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1 5th July 2017 Dear Miss Park Manuscript ID BMJ entitled "Haloperidol versus atypical antipsychotics for delirium in patients with myocardial infarction: a cohort study" Thank you for sending us your paper. We found the research question relevant to our readership and the study of interest, so we sent it for external peer review and discussed it at our manuscript committee meeting. We recognise the potential importance and relevance of this paper to general medical readers, but the reviewers and editors had some concerns that we would need addressed before we could make a final decision on your paper. In particular, there were some statistical queries at the manuscript meeting, and our statistician who attended the manuscript meeting (Richard Riley) has provided a detailed report at the end of this . If you are able to address the points from the manuscript meeting and the reviewers' comments below, we would like to consider your paper again. I'm afraid I can make no guarantees about publication of the revision at this point, and the revised article would be subject to our usual editorial process upon resubmission. I hope you will choose to revise and resubmit a revision taking on board the comments of the editors and reviewers below. When you return the paper, please include a response to reviewers document in which you detail, point by point how and where in the manuscript you have addressed the concerns of the reviewers and editors. Please do feel free to me if you have any queries. Best wishes, Dr Sophie Cook UK research editor scook@bmj.com *** PLEASE NOTE: This is a two-step process. After clicking on the link, you will be directed to a webpage to confirm. *** **Report from The BMJ s manuscript committee meeting** These comments are an attempt to summarise the discussions at the manuscript meeting. They are not an exact transcript. Members of the committee were: Chair: Wim Weber Statistician: Richard Riley Attendees: Elizabeth Loder, John Fletcher, Rubin Minhas, Sophie Cook, Daoxin Yin, Tiago Villanueva Decision: Put points Detailed comments from the meeting:

2 Comments by the committee: *The editors shared the reviewers concern that delirium was presumed based on a prescription of haloperidol or atypical agent in the absence of previous psychiatric history, but delirium was not coded for or clinically diagnosed. While this is touched upon in the manuscript, we think this warrants greater discussion particularly in this population who would likely receive an antiemetic, which may be a reason for initiation of haloperidol. *Given the concerns about the presumption of delirium, should the wording throughout the paper reflect that the study tells us about the mortality associated with prescription of haloperidol vs atypical antipsychotics in in the post MI period in people who have no previous history of psychiatric problems? * There were concerns raised with the level of selection indicated in figure 1. Why not stick with the 28k patients on oral medication but without a psychiatric diagnosis? Why whittle this down further to 6.5k and then 3.2k when matched? This was a concern for both the editors and the reviewers. * In table 1 it is surprising to see how similar the two groups were before propensity score matching. There may be a typo in the proportion of STEMI as it is unlikely (impossible?) this would reverse following matching. Please clarify. * By using the outcome of in hospital mortality, is there a competing event of discharge here? Is there potential for deaths to be missed if people died outside of hospital? You exclude 1688 with an in-hospital stay of 3 days (Fig S1). But what about those who left between 3 and 7 days? * Might you examine statistically the proportional hazards assumption, by including an interaction with time, rather than just plotting the log(log) plot and visually summarising it? * Please discuss that the prescription of haloperidol vs the 3 atypicals is not random. One editor commented how haloperidol is contraindicated in Parkinson s disease and also how it is sometimes viewed as a stronger neuroleptic agent that the others in question here, so it may have been selected for patients with more severe symptoms. In your response please provide, point by point, your replies to the comments made by the reviewers and the editors, explaining how you have dealt with them in the paper. ** Comments from the external peer reviewers** Reviewer: 1 Recommendation: Comments: This retrospective cohort study suggests an increased risk of in-hospital death following oral haloperidol treatment compared to oral atypical antipsychotic treatment among patients hospitalized for myocardial infarction. The study is well conducted, the statistical analysis is sound, and the results are intriguing, however the immediate clinical significance for delirium treatment in clinical practice may be limited, due to the following considerations. 1. The relevance for delirium treatment is implicated indirectly only. No formal clinical diagnosis of delirium was recorded in about 80% of patients. This group may include patients in whom antipsychotic treatment was deemed indicated because of acute psychosis, aggression or agitation, without delirium. Although the authors are probably correct in assuming that the large majority of subjects in their study indeed suffered from delirium, reference to this specific clinical diagnosis in the title of their paper and in their last, concluding sentence suggesting a specific treatment guideline (page 17, lines 3-5) seems not warranted. The authors could consider adding a sensitivity analysis in the 20% of patients in whom a diagnosis of delirium according to ICD-9 codes was recorded (page 16, lines 3-5). Although the authors specify several proxies for global disease severity, the direct influence of delirium severity and delirium sub-type could not be assessed.

3 2. While most choices concerning in- and exclusion criteria seems straightforward, it is not clear why exactly two days were required without antipsychotic treatment following admission, while a single, first day may be sufficient to exclude any effects of antipsychotic use before admission. This two day criterion appears to contribute to exclusion of a substantial number of subjects according to figure S1. The authors could consider adding a sensitivity analysis including those patients initially excluded based on this two days free from antipsychotic treatment criterion, restricting this exclusion critrion to the first day of admission only. 3. The authors are to be commended for their efforts to address the various sources of confounding, however, residual confounding can not be excluded due to the intrinsic limitations of the study methods. The processes that played a role in choosing for either haloperidol or an atypical antipsychotic drug remains obscure as well as the effect these mechanisms may have had on the care and survival rates of patients. There is no information on physician characteristics with respect to specialties involved (general internists, neurologists, psychiatrists, or geriatricians?), nor on the characteristics of the ICU or medical wards involved, whereas these may all have had important influence on the clinical care both with respect to the indication and specific choice of antipsychotic medication as well as the care from a more general perspective. This is illustrated by the important difference reported for the HR s for ICU s and medical wards (page 12, line 42). Moreover, potentially important clinical information is missing with respect to presence of (subtle) extrapyramidal features or movement disorders other than Parkinson s disease (included in table S1 and S2), presence of problems with swallowing, or use of cholinesterase inhibitors. 4. Table S3 highlights an important difference between the study groups with respect to the duration of exposure, which was only one day in 60% of haloperidol treated patients vs 38% of patients treated with atypical antipsychotic drugs. This large difference is difficult to interpret: does it indicate that delirium was less severe in the haloperidol group or that haloperidol treatment was more effective? 5. Attrition was large according to the numbers in figure 1 (page 28) and there appears to be a substantial and unexplained difference between the haloperidol and atypical group of about 4 to 6% of patients at risk at the 7 day time point. The modest absolute difference in mortality of 2.3% (page 12, lines 3-5) is insufficient to explain this difference. 6. The authors seem to dismiss too easily important information from RCTs as analyzed by Neufeld et al and two large observational studies. If an acute harmful effect of haloperidol (page 13, line 30) would indeed be operative, the heterogeneity of study groups in RCTs and a limited number events may not be sufficient to explain the discrepancy with their current findings. Additional Questions: Please enter your name: Willem A. van Gool Job Title: Professor of Neurology Institution: Department of Neurology Reimbursement for attending a symposium?: No A fee for speaking?: No A fee for organising education?: No Funds for research?: No Funds for a member of staff?: No Fees for consulting?: No Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No

4 Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No If you have any competing interests <A HREF=' mpeting-interests'target='_new'> (please see BMJ policy) </a>please declare them here: Reviewer: 2 Recommendation: Comments: 1. This is a pharmaco-epidemiological database study comparing the short term mortality associated with treatment with antipsychotic drugs, amongst patients who had recently had an acute myocardial infarction. Haloperidol was at least 50% more hazardous than atypical antipsychotics. 2. The study was carefully and elegantly done, reasonably large, using transparent statistical methods, and with extensive sensitivity analyses to check results. The study used propensity matching to create matched groups receiving each type of drug, and this process was highly successful judged by the characteristics at baseline. Patients following an acute myocardial infarction (AMI) are likely to be at increased risk, so studying this group allows sufficient events to be recorded to allow analyses. Since the presumed mechanism of antipsychotic harm is through causing arrhythmias effects and differences may be magnified. So this is a clever group to study, from the statistical power perspective 3. The question is important. It has proven difficult to do randomised controlled trials of antipsychotic drugs in delirium, especially outside of intensive care units. The largest trial reported by the authors has n=45. Although anti-psychotic drugs are widely used in the short term treatment of delirium, and may have a role in shortening or reducing the severity of symptoms, this is uncertain, and it remains possible that net harm results from this practice. Moreover, there are few data to guide the choice of drug. Haloperidol is often used as it is available parenterally (although rarely used IV nowadays in Europe) and has a long track record, is generally considered safe, and has few anticholinergic effects which are likely to be deleterious in delirium (or dementia). 4. The biggest problem with the study is that delirium was presumed (by virtue of the fact that an antipsychotic was prescribed) not diagnosed. A reference is presented in the discussion to justify this assumption. Delirium diagnosis is often poor (although that is rapidly improving), and if diagnosed may not be coded. Any medical diagnosis (or combination of diagnoses) can cause delirium, AMI amongst them, but AMI may be considered a slightly unusual precipitating cause (drugs including opiates further contribute to delirium risk). The study identified 6500 such cases however. Whilst indicating the value of big data to investigate questions like this, the worry is that the group is unrepresentative, or that a subtle difference in indications results in residual confounding. For example, haloperidol is an anti-emetic; I am unaware of atypical antipsychotics being used in this role. Was haloperidol being used in this role? This commonly happens in end of life care (alongside levomepromazine), and the authors attempted to exclude those at the end of life (using a number of reasonable assumptions). But it is possible that haloperidol was being used for nausea, or co-prescribed with opiate analgesia. You would have to ask an American cardiologist if this were likely. There was a curious difference in length of treatment (2.4 vs 3.9d, haloperidol shorter), which might suggest a difference in indication (or different effectiveness, which is unlikely). That said, on balance I think that these differences would increase rather than decrease the risk associated with haloperidol. The increased risk is probably real. 5. The 7-day time frame is short, but so was the drug exposure so this is appropriate 6. The authors are upfront and open about potential weaknesses.

5 7. A couple of points in the abstract. The title mentions delirium but not the abstract it probably should, and include the presumption about antipsychotic use = delirium. Secondly as-treated analysis is not clear (also p9). Does it mean an on-treatment analysis 8. The conclusion is important. The study says nothing about whether antipsychotic treatments has a beneficial effect, but clearly suggests using an atypical antipsychotic if any is chosen. In a field where trial data are unlikely to be obtained, the authors have used good statistics to come up with the next best thing. Additional Questions: Please enter your name: Rowan Harwood Job Title: consultant geriatrician/professor of geriatric medicine Institution: Nottingham University Hospitals Reimbursement for attending a symposium?: No A fee for speaking?: No A fee for organising education?: No Funds for research?: No Funds for a member of staff?: No Fees for consulting?: No Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No If you have any competing interests <A HREF=' mpeting-interests'target='_new'> (please see BMJ policy) </a>please declare them here: none Reviewer: 3 Recommendation: Comments: The paper discusses the comparison of Haloperidol versus the use of Atypical Antipsychotics, in the context of managing Delirium in patients with Myocardial Infarction. It is noted that there is an interchange of the term Delirium and Dementia within the developed abstract and title. There is an assumption of Delirium presence which is driven by the adminstered use of such medications, outwith a contextual assumption of Mental Health issues. This has an applied consideration, in that also Mental Health issues may be still present, but just undiagnosed such as which is reflected on for the presence of Delirium. The paper also positively reflects on the wider potential for residual confounding which is present within the research and explores this in a high level of detail with contextual exploration and transparency to the reader. Additional Questions: Please enter your name: Gerry Bennison

6 Job Title: Patient Reviewer Institution: Non-Applicable Reimbursement for attending a symposium?: No A fee for speaking?: No A fee for organising education?: No Funds for research?: No Funds for a member of staff?: No Fees for consulting?: No Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No If you have any competing interests <A HREF=' mpeting-interests'target='_new'> (please see BMJ policy) </a>please declare them here: There are no competing interests relating to the submitted paper. Reviewer: 4 Recommendation: Comments: This retrospective cohort study investigated whether haloperidol use was associated with an increased risk of death in hospitalized patients with acute myocardial infarction compared to atypical antipsychotics use. The large hospital administrative database guarantees sufficient power, but I have major concerns about the relevance and validity of the results. Major concerns Earlier research investigated the association between conventional versus atypical antipsychotics and the risk of mortality in elderly patients independent of the specific reason for hospital admission. The authors now focus on patients with myocardial infarction. It is not clear why an analysis in this subgroup adds additional information to the available evidence. The authors assume that the antipsychotics were given for symptoms of delirium, which seems plausible and might give a new perspective. However, the data are similar to that used in earlier publications by this and other groups (1). That is, delirium is often missed and if it is diagnosed, it is often not reported in medical records. Data on severity of illness are also lacking. As the data are similar to those of earlier publications, the results cannot be expected to be different. The main analysis is based on deaths within 7 days after start of an antipsychotic, and secondary analyses on deaths within 2, 3, 5, and 30 days. Fig 1 shows that the survival curves diverge at these points in time. However, the curves overlap at other points in time, i.e. at 13, 16, and 18 days. The chosen endpoints might suggest an increased risk of mortality, even though other endpoints suggest there is none. The overlapping curves violate the proportional hazard assumption of a Cox survival analysis. The authors should have investigated this problem, and discussed this finding. Plotting the log of negative log of the survival plot obscures this violation (fig S3).

7 The analyses are based on just 6,578 of 28,303 patients with myocardial infarction that used an antipsychotic (fig S1). To avoid the inclusion of prevalent users, the authors excluded 17,434 patients that used an antipsychotic on the first and second day of admission, and patients with bipolar disorder and schizophrenia (but not patients with dementia?). In addition, they excluded patients with CABG. The selections severely limit the generalizability of the results. The conclusion does not reflect the actual (selected) patient population to which the results apply. (If CBAG increased the risk of delirium, related antipsychotic use, and risk of death, this could have been adjusted for without excluding patients with CBAG.) Propensity scores were used to adjust for confounding. Many variables were used to calculate these scores (table S2). In contrast to the claim of the authors, many variables do not predict choice of antipsychotic drug AND death within 7 days. Discharge information is the most obvious one. Moreover, severity of illness (terminal illness) is a likely and potentially strong confounder (1), but was not taken into account. In the introduction and discussion, the authors should quote the available observational evidence fairly (not just work from their own group), and include meta-analyses of trials and other papers that refute the association between conventional antipsychotics and an increased risk of mortality (1,2,3), and refer to them adequately (not abstracts but full papers). The discussion does not provide an in-depth evaluation of the study results either. For instance, the authors suggest that the results might be confounded by terminal illness but do not explain why. Minor concerns The title does not say that the outcome is mortality risk. It mentions delirium even though delirium diagnoses were not used to select the study population. The flow-diagram is inconsistent. Patient with non-oral use are excluded from the group of patients with oral use. Patients that had an in-hospital stay of less than three days are also patients that initiated antipsychotic use on the first or second day. H.J. Luijendijk References 1 Luijendijk HJ, de Bruin NC, Hulshof TA, Koolman X. Terminal illness and the increased mortality risk of conventional antipsychotics in observational studies: a systematic review. Pharmacoepidemiol Drug Saf. 2016; 25(2): Jackson JW, VanderWeele TJ, Viswanathan A, Blacker D, Schneeweiss S. The explanatory role of stroke as a mediator of the mortality risk difference between older adults who initiate first- versus second-generation antipsychotic drugs. Am J Epidemiol. 2014; 180(8): Hulshof TA, Zuidema SU, Ostelo RW, Luijendijk HJ. The Mortality Risk of Conventional Antipsychotics in Elderly Patients: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials. J Am Med Dir Assoc. 2015; 16(10): Additional Questions: Please enter your name: Hendrika J Luijendijk Job Title: senior researcher Institution: University Medical Center Groningen Reimbursement for attending a symposium?: No A fee for speaking?: No A fee for organising education?: No Funds for research?: No

8 Funds for a member of staff?: No Fees for consulting?: No Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No If you have any competing interests <A HREF=' mpeting-interests'target='_new'> (please see BMJ policy) </a>please declare them here: K. Huybrechts and other members of her department have published multiple articles showing an observational association between conventional antipsychotics and mortality risk. Me and my colleagues have refuted those findings in a meta-analysis of trials. We also published a discussion paper about the confounding role of terminal illness in the observational results. Despite the debate, the group in Boston remains a strong proponent of the association, and keeps on performing observational studies that reiterate previous findings. Reviewer: 5 Recommendation: Comments: Thank you for the opportunity to review this interesting piece of work. The topic is clearly important and the authors have undertaken a considerable study. I have reviewed this from a statistical perspective, and have some comments for improvement and clarification 1) The analysis methods (propensity score matching) are seemingly well done, with lots of confounders adjusted for in Table S1, although residual confounding remains a concern. I wonder, how missing data (e.g. in the confounders) was handled (e.g. multiple imputation?), as I expect there to be missing data for some covariates for some patients. 2) I did not see that hospital (Facility) was adjusted for directly. Why was this? The authors may have covered this by other factors such as region, number of beds, etc anyway, but I would like to know if it would have made any difference. Perhaps this is what is meant by the random-effects model to adjust for differences in facility and practice patterns? 3) The main the outcome is in-hospital mortality by 7 days. But, is there a competing event of discharge BEFORE 7 days? E.g. it says: In the ITT analysis over 7-day followup, the absolute rate of death per 100 person-days was 1.7 for haloperidol initiators and 1.1 for atypical antipsychotic initiators. These are in-hospital deaths; but could there be people who leave before 7 days? Indeed, the authors exclude 1688 with an in-hospital stay of 3 days (Fig S1). But what about those who left between 3 and 7 days? If they are censored at discharge (which it seems was the case), then the %s relate to an artificial world where people can only ever die in hospital. (%s will be too large). Rather, competing risk methods would be required.1 This will also effect Figure 1. 4) I think the authors should examine statistically the proportional hazards assumption, by including an interaction with time, rather than just plotting the log(log) plot and visually summarising it. This holds for the 7 day analysis, as well as the 30 day analysis. It seems that the HR is coming down over time, and this needs better explanation and reporting. For example, what is the change in the HR for each day increase? This could be plotted, and the HR over time given properly, rather than is done in Table 2, where separate analyses are done for each time-point. I expect this will make the HR at later days, say 25 to 30 days, not significant anymore.

9 5) More details on how the PS was created are needed. For example, was a logistic regression model used? 6) Figure 2, subgroup comparisons. We need the authors to quantify the actual difference between the groups (not just present each group separately), and give us a CI and p-value for the difference. In particular, is the difference between 2 days and 1 days exposure beyond chance? The CIs overlap considerably, so potentially not. Same for ICU versus medical ward. I also do not like categorisation of variables, like age at 75 and 85, and CCI at 4. This loses power, say to keeping continuous, and potentially considering non-linear relationships. 7) Figure 1 (ignoring the competing risks issue) suggests that there is a statistically significant difference between the groups, but in absolute terms this is very small. The baseline hazard is low, and the study is large, and thus we could small p-values, even when the effect (HR = 1.5) is not necessarily important clinically. Would the authors respond to this please? 8) Is the sample generalizable? Lots of patients were excluded, e.g. authors excluded 17,434 patients that used an antipsychotic on the first and second day of admission. I find this a considerable omission, and am struggling to understand the justification. It limits the relevant population to which the results here apply. I am pleased to see that the authors note that residual confounding cannot be completely excluded as a possible alternative explanation despite careful study design and adjustment for a wide range of potential confounders. In summary, I hope my comments help the authors going forward. Best wishes, Richard Riley Additional Questions: Please enter your name: Richard Riley Job Title: Professor of Biostatistics Institution: Keele University Reimbursement for attending a symposium?: No A fee for speaking?: No A fee for organising education?: No Funds for research?: No Funds for a member of staff?: No Fees for consulting?: No Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No If you have any competing interests <A HREF=' mpeting-interests'target='_new'> (please see BMJ policy) </a>please declare them here:

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