article does not intend to evaluate the efficacy or safety of ChEI or atypical antipsychotic medication use in older adults with dementia as that has been addressed in other studies [53,58]. The goal was to examine published RCTs of these two medications to draw some conclusions about harm reporting in general. The selection of only two drug classes may not provide a true representation of all public reporting of harm in RCTs; however, these two drug classes were selected for several reasons including that the trials were published recently, the drugs have been used widely, and that the tradeoff between risks and benefits is particularly important in the elderly population. These two classes of drugs have recently been identified as having important safety concerns. Although not representative, our study provides an important framework. Our adaptation of the CONSORT recommendations for harm reporting has not been validated. We used the CONSORT recommendations as a generally accepted standard that could be used to systematically describe harm reporting. There may be features of harm reporting that are not covered by our abstraction tool or by the CONSORT criteria and some CONSORT criteria such as subgroup analysis may not be applicable in all circumstances.

6. Conclusions Although regulatory agencies have clear legislative responsibility and actions that they can take to protect the public from harm due to drug therapy, the publication of information on harm in journals can both inform the public and spur regulators to act. Improving methods for defining, analyzing, and reporting harm is a responsibility of both authors and editors. There is recognition that harm reporting should be part of RCT publications but there does not seem to be a standard approach to including them in the methods and results sections of publications. The CONSORT criteria are a set of guidelines that are meant to guide the appropriate reporting of harm in published trials. These recommendations might well serve as a standard for journals editors to apply to all RCTs. Most published RCTs of the drugs we reviewed lacked data on well-defined SAE and many lacked explicit data on deaths. Although most studies indicated that they would

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provide information on harm, most lacked clear definitions of harm and did not define or conduct adequate analysis of harm. At a minimum, editors of journals should ask that all RCTs provide information on mortality and that if they have collected data on SAE using regulatory agency definitions, which is the case in many trials, that they should also report the SAE data. Editors and reviewers should have the option of suggesting that this information is not relevant and need

not be included in the final publication but authors should not have the option of failing to submit the information in the first place. Better reporting of death and SAE in published RCTs and closer attention to the definition and analyses of adverse events would provide timely and important information that could help physicians and the public to make informed decisions regarding harm benefit tradeoffs.

Appendix Abstraction formdreporting harms in randomized, controlled trialsdan extension of the consort statementa Source of Information and specific question to be answered Title and abstract Is there anything in the title or abstract that indicates that the study specifically looked at harm?

Y/N

If yes, page #

If yes, then what terms and/or outcomes were included? ,Presents data on harm in abstract ,Uses term, harm ,Uses term, safety ,Uses term, tolerability ,Other (specify)

Introduction Background Is there a statement in the introduction that addresses measuring harm as part of the study? Methods Outcomes Were specific harms or adverse events defined (with attention, when relevant, to grading, expected vs. unexpected events, reference to standardized and validated definitions, and description of new definitions)?

,Death ,Life threatening ,Hospitalization/prolong ,Disability/Incapacity ,Medically important eventa ,Other (specify)

Was there a clear description of how harms related data were collected (mode of data collection, timing, attribution methods, intensity of ascertainment, and harms-related monitoring and stopping rules, if pertinent)? Statistical methods Was plan for presenting and analyzing information on harms (including coding, handling of recurrent events, specification of timing issues, handling of continuous measures, and any statistical analyses) described? Results Participant flow Was there a description for each arm of the participant withdrawals that were due to harms and their experiences with the allocated treatment? Numbers analyzed Was there information provided on denominators that could be used to calculate rates of harm? Outcomes and estimation, ancillary analyses, adverse events Was information presented on the absolute risk of harm per arm and per adverse event type, grade, and seriousness, and were appropriate metrics for recurrent events, continuous variables, and scale variables, presented whenever pertinent? Was there any description of any subgroup analyses or exploratory analyses for harms? Discussion Interpretation, generalizability, overall evidence Was there a balanced discussion of benefits and harms with emphasis on study limitations, generalizability, and other sources of information on harms? a

Ioannidis JPA, Evans SJW, Gotzsche PC, O’Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extention of the CONSORT statement. Ann Intern Med 2004;141:781e788.

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Acknowledgment This work was supported by a CIHR Chronic Disease New Emerging Team grant (NET-54010). The NET program receives joint sponsorship from the Canadian Diabetes Association, the Kidney Foundation of Canada, the Heart and Stroke Foundation of Canada, and the CIHR Institutes of Nutrition, Metabolism & Diabetes and Circulatory & Respiratory Health.

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