الثلاثاء، 28 أغسطس 2012

Effect of assertive outreach after suicide attempt in the AID (assertive intervention for deliberate self harm) trial: randomised controlled trial

Effect of assertive outreach after suicide attempt in the AID (assertive intervention for deliberate self harm) trial: randomised controlled trial | BMJ

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Research Effect of assertive outreach after suicide attempt in the AID (assertive intervention for deliberate self harm) trial: randomised controlled trial BMJ 2012; 345 doi: 10.1136/bmj.e4972 (Published 22 August 2012) Cite this as: BMJ 2012;345:e4972 Suicide (psychiatry) Suicide (public health) Adult intensive care Clinical trials (epidemiology) Psychotherapy More topics

Psychotic disorders (incl schizophrenia) Fewer topics

Article Related content Read responses (1) Article metrics Britt Morthorst, research assistant1, Jesper Krogh, research assistant1, Annette Erlangsen, senior researcher12, Francisco Alberdi, chief psychiatrist1, Merete Nordentoft, professor1
1Research Unit, Mental Health Centre Copenhagen, Faculty of Health Sciences, University of Copenhagen, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark
2Department of Mental Health, Johns Hopkins School of Public Health, Baltimore, MD, USACorrespondence to: B Morthorst britt.morthorst{at}regionh.dkAccepted 11 July 2012AbstractObjective To assess whether an assertive outreach intervention after suicide attempt could reduce the frequency of subsequent suicidal acts, compared with standard treatment.

Design Randomised, parallel group, superiority trial with blinded outcome assessment.

Setting Outpatient intervention at one location at Copenhagen University Hospital, Denmark.

Participants Patients older than 12 years admitted to regional hospitals in Copenhagen with a suicide attempt within the past 14 days. We excluded patients diagnosed with schizophrenia spectrum disorders and patients living in institutions.

Intervention Case management through assertive outreach that provided crisis intervention and flexible problem solving. This approach incorporated motivational support and actively assisted patients to scheduled appointments to improve adherence with after-treatment as an add on to standard treatment.

Main outcome Repeated suicide attempt and death by suicide, recorded in medical records and death register at 1-year follow-up.

Results 243 patients were included. During 12 months of follow-up, 20/123 (16%) patients in the intervention group had been registered in hospital records with subsequent suicide attempt, compared with 13/120 (11%) in the control group (odds ratio 1.60, 95% confidence interval 0.76 to 3.38; P=0.22). By contrast, self reported data on new events showed 11/95 (12%) in the intervention group versus 13/74 (18%) in the control group (0.61, 0.26 to 1.46; P=0.27). By imputing missing data on the selfreported outcomes, we estimated 15/123 (12%) events in the intervention group and 23/120 (19%) in the control group (0.69, 0.34 to 1.43; P=0.32).

Conclusion Assertive outreach showed no significant effect on subsequent suicide attempt. The difference in rates of events between register data and self reported data could indicate detection bias.

Trial registration ClinicalTrials.gov NCT00700089.

BackgroundSuicidal behaviour is a serious worldwide public health problem; a million suicides are estimated to occur each year.1 2 Attempted suicide is under recorded.3 4 Nevertheless, the number of non-fatal episodes is estimated to be 10 to 40 times higher than that of fatal episodes.1 5 Suicide attempts occur most frequently among young women6 and an increase in the rate of suicide attempt has been noted internationally, especially among women aged 15 to 24 years.7 8 9

Besides mental illness and substance abuse, previous suicide attempt is the most prominent predictor of subsequent suicidal behaviour.10 Median rates of repeated suicide attempt are 16% for non-fatal and 2% for fatal episodes within a year of the index attempt.11 12 A European multicentre study previously recorded repetition rates of up to 30% within the first year.13 Recent studies have presented similar repetition rates for adolescents.14 The first month after a suicide attempt carries an especially high risk of repetition.15 16

Results from randomised clinical trials of treatment after suicide attempt, synthesised in systematic reviews, are heterogeneous in interventions and effect.6 17 18 Reviews of psychosocial interventions, including a Cochrane publication and guidelines from the National Institute for Health and Clinical Excellence in England and Wales (NICE), have not found conclusive evidence on treatment strategies for this high risk group.17 19 20 21 22

Patients with suicidal behaviour have been characterised as difficult to engage in after-treatment.23 Various trials of interventions offering help after contact with emergency rooms have focused on treatment accessibility and adherence to after-treatment, to optimise the treatment chain for both adults and adolescents.18 24 25 17 19 20 21 22 To reduce the gap between treatment of suicide attempt and after-care, a specialised prevention team in Norway provided during a 23 year period a flexible, assertive, and individually shaped treatment to people who attempted suicide without severe mental illness.26 When it compared patients who received support from the prevention team with those who did not, the study found no significant difference in risk of repeating suicide at 12 months (adjusted odds ratio 0.86; 95% confidence interval 0.5 7 to 1.30). The study, however, did not have a randomised design and could therefore have been influenced by selection bias. A recent randomised trial27 evaluated the Norwegian model by offering six to eight assertive and motivational consultations, while a similar control group received standard care from a general practitioner. The study, which included 133 patients, found a significant difference in favour of the intervention compared with standard treatment with rates of repeat suicide attempt being 9% v 22%; P=0.04). However, the power of the study was limited. To confirm these promising findings, our objective was to replicate the study with higher power as a randomised, parallel group, superiority trial.

The aim of this study was to investigate whether an assertive outreach intervention assigned after suicide attempt could reduce the frequency of subsequent suicidal acts, compared with standard treatment.

MethodsThe assertive intervention for deliberate self harm (AID) trial was designed as a pragmatic, randomised, parallel group, superiority trial with blinded outcome assessment. The trial protocol was approved by the local ethics committee (journal number KF-01 271146), the Danish Data Protection Agency (journal number 2011-41-6398), and registered at clinicalTrials.gov (identifier NCT00700089). It was undertaken at a single location at the Copenhagen University Hospital, Copenhagen, Denmark.

ParticipantsParticipants were patients admitted after a suicide attempt to acute emergency units, intensive care units, paediatric units, and psychiatric emergency rooms in six regional hospitals in the catchment area of Copenhagen. We made referral agreements through personal meetings with units in charge of standard treatment provided to patients with suicide attempts. We distributed pocket sized laminated sheets with inclusion and exclusion criteria to doctors in somatic and psychiatric units. Children and adolescents were referred to the AID trial from the hospital conducting the trial and from other hospitals treating children, in addition to standard procedures for psychiatric consultation. General practitioners who contacted hospitals to refer possible patients with recent suicide attempt were also informed about the trial.

Inclusion criteriaWe included male and female patients aged 12 years and older with a suicide attempt within the past 14 days who were able to read and understand the informed consent statement. We made one exception with regard to the age criteria; a female patient was included shortly before her twelfth birthday.

All the suicide attempts of included patients fulfilled the WHO definition: “An act with a non-fatal outcome, in which an individual deliberately initiates a non-habitual behaviour that without intervention from others will cause self harm, or deliberately ingests a substance in excess of the prescribed or generally recognized therapeutic dosage, and which is aimed at realizing changes which the subject desired via the actual or expected physical consequences.”28 Patients presenting with self injuries, such as cutting, were only included if they also met the definition of non-habitual behaviour. This was verified for each single case through patients’ self reports and medical records. Patients diagnosed with severe personality disorders, including eating disorders, were invited to join the study, as were patients with alcohol misuse or with no offer of subacute treatment meeting the need for suicide prevention.

Exclusion criteriaWe excluded patients admitted to a psychiatric ward for more than 14 days after the index attempt. This enabled us to investigate the effect of the intervention for high risk patients in subacute phases. We also excluded patients who had been diagnosed with schizophrenia spectrum disorders (ICD-10: F20-29), severe depression (ICD-10: F32.2, F32.3, F33.2, and F33.3.), severe bipolar disorder (ICD 10: F30 and F31), and severe dementia (ICD 10: F0-9), because intensive outreach teams are already implemented as standard care for these patients in Denmark. Furthermore, patients with severe depression or bipolar disorder and suicidal behaviour would probably need inpatient care and would not be eligible for outpatient treatment. We also excluded patients who were receiving outreach services from social service agencies or living in institutions, to prevent mixing different effects and avoid confounders.29

Standard treatmentThe standard treatment consisted of referral to a range of different treatment modalities, dependent on the diagnosis and the clinical and social conditions of the patient. While the patient was still being treated for the self injury, a routine psychiatric evaluation would often be used to determine whether he or she should be referred for further treatment—for example, general practitioner, psychological therapy, or treatment for alcohol abuse. In the standard treatment there was no procedure to ensure compliance with the recommended treatment. For the most part, the patients were responsible for contacting the treatment provider to which they were referred. As a part of the standard treatment, the Centre of Excellence in Suicide Prevention Copenhagen offered six to eight therapeutic sessions to patients who did not abuse substances and were not receiving other ongoing treatments. A psychologist provided these sessions as short term therapy with risk assessment tools from the Collaborative Assessment and Management of Suicidality (CAMS) approach.30 31 This option of after-treatment was available to patients in both groups. Pharmacological treatment of any kind was continued or prescribed in both groups when relevant.

InterventionThe AID intervention was provided as case management with crisis intervention and flexible, problem solving, assertive outreach through motivational support and actively assisting patients to and from scheduled appointments, to improve compliance with after-treatment. The intervention represented eight to 20 flexible outreach consultations performed by specialised nurses (AID managers) over 6 months in addition to standard treatment. The first consultation was offered a few days after discharge and focused on acute prevention strategies, such as developing a crisis intervention plan in case of relapse. Subsequent consultations established a professional relationship, addressed problem solving strategies, and undertook specific actions. To ensure continuity, the same AID manager contacted the patient throughout the 6 months of the intervention. Motivation towards after-treatment was stressed as a core feature and referral was organised. Consultations were provided equally as home visits or meetings in cafes, as preferred, as well as meetings with healthcare, official, and social services to accommodate individual needs. The AID manager was responsible for maintaining contact, but the patient was asked to make contact between consultations if necessary. Telephone calls and text messages were frequently used to strengthen the alliance. The manager offered mediating family consultations to adolescents and their relatives, and suggested the involvement of social or professional networks irrespective of age. During relapse or stressful life events, frequency of contact was intensified, including availability of contact out usual hours to prevent subsequent suicidal behaviour. If the patient had severe suicidal impulses, the manager asked him or her to take a prepaid taxi to the psychiatric emergency room if all other items on the crisis intervention plan had failed in changing the impulses or providing relief of psychic pain. A minimum of four personal contacts was defined as adherence to the AID intervention; additional phone calls and text messages were not defined. Cafe visits did not count as crisis interventions. If, however, the patient revealed severe suicidal impulses during a cafe visit, the manager would usually prolong contact to cover decisions of crisis management.

Staff requirementsThe intervention staff (AID managers) were highly qualified psychiatric nurses with specialised training in suicidology. Regular consultations were done with the supervising chief psychiatrist and research assistant to ensure adherence to the research protocol. The target for maximum caseload for each AID manager was 20 patients in active intervention treatment at any time. If a patient died by suicide, the AID manager assigned the patient would immediately be relieved from duty for a period of time.

OutcomeWe interviewed patients at baseline to obtain information on socio-demographic variables and method used for the index suicide attempt. The outcomes of interest were repeated suicide attempt and death by suicide with a follow-up period of one year after inclusion date. We obtained information on these events through ICD-10 diagnoses (recorded as part of standardised hospital registration procedure) and review of medical records. Additionally, we collected self reported data on events within the first year of follow-up, through telephone interviews with patients. Patients who could not be reached by phone after persistent attempts were contacted by regular mail.

BlindingAn external medical evaluation committee conducted a blinded outcome assessment using medical records. Owing to the nature of the study design, the intervention staff were not blinded. The researcher conducting the analyses on self reported outcomes was also not blinded.

Statistical powerOn the basis of previous studies,27 we estimated an expected repetition risk of 30% in the standard group and 15% in the intervention group within one year of the index attempt. With an a value of 0.05, we required 120 patients randomised to each treatment arm to reach a power of 80%.32

RandomisationComputer randomisation was done by an independent research assistant at the Mental Health Centre Copenhagen, stratified by whether the patient had previously attempted suicide (first attempt v previous attempt), previous psychiatric contacts or hospitalisation (none v previous contacts), and alcohol consumption at time of suicide attempt (none v alcohol consumption). The AID managers were informed of the allocation by phone and the patients were immediately informed of the outcome. The randomisation procedure ensured adequate sequence generation and allocation concealment.

Statistics and data analysisWe assessed frequencies, means, and standard deviations of socio-demographic and patient characteristics and tested differences between groups with ?2 or independent sample t tests. We calculated the log odds of a patient having a recorded or self reported new suicide attempt in the 12 months following the index attempt. In subsequent planned analyses, we adjusted for possible baseline differences relevant for the primary outcome. All patients were included in the analysis regardless of subsequent adherence to treatment, according to the intention to treat principle. All statistical tests were two sided and P values less than 0.05 were considered statistically significant. We imputed missing values for the self reported outcome as a dependent variable using multiple imputations by applying a linear regression model with the following predictor variables: allocation, suicide attempt prior to index attempt, alcohol intoxication at index attempt, psychiatric contact prior to index attempt, unemployment, antidepressant medication, and discharge from a psychiatric hospital within the previous four weeks. The imputation was conducted using 100 imputations and 20 iterations. The pooled estimates from these imputations were subsequently used for analysis. The statistical software package SPSS version 19.0 was used for the analyses.

Ethical considerationsWe obtained written consent from all participants after providing them with both oral and written information about the conditions of participating in scientific research in general and with specific details of the AID trial. Age specific consent forms were developed for children and adolescents. Written consent from both custody holders was required and obtained for children aged 11-14 years. Adolescents aged 15-17 years were allowed to decide and give written consent themselves as long as their parents were informed, according to the Danish Committee on Biomedical Research Ethics.

ResultsPatientsBetween November 2007 and March 2010, 305 patients were invited to participate in the trial (figure 1?). During the 29 months, 243 patients (184 women; 76%) were included. The mean age was 31 years in the control group (standard deviation (SD) 12) and 31 years in the intervention group (SD 14; range 11-69 years). Of those included, 67 (28%) were aged 20 years or younger. The only differences between participants at baseline were that patients in the intervention group were more frequently being treated with antidepressants at inclusion (?2 6.76, df 1, P=0.03) and more frequently used narcotics as method of suicide attempt, compared with controls (P=0.05) (table 1?). Self reported data on subsequent events were obtained from 169/243 patients (70%). Significantly more patients provided this information in the intervention group (95/123, 77%) than in the control group (74/120, 62%, ?2 7, df 1; P=0.01).

View larger version:In a new windowDownload as PowerPoint SlideFig 1 The AID trial profile

View this table:View PopupView InlineTable 1 Baseline characteristics of included patients with recent suicide attempt during 2007 to 2010. Values are number (percentage) unless otherwise stated

Service use in the intervention groupThe service offered in the AID-intervention was flexible, with a median of 9 (interquartile range (IQR) 6-12) home consultations including cafe visits, 1 (0-3) attendances to healthcare services, 12 (7-21) phone calls to patients and relatives, and 2.5 (0-5) and 5 (0 to 8) phone calls to healthcare and social services, respectively. The median number of text messages sent was 17 (IQR 8 to 30). In total, 91 crisis interventions were provided. These interventions included phone calls when severe suicidal ideation or impulses were present and emergency calls when either somatic or psychiatric admission was requested. Five patients did not receive the allocated intervention because they withdrew from the study.

Primary outcomeDuring the 12 months’ follow-up, we found that 20/123 (16%) patients in the intervention group had been registered in hospital records with subsequent attempts, compared with 13/120 (11%) in the control group (odds ratio (OR) 1.60, 95% confidence interval 0.76 to 3.38; P=0.22 (table 2?). Adjusting the primary analysis with the use of antidepressants at baseline did not markedly alter the results (1.67, 0.78 to 3.58; P=0.19). Our analysis suggested no association between antidepressants and allocation (P=0.48).

View this table:View PopupView InlineTable 2 Number of patients with subsequent suicide attempt at one year follow-up, by source of data on new events and by subgroup. Values are number of patients with one or more new events/number in group with available data (percentage) unless otherwise stated

By contrast, self reported data on new events showed 11/95 (12%) in the intervention group versus 13/74 (18%) in the control group (OR 0.61, 95% confidence interval 0.26 to 1.46; P=0.27; table 2). Seven patients (four in the intervention group versus three in standard care) were identified with a subsequent suicide attempt in the hospital records although the patients themselves had reported none. Correspondingly, nine patients (one in the intervention group versus eight in standard care) themselves reported subsequent attempts that were not listed in the hospital records. Analysis of missing self reported data based on baseline information about relevant risk factors (sex, age, unemployment, suicide attempts prior to index attempt, prior psychiatric admission, and alcohol consumption at index attempt) assumed data were missing at random. By imputing missing data on the self reported outcome as described above we estimated 15/123 (12%) in the intervention group and 23/120 (19%) in the control group (OR=0.69, 95% confidence interval 0.34 to 1.43; P=0.32; table 2).

We identified two deaths due to causes other than suicide; one in the intervention group and one in the control group. One patient died by suicide in the intervention group within two weeks of the index attempt.

Combining the self reported outcome with the hospital records in post-hoc analyses did not markedly alter results (OR=0.97; 95% confidence interval 0.50 to 1.89; P=0.93).

Additional analyses using attendance to healthcare services as the outcome did not show more health care contacts by participants in the intervention compared with the standard group (OR=0.57 95% confidence interval 0.29 to 1.14; P=0.11). Similarly, attendance to social services was similar between in the two groups (1.01, 0.61 to 1.68; P=0.96).

Subgroup analysisA separate subgroup analysis conducted by age group showed no impact of age on estimated effects of the intervention (table 2). Subgroup analyses by sex and by diagnoses of mild to moderate depression and personality disorders did not obtain differences in effects.

DiscussionPrincipal findingsThis pragmatic, randomised controlled clinical trial investigated the effect of assertive outreach as a preventive treatment strategy for patients with a recent suicide attempt. The trial did not find any significant difference in repetition rates between the group receiving the intervention and the group receiving standard treatment. We noted a difference between register data and self reported data for subsequent suicide attempts, especially in the control group. The AID trial has contributed to international research by investigating an assertive approach demanded by experts and clinicians.

Strengths and weaknesses of the trialA strength of the trial was the randomised design and high methodological quality, associated with a low risk of bias.29 The robustness was increased by a relatively large sample size and use of detailed register data to ensure that no patients were lost to follow-up. The frequency of assertive consultations and service use suggest that patients accepted the experimental intervention by adhering to the approach. The study covered a heterogeneous population, including patients with alcohol and substance abuse problems, and those diagnosed with borderline personality disorder and various other diagnoses. Both these groups are at high risk,12 33 often with limited or already rejected treatment opportunities. The trial population was therefore similar to that seen in clinical reality, leading to high external validity of the study. Since patients diagnosed with schizophrenia spectrum disorders were excluded, the findings do not apply to these patients, but they do apply to other groups of high risk patients without psychosis.

The lack of a manual based approach for the AID intervention and the presence of various kinds of after-treatment modalities in both study groups makes replication less feasible and could affect the internal validity. Marked distinctions between the standard and intervention approaches were the assertiveness, the accessibility, and the active assistance of patients to scheduled appointments in the intervention group; these parts were all thought to be substantially relevant for this patient group.18 23 24 25 The standard treatment offered by the Centre of Excellence in Suicide Prevention Copenhagen improved during the study period and is judged to be after-treatment of good quality. As the AID intervention was an add-on, the standard treatment was also offered to patients in the intervention group, thus avoiding risk of bias. Although the study groups were located in different settings, contamination of standard treatment cannot be excluded. Different motivational factors might explain the lack of a difference between the groups in attendance of health and social services. During the study period, the Danish government’s requirements for receiving sick leave benefits included mandatory frequent contact with social services; if citizens did not attend scheduled appointments, they risked losing their sick leave benefits. Also, social services often require medical documentation in order to issue sick leave benefits. Figures of attendance to health and social services in the control group do not show whether patients were adherent to service requirements.

The significantly higher proportion of patients prescribed antidepressants at baseline in the intervention group could constitute a source of bias. These patients might represent a group with more severe mental illness who might also be more difficult to prevent from subsequent suicidal behaviour.18 On the other hand, patients already receiving drug treatment might, arguably, be less depressed than those not receiving pharmacotherapy.18 20 However, the analysis adjusting for this potential confounder found no indication of bias.

The relatively wide age range of the study population, which included teenagers and older people as well as people of both sexes, could be considered a potential limitation owing to the varied needs and help seeking behaviours of different groups. However, our subgroup analyses showed no effect of age or sex on the findings. The recorded rate of subsequent suicide attempts among males was slightly higher in the intervention group than in the standard group, which might give rise to speculation that males in the standard group were less inclined to seek help, leading to detection bias. However, the difference in rates between the groups was not significant.

We expected that adherence to the AID intervention would reduce subsequent suicide attempts. However, we also expected that the intervention would encourage participants to seek contact more frequently, which could have increased the likelihood that subsequent attempts were reported. The higher repetition rate shown in the hospital records might suggest that patients in the intervention arm, after subsequent attempts, called the AID manager, who then provided emergency arrangements. The weakening of differences in effect when self reported information was added to the analysis adds to this argument.10

The power calculation, in which we estimated a repetition risk of 30% in the standard group and 15% in the intervention group, could be judged to be too optimistic. The calculation relied on rates recorded in past European studies13 34 but might not have been powered to detect smaller differences such as those present in this trial.

There was disagreement between the two data sources over the number of suicide attempts. The clinical decision to classify a self inflicted episode as a suicide attempt corresponding to a diagnosis in hospital records is often not consistent. Also, in the acute phase of treating the trauma, diagnoses from emergency departments do not always reflect the suicidal dimension of the event,3 unless the risk of suicide is ongoing. The WHO definition of suicide attempt used in this trial also leaves room for interpretation; although a blinded external evaluation committee examined doubtful cases in detail, a small number of false positives was unavoidable, especially since the medical records in some cases provided limited information. The dissonance in number of suicide attempts between the two data sources could also have been due to differences between the groups in the participants’ perception of their own need or attitudinal barriers—for example, the wish to handle problems alone, which is related to lower tendency for help seeking behaviours.35 36 37 Furthermore, some patients might not be completely truthful about subsequent suicide attempts in order to perform well when interviewed by the researcher, hence a risk of performance bias. On the other hand, patients who reported subsequent attempts but had no hospital record of such an event might have preferred to avoid hospital contact, because they feared being registered and potentially stigmatised later on. These factors reflect a risk in this trial of detection bias related to both underestimation and overestimation.

The multiple imputations indicated a potential underestimation based on self reported data.29 However, given that suicidal patients tend to display a lack of treatment seeking behaviour, self reported data might actually have a higher validity than register data.

Restrictions by the Danish Data Protection Agency did not allow analysis of information on patients who refused to participate in the trial. Because the inclusion criteria were pragmatic, we did not expect this to affect the external validity.

Previous studies have recommended a structured risk assessment as an important tool in suicide prevention.22 Although suicidal behaviour was routinely addressed as a pivotal point of all consultations in the AID intervention, no formal risk assessment tool was used besides the development of crisis intervention plans and individual psychoeducation.

Comparison with other studiesThe result of the present trial are similar to those presented in reviews of psychosocial interventions in general.18 19 20 However, a study of a similar intervention by Hvid and colleagues did find an effect.27 The differences in baseline characteristics between that trial and the AID trial suggest that our study included more patients with previous suicide attempts and former psychiatric contacts. The study populations might have differed, therefore, in severity of mental illness. However, Hvid and colleagues did not provide information on diagnosis, and data on service use were only provided for the intervention group. Interestingly, both trials used same inclusion and exclusion criteria and were conducted within a few years and a radius of 5 km. The most likely explanation for the difference in effects seems to be type one error, or that the standard treatment offered in the previous study was less intensive. Standard treatment in the previous study mainly consisted of standard care in general practice, whereas the current study was able to offer an enhanced treatment through the Centre of Excellence during the AID trial.

Baseline characteristics of the current sample resembled populations in international studies; for instance, three quarters of those who attempted suicide were women,6 one quarter were of younger age (<20 years),8 9 38 and overdose was the most frequent method.6 16 Based on post-hoc analysis, the combined repetition rates based on medical records and self reported data were estimated to be 17% for the intervention group and 18 % in the standard, respectively, which corresponded to repetition rates previously outlined in international reviews.10 11 12

Possible explanations and implications for clinicians and policymakersAlthough experts, clinicians, and patients have called for an assertive approach to suicide prevention, we did not find evidence to recommend such a strategy. However, the complexity of suicidal behaviour might not be addressed adequately by accompanying patients to after-treatment if waiting lists are extensive, or if the treatment modalities are not evidence-based. By comparison with other settings, the standard treatment in our trial was of good quality, and this could affect the external validity. However, the repetition rate among recipients of standard treatment was still very high. We do not believe, therefore, that the threshold for improvements has been reached. It would have been appropriate and interesting to rate patients on relevant suicidal scales (for example, for depressive symptoms, substance abuse, and self efficacy) at baseline and follow-up, to detect any difference in secondary outcomes in relation to treatment modalities.

Extensive information is available on risk factors for suicidal behaviour,6 10 39 but less is known about recommendations for psychosocial treatment.19 20 Evidence of benefit has been shown for cognitive behaviour therapy21 22 and for psychosocial treatment within a family context for adolescents.40 However, this evidence relates to specific subgroups and has yet to be replicated in heterogeneous populations.

A remarkable relative difference was noted between the number of registered and self reported repeated suicide attempts among patients in the standard treatment. Suicide attempts are probably under recorded in general.1 5 6 However, it is worrisome that these people did not seek help despite being enrolled in an ongoing treatment programme. The estimate of multiple imputations on self reported data suggested that there could be even more patients with subsequent unrecorded events in both groups. The long term consequences of untreated deliberate self harm are unknown, but are certainly a potential risk factor.

Patients attempting suicide constitute a heterogeneous group, differing in age, life conditions, and risk factors. Prevention strategies targeting repeated suicide attempts need to address most of the raised risk factors by providing crisis intervention, being assertive and accessible, and at the same time offering individually shaped support. The AID intervention aimed to incorporate all these essential elements and yet failed to reduce the repetition frequency in a large, representative sample. Future research could target subgroups with even more specialised therapeutic interventions, such as specialised cognitive behavioural therapy, or could focus on primary prevention strategies addressing risk and vulnerability before the first suicide attempt.

What is already known on this topicSuicide attempt is often associated with subsequent suicidal behaviour, but patients can be difficult to engage in after-treatment

A previous study with limited power suggested that assertive and motivational consultations could reduce the rate of repeated suicide attempts

What this study addsThis randomised clinical trial did not find evidence to recommend an assertive intervention over standard care for patients after suicide attempt

Patients allocated to the intervention were more likely than controls to be hospitalised and treated for subsequent suicide attempts

Patients were compliant with the intervention

NotesCite this as: BMJ 2012;345:e4972

FootnotesWe thank all included patients and relatives, intervention staff Agnete Birktoft and Hanne Frandsen, all collaborating partners in intensive units both somatic and psychiatric, Centre of Excellency in Suicide Prevention, social services, external psychiatrists, and psychologists. We thank the investigators Hvid and Wang for their collaboration.

Contributors: MN was primary investigator. BM and MN developed the research protocol, designed the study, acquired funding, carried out the intervention, and gathered data. FA was administrative collaborator and consulting physician for the research assistant. FA, AE, and MN were the blinded external evaluation committee. BM and JK constructed the database and conducted the statistical analysis. All authors contributed to writing and revising the manuscript. BM and MN are guarantors.

Funding: The study received funding from the Ministry of Health and Internal Affairs, Denmark, the National Board of Social Services, an independent subdivision of The Ministry of Social Affairs and Integration, TrygFonden, and Aase og Ejnar Danielsens Foundation.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: the study received funding from the Ministry of Health and Internal Affairs, Denmark, the National Board of Social Services, an independent subdivision of The Ministry of Social Affairs and Integration, TrygFonden, and Aase og Ejnar Danielsens Foundation; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: The trial was approved by the Danish Ethic Committee (journal number KF-01 271146) and by the Danish Data Protection Agency (journal number 2011-41-6398). All participating patients gave written informed consent.

Data sharing: No additional data available.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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Epidemiological studies of suicide and intervention studies in selected risk groups. Faculty of Health Sciences, Copenhagen University Hospital, Psychiatric Center Bispebjerg, 2007.?Schmidtke A, Bille-Brahe U, DeLeo D, Kerkhof A, Bjerke T, Crepet P, et al. Attempted suicide in Europe: rates, trends and sociodemographic characteristics of suicide attempters during the period 1989-1992. Results of the WHO/EURO Multicentre Study on Parasuicide. Acta Psychiatr Scand1996;93:327-38.OpenUrlMedlineWeb of Science?Brent DA, Greenhill LL, Compton S, Emslie G, Wells K, Walkup JT, et al. The treatment of adolescent suicide attempters study (TASA): predictors of suicidal events in an open treatment trial. J Am Acad Child Adolesc Psychiatry2009;48:987-96.OpenUrlCrossRefMedline?Cedereke M, Ojehagen A. Prediction of repeated parasuicide after 1-12 months. Eur Psychiatry2005;20:101-9.OpenUrlCrossRefMedlineWeb of Science?Qin P, Jepsen P, Norgard B, Agerbo E, Mortensen PB, Vilstrup H, et al. 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Feasibility (acceptability, adherence, and effectiveness) of a Baerum-model like aftercare. Nord J Psychiatry2009;63:148-53.OpenUrlCrossRefMedlineWeb of Science?Pagura J, Fotti S, Katz LY, Sareen J. Help seeking and perceived need for mental health care among individuals in Canada with suicidal behaviors. Psychiatr Serv2009;60:943-9.OpenUrlCrossRefMedlineWeb of Science?Bruffaerts R, Demyttenaere K, Hwang I, Chiu WT, Sampson N, Kessler RC, et al. Treatment of suicidal people around the world. Br J Psych2011;199:64-70.OpenUrlFREE Full Text?Gulliver A, Griffiths K, Christensen H. Perceived barriers and facilitators to mental health help-seeking in young people: a systematic review. BMC Psychiatry2010;10:113.OpenUrlCrossRefMedline?Pelkonen M, Marttunen M. Child and adolescent suicide: epidemiology, risk factors, and approaches to prevention. Paediatr Drugs2003;5:243-65.OpenUrlMedline?Bergen H, Hawton K, Waters K, Cooper J, Kapur N. Epidemiology and trends in non-fatal self-harm in three centres in England, 2000 to 2007. Br J Psychiatry2010;197:493-8.OpenUrlFREE Full Text?Daniel SS, Goldston DB. Interventions for suicidal youth: a review of the literature and developmental considerations. 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Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing’s syndrome: cohort study

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Research Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing’s syndrome: cohort study BMJ 2012; 345 doi: 10.1136/bmj.e4928 (Published 30 July 2012) Cite this as: BMJ 2012;345:e4928 Drugs: cardiovascular system Epidemiologic studies Stroke Screening (epidemiology) Screening (public health) More topics

Chemotherapy Health education Health promotion Ischaemic heart disease Smoking Smoking and tobacco Fewer topics

Article Related content Read responses (1) Article metrics Laurence Fardet, associate professor and senior consultant in internal medicine1234, Irene Petersen, principal research associate in statistics and epidemiology4, Irwin Nazareth, professor in primary care and population sciences and senior academic general practitioner14
1MRC General Practice Research Framework, University College London Medical School, London, UK
2AP-HP Hospital Saint-Antoine, Service de Médecine Interne, Paris, France
3Université Pierre et Marie Curie, UPMC Paris 6, Faculté de Médecine, Paris, France
4Research Department of Primary Care and Population Health, University College London Medical School, London, UKCorrespondence to: L Fardet laurence.fardet{at}sat.aphp.frAccepted 6 July 2012AbstractObjective To investigate whether there is an increased risk of cardiovascular events in people who exhibit iatrogenic Cushing’s syndrome during treatment with glucocorticoids.

Design Cohort study.

Setting 424 UK general practices contributing to The Health Improvement Network database.

Participants People prescribed systemic glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome (n=547) and two comparison groups: those prescribed glucocorticoids and with no diagnosis of iatrogenic Cushing’s syndrome (n=3231) and those not prescribed systemic glucocorticoids (n=3282).

Main outcome measures Incidence of cardiovascular events within a year after diagnosis of iatrogenic Cushing’s syndrome or after a randomly selected date, and association between iatrogenic Cushing’s syndrome and risk of cardiovascular events.

Results 417 cardiovascular events occurred in 341 patients. Taking into account only the first event by patient (coronary heart disease n=177, heart failure n=101, ischaemic stroke n=63), the incidence rates of cardiovascular events per 100 person years at risk were 15.1 (95% confidence interval 11.8 to 18.4) in those prescribed glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome, 6.4 (5.5 to 7.3) in those prescribed glucocorticoids without a diagnosis of iatrogenic Cushing’s syndrome, and 4.1 (3.4 to 4.8) in those not prescribed glucocorticoids. In multivariate analyses adjusted for sex, age, intensity of glucocorticoid use, underlying disease, smoking status, and use of aspirin, diabetes drugs, antihypertensive drugs, lipid lowering drugs, or oral anticoagulant drugs, the relation between iatrogenic Cushing’s syndrome and cardiovascular events was strong (adjusted hazard ratios 2.27 (95% confidence interval 1.48 to 3.47) for coronary heart disease, 3.77 (2.41 to 5.90) for heart failure, and 2.23 (0.96 to 5.17) for ischaemic cerebrovascular events). The adjusted hazard ratio for any cardiovascular event was 4.16 (2.98 to 5.82) when the group prescribed glucocorticoids and with iatrogenic Cushing’s syndrome was compared with the group not prescribed glucocorticoids.

Conclusion People who use glucocorticoids and exhibit iatrogenic Cushing’s syndrome should be aggressively targeted for early screening and management of cardiovascular risk factors.

IntroductionAbout 1% of the general population are long term users of systemic glucocorticoids1 2 and about two thirds exhibit iatrogenic manifestations related to excessive exposure to glucocorticoids,3 many after only a few weeks or months of use. Although iatrogenic Cushing’s syndrome may vary in intensity and clinical presentation (the characteristic muscular or cutaneous disorders may be present or absent for example), the condition is mostly characterised by a typical “cushingoid adiposity,” reflecting less weight gain than abnormalities of adipose tissue distribution, with hypertrophy of adipose tissue in the face (“moon face”), dorsocervical region (“buffalo hump”, double chin, accumulation of fat in the supraclavicular area), and abdomen (”pendulum” abdomen) and thinning of the subcutaneous adipose tissue of the limbs.4 This typical redistribution of the adipose tissue induced by glucocorticoids can be considered as an iatrogenic form of lipodystrophy.5

It is known that the glucocorticoid induced morphological changes are associated with cardiovascular risk factors such as high blood pressure, blood glucose and triglyceride levels, and low high density lipoprotein cholesterol levels,6 and that many forms of lipodystrophy are associated with metabolic disorders and premature atherosclerosis.7 8 9 10 We therefore hypothesised that the increased risk of cardiovascular events observed in people treated with glucocorticoids11 12 13 is strongly associated with those who develop iatrogenic Cushing’s syndrome compared with those who do not.

MethodsAbout 98% of the population in the United Kingdom is registered with a general practitioner.14 The Health Improvement Network (THIN) is a database of electronic medical records from UK general practices. Participating general practitioners systematically and prospectively retrieve and enter clinical information on patients, including personal data, diagnoses, and prescriptions so that the database provides a longitudinal medical record for each patient. All sections of the population are represented in THIN. The data are collected in a non-interventional way during routine general practice and therefore reflect “real life” clinical care. The information is continually updated. Information from secondary care and other medically related information received by the practice is transcribed and entered retrospectively. Prescribing by general practitioners is particularly well recorded since the computerised entry made by the doctor is also used as the prescription form. Previous comparison with external statistics and other independent studies have shown that both the clinical diagnostic and prescribing information are well recorded and accurate.15 16 17 18 THIN, however, represents data collected from the general practitioner’s medical records and reflects only those events that are deemed to be relevant to the patient’s care and not for research purposes. In most cases a medicine prescribed for the first time is temporally linked with a medical event record (symptom or diagnosis), but no permanent link exists between a prescribed treatment and the reason for prescription. Drugs prescribed by hospital doctors or other specialists do not appear in THIN data unless the treatment is to be continued by the general practitioner. However, due to the constraints of specialist and hospital prescribing budgets many prescriptions issued outside of the general practice are sufficient to cover only the first seven days. After this time the patient usually obtains subsequent prescriptions from their general practitioner. Lastly, some of the drugs used in the United Kingdom are obtained over-the-counter so are not entered in general practitioner records. For this study we used data from 1 January 1990 to 31 December 2008 from 424 general practices and we excluded events that occurred within six months after registration to include only incident cases of outcomes.19

Prescriptions of glucocorticoidsEach prescription of a drug is recorded in THIN as encrypted multilex codes, along with reference to the chapter in the British National Formulary describing the drug.20 We selected all glucocorticoids prescribed orally or by intramuscular or intravenous injection and this included prednisolone, prednisone, dexamethasone, triamcinolone, betamethasone, methylprednisolone, and deflazacort. We included people aged 18 years and older and identified all who were prescribed such treatment. For multiple consecutive prescriptions we considered that these were part of a unique course of treatment if the gap between two consecutive prescriptions was less than three months. For each course we defined the treatment duration as the time from the first to the last prescription plus the duration of the last prescription. Data on adherence to treatment are not routinely recorded in THIN. To ensure that our samples comprised those people who were most likely taking the drug, we restricted our populations of glucocorticoid users to those who received at least two successive prescriptions for glucocorticoids. We calculated the average daily dosage by multiplying the number of pills prescribed by the dose per pill (calculated in prednisone equivalent) and then divided this by the number of days for which the drug was prescribed. The medical diagnosis recorded on the date of starting glucocorticoids was used as the indication for the prescription. We excluded people taking substitutive glucocorticoids for adrenal insufficiency.

Identification of iatrogenic Cushing’s syndromeAll diagnoses and symptoms are recorded in THIN using the Read classification system.21 Using the method described previously22 we retained four codes to define iatrogenic Cushing’s syndrome: iatrogenic Cushing’s syndrome, drug induced Cushing’s syndrome, steroid facies, and cushingoid facies.

Study groupsWe selected two cohorts from patients recorded in THIN. The first comprised all those prescribed systemic glucocorticoids and the other those who were never prescribed systemic glucocorticoids. Among patients prescribed glucocorticoids, we defined those with a recorded diagnosis of iatrogenic Cushing’s syndrome as the exposed group and those without a recorded diagnosis of iatrogenic Cushing’s syndrome as eligible for inclusion in the first comparison group. Anyone in the second cohort was eligible to be included in the second comparison group, comprising those who had never been prescribed systemic glucocorticoids. When selecting the comparison groups we stratified the samples to ensure the same distribution among groups for sex and age (within 10 year age bands). Additionally, for the first comparison group we stratified the sample to ensure that the distribution for duration of use of glucocorticoids and initial dosage were similar to that of the group prescribed glucocorticoids and with iatrogenic Cushing’s syndrome. Lastly, because of the possible association between indications for treatment with glucocorticoids and cardiovascular disease, in the comparison groups we preferentially selected people with the same underlying diseases as those in the group prescribed glucocorticoids and with iatrogenic Cushing’s syndrome. We selected up to six times as many people in each of the two comparison groups as those in the group prescribed glucocorticoids with iatrogenic Cushing’s syndrome. Patients in both groups were selected at random from the pool of eligible patients. The start of the follow-up period for the analyses was defined by an index date. For those from the group prescribed glucocorticoids with iatrogenic Cushing’s syndrome, this index date was defined as the first record of iatrogenic Cushing’s syndrome. For patients in the comparison groups the index date was randomly selected from within the time they were registered with the general practice. In the case of those prescribed glucocorticoids with no record of iatrogenic Cushing’s syndrome, this period was restricted to that during which they were prescribed the drug.

Covariates of interestWe identified smoking status based on the nearest record before the index date, including data up to five years before this date. For each included patient we extracted clinical data (height, weight, and blood pressure) and biological data (fasting glucose, total cholesterol, and triglycerides levels) from his or her medical records. Data were collected for two periods: in the six months before the index date and in the six months after the index date. Moreover, we searched the drug treatment files for relevant prescriptions. If patients had at least two prescriptions for either diabetes drugs, antihypertensive drugs, cholesterol lowering drugs, oral anticoagulants, or antiplatelet drugs we defined them as being treated with that particular drug. To ascribe the hazard of cardiovascular events to the presence of iatrogenic Cushing’s syndrome, we examined the risk of some diseases which were a priori not related to Cushing’s syndrome. For cardiovascular disorders we searched for valvular heart diseases. For non-cardiovascular events, we defined impacted cerumen in the ear (one of the most common diagnoses recorded in THIN), sprain, and neoplasm (malignant neoplasm of digestive organs, skin, breast, or genitourinary organ) as negative control diseases.

Identification of cardiovascular eventsUsing the same method as for iatrogenic Cushing’s syndrome, we developed Read code lists to identify recorded diagnoses of either coronary heart disease, heart failure, or ischaemic cerebrovascular events. To exclude a possible but not confirmed diagnosis we only selected stringent codes—for example, acute myocardial infarction, cardiac failure, transient cerebral ischaemia, stroke. Moreover, we also examined anonymised free text associated with records of death to capture fatal events that may not have been recorded by Read codes.

Statistical analysisIn each group we calculated the incidence of cardiovascular events within the first year after the index date by dividing the number of newly diagnosed cases by the follow-up time up to one year after the index date. If patients had several events we censored them at their first event. We compared the three groups to assess hazard ratios associated with iatrogenic Cushing’s syndrome. We adjusted the estimated hazard ratio for age (continuous variable); sex; underlying disease; smoking status; history of prescription for aspirin, oral anticoagulants, diabetes drugs, antihypertensive drugs, or cholesterol lowering drugs; and initial dosage (continuous variable) and duration (continuous variable) of glucocorticoid use for people prescribed the drug. Using Cox proportional hazards models we accounted for clustering at the general practice level. Proportional hazard assumptions were checked graphically and by analysing Schoenfeld residuals. We checked linearity for continuous variables by comparing two models, one with the linear term and the other with the categories, using the log likelihood ratio test. Continuous variables are presented as medians and 25th to 75th centile values. Categorical variables are presented as proportions, with 95% confidence intervals indicating precision of estimates. Incidence rates are reported per 100 person years at risk. All analyses were done using Stata, version 11.1.

ResultsA diagnosis of iatrogenic Cushing’s syndrome was found in the medical records of 585 people. Among these patients, 38 (6.5%) were prescribed glucocorticoids at some point in their medical history but as they were not receiving them at the time iatrogenic Cushing’s syndrome was recorded they were not included in the analyses. The 547 remaining patients prescribed glucocorticoids and with iatrogenic Cushing’s syndrome were mainly women (n=391, 71.5%), with a median age of 64.7 (interquartile range 51.1-74.4) years (table 1?). The group prescribed glucocorticoids but without iatrogenic Cushing’s syndrome and the group not prescribed glucocorticoids were made up of 3231 patients (women: 2301 (71.2%), median age 64.3 (interquartile range 51.0-74.4) years) and 3282 patients (women: 2346 (71.5%), median age 63.7 (50.9-74.4) years), respectively (table 1). Table 2? lists their baseline clinical and biological characteristics and changes in the variables over time. Six months after the index date, people with a diagnosis of iatrogenic Cushing’s syndrome had higher body mass index, higher blood pressure, and higher fasting glucose, total cholesterol, and triglyceride levels than people from the two comparison groups. Moreover, within the year after the index date they were more likely to be prescribed antihypertensive and diabetes drugs (table 3?).

View this table:View PopupView InlineTable 1 Baseline characteristics of patients. Values are numbers (percentages) of participants unless stated otherwise

View this table:View PopupView InlineTable 2 Variations in body mass index, blood pressure, and laboratory test results over time in relation to index date

View this table:View PopupView InlineTable 3 Initiation of treatments within year after index date (up to date of cardiovascular event). Values are numbers (percentages) of participants unless stated otherwise

Incidence of cardiovascular eventsOverall, 417 cardiovascular events were recorded within the year after the index date in 341 patients. Taking into account only the first cardiovascular event by patient, coronary heart disease was the most common (n=177, 52%) followed by heart failure (n=101, 30%) and cerebrovascular events (n=63, 18%, table 4?). The incidence of cardiovascular events was higher in the group prescribed glucocorticoids with iatrogenic Cushing’s syndrome (incidence rate per 100 person years at risk 15.1, 95% confidence interval 11.8 to 18.4) than in the group prescribed glucocorticoids but without iatrogenic Cushing’s syndrome (6.4, 5.5 to 7.3) or in the group not prescribed glucocorticoids (4.1, 3.4 to 4.8, figure?).

View larger version:In a new windowDownload as PowerPoint SlideKaplan-Meier survival curves showing cumulative incidence of cardiovascular events over time in the three study groups

View this table:View PopupView InlineTable 4 Recorded codes for cardiovascular events within year after index date

Association between iatrogenic Cushing’s syndrome and cardiovascular eventsCompared with the group prescribed glucocorticoids without iatrogenic Cushing’s syndrome, the adjusted overall hazard ratio of developing a cardiovascular event for those prescribed glucocorticoids with iatrogenic Cushing’s syndrome was 2.74 (95% confidence interval 2.06 to 3.62, table 5?). Analyses by the type of outcome indicated that patients prescribed glucocorticoids with iatrogenic Cushing’s syndrome were at higher risk of coronary heart disease and cardiac insufficiency than those prescribed glucocorticoids without iatrogenic Cushing’s syndrome (table 5). Patients prescribed glucocorticoids with iatrogenic Cushing’s syndrome had a higher adjusted hazard ratio of any cardiovascular events (4.16, 2.98 to 5.82) compared with those not prescribed glucocorticoids (table 5). The results were similar when people with a history of cardiovascular events (n=1004) were excluded from the analyses: adjusted hazard ratios of all cardiovascular events 2.56 (1.66 to 3.94) compared with patients prescribed glucocorticoids without iatrogenic Cushing’s syndrome and 4.26 (2.49 to 7.29) compared with the group not prescribed glucocorticoids.

View this table:View PopupView InlineTable 5 Adjusted hazard ratios (95% confidence intervals) of cardiovascular events in patients with iatrogenic Cushing’s syndrome

Risk of negative control diseasesCompared with patients prescribed glucocorticoids and without iatrogenic Cushing’s syndrome, those with a diagnosis of iatrogenic Cushing’s syndrome were not at higher risk for any of the diseases chosen as negative controls (table 6?). Compared with people not prescribed glucocorticoids, those prescribed glucocorticoids with iatrogenic Cushing’s syndrome were at higher risk of a diagnosis of malignant neoplasm.

View this table:View PopupView InlineTable 6 Risk of negative control diseases in patients with iatrogenic Cushing’s syndrome

DiscussionPatients prescribed systemic glucocorticoids who developed iatrogenic Cushing’s syndrome had nearly a three times greater risk of cardiovascular disease, including coronary heart disease, heart failure, and cerebrovascular disease than patients prescribed glucocorticoids who were not known to have developed a cushingoid appearance. This risk increased to over fourfold in comparison with people not prescribed glucocorticoids. These results raise the question of whether glucocorticoids increase the risk of cardiovascular events in all patients or only in those who develop iatrogenic Cushing’s syndrome.

Comparison with other studiesGlucocorticoid treatment is associated with an increased risk of cardiovascular events11 12 13 and there is a reasonable clinical and biological basis on which to hypothesise that this risk is higher in people who develop a cushingoid appearance. Firstly, even though no consensual definition exists, the diagnosis of iatrogenic Cushing’s syndrome is mostly based on a typical distribution of the adipose tissue. Indeed, many people prescribed glucocorticoids do not just gain weight, they also present with localised hypertrophy of adipose tissue including the typical “moon face,” double chin, “buffalo hump,” “bull neck,” or “pendulum” abdomen. This central hypertrophy of adipose tissue is probably associated with a concomitant thinning of the subcutaneous adipose tissue of the limbs.4 This typical cushingoid adiposity is associated with metabolic disorders such as high blood pressure, high fasting blood glucose and triglycerides levels, and low high density lipoprotein cholesterol levels.6 Secondly, the glucocorticoid induced redistribution of adipose tissue can be considered as a form of iatrogenic lipodystrophy.5 Many forms of lipodystrophy have been associated with a high risk of type 2 diabetes, hypertension, dyslipidaemia, and premature atherosclerosis7 8 9 10 23 24 and it has been shown that people with the Dunnigan-type lipodystrophy have almost a six times increased risk of coronary heart disease compared with controls.8 Lastly, glucocorticoid induced Cushing’s syndrome and the metabolic syndrome share clinical (for example, central adiposity) and biological (for example, dysglycaemia, dyslipidaemia, hypertension) features, and multiple lines of evidence link disordered glucocorticoid metabolism to the metabolic syndrome.25 Central obesity has been suggested to reflect “Cushing’s disease of the omentum,” and the metabolic syndrome a mild form of Cushing’s syndrome.25 26

In daily practice some patients who are adherent to glucocorticoids will never exhibit a cushingoid appearance, whereas some others develop severe cushingoid adiposity after only a few days or weeks of treatment. In a previous prospective study of patients prescribed glucocorticoids for vasculitis or connective tissue diseases, we found that some patients’ characteristics (for example, female sex, younger age, baseline higher body mass index) were strongly associated with an increased risk of abnormalities of adipose tissue distribution.6 27 In another prospective study, the baseline level of some adipokines (for example, leptin, resistin) was found to be predictive of the occurrence of central adipose tissue hypertrophy in people taking glucocorticoids.28 In these studies the biological inflammatory markers improved both in patients who developed a cushingoid appearance during follow-up and in those who did not, indirectly reflecting a relatively similar level of adherence to glucocorticoids. If some patients without cushingoid adiposity are probably poorly adherent to glucocorticoids, it is noteworthy that the presence of morphological changes is not synonymous with optimal adherence to the drug as some patients with a cushingoid appearance report being poorly adherent to glucocorticoids.29

Multiple pathways may be involved in the increased risk of cardiovascular events in people who develop iatrogenic Cushing’s syndrome.30 Some well known cardiovascular risk factors, such as hypertension, hyperglycaemia, and dyslipidaemia, are more commonly observed in those people, probably because of an increase of visceral obesity.31 However, the development of cardiovascular disease may also be related to some mechanisms other than the metabolic syndrome or insulin resistance. For instance, we found that patients with iatrogenic Cushing’s syndrome were at high risk of heart failure. Heart failure could represent a chronic complication of increased cardiometabolic risk but its evolution would be expected to be more chronic than the time course of the current observations. It is thus possible that other mechanisms besides atherosclerosis are involved. Cardiac abnormalities, including cardiomegaly, dilated cardiomyopathy, and congestive heart failure are frequent findings in people with congenital and acquired generalised lipodystrophy, but the mechanisms involved in the development of these conditions are unclear.32 Previous research in patients with impaired glucose tolerance or type 2 diabetes has suggested that accumulation of triglycerides in the myocardium can cause cardiac steatosis, which is associated with impaired left ventricular filling dynamics.33 34 35 Patients with lipodystrophy have ectopic accumulation of fat in organs such as liver and muscle, but whether fat is deposited in the myocardium of these patients remains to be assessed. Moreover, a hypercoagulability state has been reported in patients with endogenous Cushing’s syndrome.36

Strengths and weaknesses of the studyOur study has several strengths. We used a large population based sample of patients of both sexes and across all age groups. Moreover, the underlying disease had to be taken into account in the analyses since many diseases for which systemic glucocorticoids are indicated (asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, giant cell arteritis) may be associated by themselves with an increased risk of cardiovascular disease.37 38 39 40 The number of patients included in the study enabled analyses to be adjusted for underlying disease and other potential confounders such as drug prescriptions. In our study the two groups of patients treated with glucocorticoids differed essentially by an entry of iatrogenic Cushing’s syndrome in their medical records. Both groups were treated for a similar duration and with a similar dosage of glucocorticoids, and they had comparable underlying diseases. Hence the heightened risk of cardiovascular events observed in patients with iatrogenic Cushing’s syndrome was not due to indication bias as might have been determined by the disease. Moreover, we accounted for clustering at the general practice level since we thought that doctors who are more likely to record iatrogenic Cushing’s syndrome may also be ones more likely to record other outcomes such as cardiovascular events. Lastly, we found than the risk of negative control diseases was not higher in people with iatrogenic Cushing’s syndrome than in people without iatrogenic Cushing’s syndrome, which reinforces the relation between morphological changes and cardiovascular events.

Our study does, however, have some limitations. Firstly, even though it was likely that the iatrogenic Cushing’s syndrome recorded by doctors mostly reflected abnormalities of adipose tissue distribution, our study did not assess fat distribution using reference methods such as dual x ray absorptiometry, tomodensitometry, or magnetic resonance imaging. Secondly, iatrogenic Cushing’s syndrome is not always recorded by doctors, and some milder forms were more than likely not recorded. For this reason, some patients prescribed glucocorticoids with no recorded diagnosis of iatrogenic Cushing’s syndrome may have been subject to misclassification. This potential classification bias could have led to an underestimation of the effect of morphological changes on the risk of cardiovascular disease. On the other hand, it could be hypothesised that only the most severe forms of iatrogenic Cushing’s syndrome were recorded. Thirdly, no data were available on adherence to glucocorticoids. However, the frequency and dosage of glucocorticoid prescribing (duration of use, initial daily dosage, number of prescriptions during a treatment course) were similar in the two groups prescribed glucocorticoids, indicating that, on average, the level of adherence to the drug was probably quite similar between the groups. Another potential limitation is that some variables of interest could not be assessed because too few data were available during the periods of interest (for example, levels of high or low density lipoprotein cholesterol, waist to hip ratio) or because they were not routinely recorded in the database, such as exercise. Lastly, since THIN has no data on the resolution of diseases or symptoms, we were unable to ascertain whether the iatrogenic Cushing’s syndrome persisted or disappeared after stopping glucocorticoids. We therefore focused merely on the first year after the index date to estimate the cardiovascular risk in people actually exhibiting morphological changes.

Conclusions and policy implicationsOverall, we believe that a glucocorticoid induced cushingoid appearance should no longer be considered as a minor adverse event of glucocorticoids. It has been reported by patients as the most distressing adverse event affecting daily living and is associated with some features of the metabolic syndrome.3 6 Furthermore, we found that it is associated with a higher risk of cardiovascular events, particularly heart failure and coronary heart disease. It is therefore essential that patients prescribed glucocorticoids who develop iatrogenic Cushing’s syndrome are assessed for cardiovascular risk and monitored regularly in both primary care and secondary care for early prevention of cardiovascular diseases.

What is already known on this topicAbout 1% of the general population use systemic glucocorticoids long term

Glucocorticoids are associated with an increased risk of cardiovascular events

Many people taking glucocorticoids develop iatrogenic Cushing’s syndrome and such people are at higher risk of metabolic disorders

What this study addsThe risk of cardiovascular events in people treated with glucocorticoids is nearly three times greater in those who develop iatrogenic Cushing’s syndrome

This raises the question of whether glucocorticoids increase the risk of cardiovascular events in all users or only in those with iatrogenic Cushing’s syndrome

People treated with glucocorticoids who develop iatrogenic Cushing’s syndrome should be aggressively targeted for early screening and management of cardiovascular risk factors

NotesCite this as: BMJ 2012;345:e4928

FootnotesContributors: LF had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. LF did the statistical analyses and wrote the manuscript. IP supervised the statistical analyses and contributed to writing the manuscript. IN contributed to writing the manuscript. All authors designed the study and interpreted the data.

Funding: This study received no funding.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: This study was approved by the University College London THIN steering committee and by the THIN scientific review committee.

Data sharing: No additional data available.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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