Clara Goulas

Laura Lohan

Marion Laureau

Damien Perier

Véronique Pinzani

Marie Faucanie

Valérie Macioce

Grégory Marin

Isabelle Giraud

Maxime Villiet

Mustapha Sebbane

Cyril Breuker
email: c-breuker@chu-montpellier.fr

Errors in the Medication History and the Impact on Adverse Drug Event Detection

Keywords: adverse drug event, medication history, emergency department, pharmacist

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Adverse drug events (ADEs) are defined as any injury occurring to patients in relation to their medication management and resulting from appropriate care, inappropriate care or care deficit [START_REF] Bates | Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group[END_REF][START_REF] Nebeker | Clarifying adverse drug events: A clinician's guide to terminology, documentation, and reporting[END_REF]. This definition includes injuries (signs, symptoms or laboratory abnormalities) resulting from adverse drug reactions (ADRs), or non-compliance with medication prescriptions [START_REF] Naranjo | A method for estimating the probability of adverse drug reactions[END_REF]. Given their human and medico-economic impacts, and their role in unfavorable clinical evolution, ADEs are currently a major public health problem [START_REF] Khan | Comparative epidemiology of hospital-acquired adverse drug reactions in adults and children and their impact on cost and hospital stay-A systematic review[END_REF][START_REF] Hohl | Outcomes of emergency department patients presenting with adverse drug events[END_REF][START_REF] Lahue | National burden of preventable adverse drug events associated with inpatient injectable medications: Healthcare and medical professional liability costs[END_REF]. According to the literature, the ADE incidence ranges from 2 to 21% in inpatients [START_REF] Martins | Adverse drug events among adult inpatients: A meta-analysis of observational studies[END_REF], and from 5 to 35% in outpatients [START_REF] Tache | Prevalence of adverse drug events in ambulatory care: A systematic review[END_REF]. ADEs are the leading cause of unplanned admissions and death in hospitals [START_REF] Bailey | Adverse drug event reporting systems: A systematic review[END_REF][START_REF] Queneau | Association Pedagogique Nationale pour l'Enseignement de la, Emergency department visits caused by adverse drug events: Results of a French survey[END_REF][START_REF] Budnitz | Emergency hospitalizations for adverse drug events in older Americans[END_REF]. According to the longitudinal, prospective study on ADE incidence (ENEIS-3) conducted in France in 2019, between 176,000 and 372,000 stays are caused annually by ADEs, including 93,000 to 197,000 stays caused by avoidable ADEs [START_REF]Incidence des Événements Indésirables Graves Associés aux Soins Dans les Établissements de Santé (Eneis 3): Quelle Évolution dix ans Après[END_REF]. If we focus on emergency departments (ED), several teams that were trained to detect ADEs found up to 25% of patients with ADEs in EDs in France [START_REF] Roulet | Implementing a clinical pharmacy survey of adverse drug events in a French emergency department[END_REF] and abroad [START_REF] Budnitz | Emergency hospitalizations for adverse drug events in older Americans[END_REF]. In order to limit readmissions, it is necessary to detect these ADEs and review the drug treatments. However, ADEs are difficult to detect within the ED [START_REF] Hohl | Do emergency physicians attribute drug-related emergency department visits to medicationrelated problems?[END_REF][START_REF] Stergiopoulos | A Survey of Adverse Event Reporting Practices among US Healthcare Professionals[END_REF][START_REF] Hazell | Under-reporting of adverse drug reactions: A systematic review[END_REF]. Most ED physicians have minimal to modest success in identifying ADEs [START_REF] Hazell | Under-reporting of adverse drug reactions: A systematic review[END_REF][START_REF] Howe | A review of the Office of Inspector General's reports on adverse event identification and reporting[END_REF]. One of the main reasons for this is incomplete or unavailable medication histories [START_REF] Hohl | Can reporting of adverse drug reactions create safer systems while improving health data?[END_REF]. According to the literature, a vast majority of medication histories contain at least one error, particularly in EDs [START_REF] Shepherd | Frequency of incomplete medication histories obtained at triage[END_REF][START_REF] Mazer | Medication history taking in emergency department triage is inaccurate and incomplete[END_REF][START_REF] Tam | Frequency, type and clinical importance of medication history errors at admission to hospital: A systematic review[END_REF][START_REF] Caglar | Emergency department medication lists are not accurate[END_REF]. A loss of information about drug treatment between health professionals and the transition points in the patient's care pathway, such as an outpatient's entrance to the ED or the transfer of a patient from the ED to a hospital unit, is the main cause for these errors [START_REF] Hohl | Do emergency physicians attribute drug-related emergency department visits to medicationrelated problems?[END_REF][START_REF] Boockvar | Prescribing discrepancies likely to cause adverse drug events after patient transfer[END_REF]. These errors in medication history prevent physicians from establishing the link between the symptomatology and the medication, and therefore, from detecting ADEs. Moreover, these medication errors pose a potential danger to the patient. According to the national drug safety agency (ANSM, Agence Nationale de Sécurité du Médicament et des Produits de Santé), a medication error is the unintentional omission or unintended performance of an act during the care process involving a drug, which may result in a risk or adverse event for the patient [START_REF]Qu'est ce Qu'une Erreur Médicamenteuse[END_REF]. The introduction of medication reconciliation enables the correction of errors in medication histories, and thus both reduces the risk of medication errors and may improve ADE detection. It has been shown that pharmacists and pharmacist-technicians are among the most effective healthcare professionals for performing medication reconciliation [START_REF] Breuker | Patients with diabetes are at high risk of serious medication errors at hospital: Interest of clinical pharmacist intervention to improve healthcare[END_REF][START_REF] Lancaster | Impact of students pharmacists on the medication reconciliation process in high-risk hospitalized general medicine patients[END_REF][START_REF] Mathys | Effect of pharmacy students as primary pharmacy members on inpatient interdisciplinary mental health teams[END_REF][START_REF] Mergenhagen | Pharmacist-versus physician-initiated admission medication reconciliation: Impact on adverse drug events[END_REF][START_REF] Arrison | Comparing medication histories obtained by pharmacy technicians and nursing staff in the emergency department[END_REF]. It has also been shown that a clinical pharmacist positioned within the ED medical team enhances both the pharmaceutical and medical care to patients with varied complaints [START_REF] Greenwood | Development of an Emergency Department Pharmacist Practitioner service specification[END_REF], and can improve ADE detection [START_REF] Roulet | Implementing a clinical pharmacy survey of adverse drug events in a French emergency department[END_REF][START_REF] Roulet | Assessment of adverse drug event recognition by emergency physicians in a French teaching hospital[END_REF][START_REF] Roulet | Establishing a pharmacy presence in the emergency department: Opportunities and challenges in the French setting[END_REF][START_REF] Leenhardt | Pharmacist intervention to detect drug adverse events on admission to the emergency department: Two case reports of neuroleptic malignant syndrome[END_REF]; these professionals bring pharmaceutical expertise, and help ensure the production of a reliable medication history. In a cohort of patients who were admitted to the ED with ADE presentations, we compared medication histories obtained by physicians and pharmacists, and hypothesized that the medications missing from the physicians' medication histories may well have resulted in missed diagnoses of ADE-related presentations (Figure 1). Our primary objective was to assess errors in the medication lists obtained by physicians that may have led to a missed diagnosis of ADE if not corrected by pharmacists. Our secondary objective was to assess the transmission of information about ADE detection, and the involved medications at ED discharge.

Materials and Methods

Study Design and Setting

This study is ancillary to a study on ADE detection in EDs (ADEsED). This prospective observational monocentric study was conducted in the adult ED of a university hospital in France, from November 2011 to November 2018, and the primary objective was to assess the rate and characteristics of ADEs identified by the pharmacist team in an ED [START_REF] Laureau | Adverse Drug Events Detected by Clinical Pharmacists in an Emergency Department: A Prospective Monocentric Observational Study[END_REF][START_REF] Lohan | Impact of medication characteristics and adverse drug events on hospital admission after an emergency department visit: Prospective cohort study[END_REF][START_REF] Lohan | Characteristics, and Predictive Factors of Adverse Drug Events in an Adult Emergency Department according to Age: A Cross-Sectional Study[END_REF].

Participation in the study was proposed by clinical pharmacists for all adult patients (>18 years) admitted to the ED during the study period. Patients were prospectively and consecutively included, and were followed up until ED discharge. Patients were not included if they presented with acute psychological problems, or if they (or a family member) refused to participate in the study. The pharmaceutical team carried out structured interviews to determine the best possible medication history (BPMH), including selfmedication and as required medications, and a medication reconciliation according to the High 5s project standard operating procedures (see description in the section, Errors on medication lists and ADE detection). Physicians also drew up medication lists after interviewing patients according to the usual care, without any standardized procedure. The medication lists collected from the clinical pharmacists and those collected from the medical team were obtained independently and blinded from each other. Since 2016, both types of lists are collected in the medical records, and it was during this same period that data about medication errors were collected. For this subgroup analysis, we extracted a cohort of patients with the following criteria: patients with ADE detected at ED admission, patients with an admission medication list established by both the pharmaceutical team and the medical team, and patients with medication error detection. Thus, we excluded from the ADEsED study cohort those patients without an ADE (n = 11,763), and those for whom a medication list established by the clinical pharmacy team was not recorded in the medical report (n = 2121) (Figure 2, flow chart).

Errors on Medication Lists and ADE Detection

Our process of medication reconciliation [START_REF] Breuker | Medication Errors at Hospital Admission and Discharge: Risk Factors and Impact of Medication Reconciliation Process to Improve Healthcare[END_REF] and ADE detection has been previously published [START_REF] Laureau | Adverse Drug Events Detected by Clinical Pharmacists in an Emergency Department: A Prospective Monocentric Observational Study[END_REF][START_REF] Lohan | Impact of medication characteristics and adverse drug events on hospital admission after an emergency department visit: Prospective cohort study[END_REF], and is briefly described below. The process is conducted by a clinical pharmacy team that includes one senior pharmacist, one pharmacist resident and four pharmacy students. All clinical pharmacy team members received specific training on taking medication histories according to the High 5s project standard operating procedures [START_REF] Van Den Bemt | Effect of medication reconciliation on unintentional medication discrepancies in acute hospital admissions of elderly adults: A multicenter study[END_REF], and on ADE detection documentation [START_REF] Naranjo | A method for estimating the probability of adverse drug reactions[END_REF][START_REF] Arimone | Updating the French method for the causality assessment of adverse drug reactions[END_REF]. The World Health Organization (WHO) initiated the Action on Patient Safety High 5s Project. The aim of this project was to achieve a significant reduction in five highly prevalent patient safety problems by applying standardized patient care processes. Medication reconciliation was chosen as one of these processes.

Best Possible Medication History

The clinical pharmacy team carried out patient-structured interviews in the ED to determine the BPMHs (including self-medication and when-required medication) and selfreported adherence. If the interview could be conducted with the patient, it was conducted with a reliable person or family member. The BPMH is based on this interview and on additional sources, such as medication prescriptions, medical records, and contact with the community pharmacy, general practitioner or nurse.

Error Detection

The medication lists obtained by the pharmaceutical and medical teams were compared to identify errors. In agreement with the ED pharmacists and physicians, we defined errors on medication lists as any difference observed on the medication list obtained by the medical team as compared to the list obtained by pharmacists. These errors could be (i) an added medication; (ii) a missing medication due to medication omission or incorrect medication; or (iii) a medication mischaracterization, such as incorrect dosage, incorrect frequency, omission of dosage, omission of frequency, or omission of both frequency and dosage.

Missed Diagnosis of ADE and Medication List Errors

To confirm our hypothesis that the medications identified by pharmacists enabled ADE detection, the relationship between medication list error and ADE detection was retrospectively evaluated by an expert committee that included ED physicians, clinical pharmacists and a pharmacovigilance physician. In order to limit the risk of bias, and in agreement with the expert committee, only errors concerning missing medication (omission and wrong molecule) involved in an ADE were analyzed. Indeed, the expert committee stated that mischaracterization errors (dosage or frequency) were not analyzed, and that the correction of the mischaracterization errors alone would not be sufficient to detect an ADE, but would contribute to the better detection of ADEs.

ADE Detection

In our center, an ADE was defined as an injury resulting from a medication [START_REF] Bates | Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group[END_REF][START_REF] Nebeker | Clarifying adverse drug events: A clinician's guide to terminology, documentation, and reporting[END_REF][START_REF] Roulet | Assessment of adverse drug event recognition by emergency physicians in a French teaching hospital[END_REF]. This definition included injuries (signs, symptoms or laboratory abnormalities) resulting from adverse drug reactions (ADRs) or non-compliance with medication prescriptions [START_REF] Naranjo | A method for estimating the probability of adverse drug reactions[END_REF]. Voluntary medication poisoning was excluded from our ADE definition. All members of the clinical pharmacy team had received specific training in ADE detection, based on recommended methods such as the Naranjo tool [START_REF] Naranjo | A method for estimating the probability of adverse drug reactions[END_REF][START_REF] Arimone | Updating the French method for the causality assessment of adverse drug reactions[END_REF][START_REF] Trotti | CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment[END_REF]. They conducted an analysis of the patient's medical file and the BPMH to detect a possible ADE based on chronological, semiological (symptoms, contributing factors, complementary examination results, etc.) and bibliographic objective criteria. The ADE severity was assessed according to the Common Terminology Criteria for Adverse Events as spontaneous regression, regression after symptomatic treatment, hospitalization with no life-threat, life-threatening risk, and death [START_REF] Trotti | CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment[END_REF]. In order to detect ADEs, the name of the drug and its dose and intake frequency are necessary. ADEs were attributed to a medication by the pharmacist, and confirmed in real time by the treating senior ED physician. In the case of doubt about the diagnosis or the category of an ADE during the study, the case was reviewed by the expert committee. At the end of the study, ADE cases were verified by two expert clinical pharmacists and/or the expert committee, if necessary (Figure 1) [START_REF] Lohan | Impact of medication characteristics and adverse drug events on hospital admission after an emergency department visit: Prospective cohort study[END_REF].

Transmission of Information

We examined the notifications of an ADE and the involved medication by reviewing the ED discharge reports. We considered that the ADE was notified if any evidence of an ADE suspicion, diagnosis or management was documented in the discharge report.

Data Collection

For each patient, we collected the following: demographic data (age and sex); the FRench Emergency Nurses Classification in Hospital (FRENCH); the main cause for the ED visit; medication lists obtained by the pharmaceutical and medical teams (name of medication, dosage, frequency of administration); number of daily medications; number and nature of the data sources used for the BPMH; medication involved in the ADE [name of medication and Anatomical Therapeutic Chemical (ATC) classification]; severity of the ADE (spontaneous regression, regression after symptomatic treatment, hospitalization with no life-threat, hospitalization with life-threatening risk, death and undetermined); symptoms of the ADE; and ED patient outcome (discharge, hospitalization, death). The FRENCH triage classification has five levels: 1: Immediately life-threatening; 2: Marked impairment of a vital organ, or imminently life-threatening, or functionally disabling traumatic lesion; 3: Functional impairment, or organic lesions likely to deteriorate within 24 h, or complex medical situation justifying the use of several hospital resources; 4: Stable, non-complex functional impairment or organic lesions, but justifying the urgent use of at least one hospital resource; and 5: No functional impairment or organic lesion justifying the use of hospital resources. For each error on the medication list, the medication class (according to the ATC classification system) and the type of medication error were analyzed.

Statistical Analysis

The data were described with percentages for categorical variables and means and standard deviations (SD) for quantitative variables. Variables of interest were compared with Student's t-test.

Ethical Consideration

Our study was performed according to the World Medical Association Declaration of Helsinki, and was approved by the Montpellier University Hospital Institutional Review Board. Oral consent was obtained by a clinical pharmacist from all participants, or from a member of their family (written informed consent for participation was waived for this study by the Montpellier University Hospital Institutional Review Board). This study was registered on ClinicalTrials.gov (NCT03442010).

Results

Characteristics of the Study Population

During the study period, 210,587 ED visits were made, and 6.9% were managed by the pharmaceutical team. In total, 735 patients were included in our ancillary study. Baseline characteristics of our patients are presented in Table 1. The mean age was 74.3 ± 17.4 years, and the sex ratio was close to 1. The main causes for the ED visit were neurological disorders (20.3%), bleeding (13.7%) and falling (12.8%). The major ADE symptoms were bleeding (26.8%), metabolic disorders (15.5%) and neurological disorders (15.0%). In 42.2% of the cases, the ADE regressed after symptomatic treatment. The ED outcomes were discharge for 47.1% of our population, hospitalization for 51.6% and death for 1.4%. Our population (n = 735) was comparable to the total ADEsED population with an ADE (n = 2856) in terms of age, gender, FRENCH triage scale, number of daily medications, ADE severity and ED outcomes.

Medication Histories Obtained by the Pharmaceutical and Medical Teams

The BPMHs of the clinical pharmacy team were based on an average of 2.9 •} 0.6 different sources of information, described in Table 2. The daily medication lists contained significantly fewer medications when obtained by the medical team than by the clinical pharmacy team (6.6 •} 3.9 vs. 8.8 •} 4.1, p < 0.0001).

Medication Histories Obtained by the Pharmaceutical and Medical Teams

Nearly all patients (93.1%) had at least one error on the physicians' medication lists as compared to those obtained by pharmacists. Moreover, in 57.1% of the population, at least one of the errors on the physicians' medication lists concerned a medication involved in an ADE. The mean number of errors per patient was 5.7 •} 4.1 (Table 2). In total, 4186 errors were found. Characteristics of the errors on medication lists obtained by ED physicians are described in Table 3.

Errors on Medication Lists Obtained by the Medical Team and ADEs

Of the 1047 medications involved in an ADE, 51.3% were associated with an error on the medication lists obtained by ED physicians (Table 3). Those errors were mainly medication omissions (41.9%), frequency omissions (24.6%), and both dosage and frequency omissions (14.3%). In total, 23.1% of the medications involved in an ADE were not identified by the medical team (21.5% with the medication missing and 1.6% of wrong molecule) and were indicated by the pharmacist, allowing for the detection of the ADE. The analysis of these 242 errors (medication missing and wrong molecule) confirmed that, without their correction, the ADE would not have been detected. Table 4 summarizes the relationship between the missing medication on the physician medication list and the related ADE symptoms. The most frequent situations involved bleeding (n = 30) and disturbed consciousness/ fall (n = 33) without knowledge of involved medications. For 28.2% of the medications involved in an ADE, the missing information (dose and/or frequency) was provided by the pharmacists, which contributed to a better detection of ADEs but was not sufficient alone to detect the ADE according to the expert committee. The medication ATC classifications most concerned by these errors were the neurological system (30.2%), blood and blood-forming organs (28.3%), and the cardiovascular system (17.5%). ADEs and the involved medications were mentioned in the ED discharge report in 41.0% (301/735) and 30.5% (224/735) of the cases, respectively.

Discussion

To the best of our knowledge, our study is the first to describe the thoroughness and accuracy of the medication histories of patients admitted to an ED along with the involvement of these medications in ADEs. We found that about half the medications involved in an ADE were associated with an error in the physician medication history. The medication reconciliation process conducted by the pharmacists was able to correct these errors and improve ADE detection. We found that 93.1% of the patients visiting the ED had at least one error in their physician medication history. A systematic literature review of medication history errors at admission to hospital reported an error rate of 27% to 83% when non-prescription drugs were included [START_REF] Tam | Frequency, type and clinical importance of medication history errors at admission to hospital: A systematic review[END_REF]. In EDs, 33-96% of ED medication lists contain at least one error [START_REF] Shepherd | Frequency of incomplete medication histories obtained at triage[END_REF][START_REF] Mazer | Medication history taking in emergency department triage is inaccurate and incomplete[END_REF][START_REF] Caglar | Emergency department medication lists are not accurate[END_REF][START_REF] Dewinter | Pharmacistversus physician-acquired medication history: A prospective study at the emergency department[END_REF][START_REF] Miller | Medication reconciliation in a rural trauma population[END_REF][START_REF] Gleason | Reconciliation of discrepancies in medication histories and admission orders of newly hospitalized patients[END_REF][START_REF] Cohen | Variation in medication information for elderly patients during initial interventions by emergency department physicians[END_REF][START_REF] Carter | Pharmacist-acquired medication histories in a university hospital emergency department[END_REF]. These results are concordant with our findings; however, the studies that were carried out are not totally comparable to ours, since they differed in terms of methodology, definition of error and population. Indeed, some studies underestimated errors in the medication histories as a result of involving a young population with few daily medications [START_REF] Shepherd | Frequency of incomplete medication histories obtained at triage[END_REF][START_REF] Mazer | Medication history taking in emergency department triage is inaccurate and incomplete[END_REF][START_REF] Dewinter | Pharmacistversus physician-acquired medication history: A prospective study at the emergency department[END_REF][START_REF] Miller | Medication reconciliation in a rural trauma population[END_REF][START_REF] Gleason | Reconciliation of discrepancies in medication histories and admission orders of newly hospitalized patients[END_REF][START_REF] Carter | Pharmacist-acquired medication histories in a university hospital emergency department[END_REF], or only focusing on omissions without including frequency or dosage errors [START_REF] Mazer | Medication history taking in emergency department triage is inaccurate and incomplete[END_REF][START_REF] Cohen | Variation in medication information for elderly patients during initial interventions by emergency department physicians[END_REF], or only accounting for prescribed medications [START_REF] Miller | Medication reconciliation in a rural trauma population[END_REF]. Other studies used fewer sources of information to take the medication histories [START_REF] Caglar | Emergency department medication lists are not accurate[END_REF][START_REF] Dewinter | Pharmacistversus physician-acquired medication history: A prospective study at the emergency department[END_REF][START_REF] Gleason | Reconciliation of discrepancies in medication histories and admission orders of newly hospitalized patients[END_REF]. We found that most of the errors on the ED physicians' medication lists compared to those on the ED pharmacists' lists were omissions (48.1%), consistent with the literature data [START_REF] Mazer | Medication history taking in emergency department triage is inaccurate and incomplete[END_REF][START_REF] Tam | Frequency, type and clinical importance of medication history errors at admission to hospital: A systematic review[END_REF][START_REF] Boockvar | Prescribing discrepancies likely to cause adverse drug events after patient transfer[END_REF][START_REF] Dewinter | Pharmacistversus physician-acquired medication history: A prospective study at the emergency department[END_REF][START_REF] Miller | Medication reconciliation in a rural trauma population[END_REF][START_REF] Gleason | Reconciliation of discrepancies in medication histories and admission orders of newly hospitalized patients[END_REF][START_REF] Carter | Pharmacist-acquired medication histories in a university hospital emergency department[END_REF][START_REF] Fitzsimons | Sources of pre-admission medication information: Observational study of accuracy and availability[END_REF][START_REF] Cornish | Unintended medication discrepancies at the time of hospital admission[END_REF][START_REF] Lau | The completeness of medication histories in hospital medical records of patients admitted to general internal medicine wards[END_REF][START_REF] Vira | Reconcilable differences: Correcting medication errors at hospital admission and discharge[END_REF].

Our study has several original features: (i) we focused on a large cohort of patients with ADRs, using a robust prospective detection methodology and an exhaustive data collection that allowed for a complete description of the ADEs (symptoms, severity, etc.) and of the medication involved; (ii) we performed a complete analysis of the ME found and (iii) we evaluated the impact of these medication errors on the detection of ADEs. Thus, we presented innovative results which, to our knowledge, have not yet been described in the literature, on the impact of medication errors on the detection of ADEs, and the importance of their correction.

Indeed, 23.1% of the ADEs could not have been detected without a pharmacist's intervention, because the ED physician had an incomplete medication list with an omission of the medication involved in the ADE, or an error in the molecule name. It appears obvious that ED medical teams have diagnostic and treatment priorities that prevent them from retrieving a complete medication history. Moreover, a pharmacist's intervention may have contributed to better detection, with 28.2% more ADEs detected through the recovery of missing information on doses and frequencies of administration. In a previous study, our team highlighted the independent predictors for hospitalization following an ED visit. Thus, we identified some of the variables associated with treatment (polypharmacy, treatment by antineoplastic or immunomodulating agents, blood, systemic anti-infectiv and metabolism medications) and the presence of an ADE. These results point to the importance and relevance of collecting medication data in the context of an ED visit [START_REF] Lohan | Impact of medication characteristics and adverse drug events on hospital admission after an emergency department visit: Prospective cohort study[END_REF]. Furthermore, our population sample for this ancillary study (n = 735 patients with an ADE) was comparable to the total population with ADEs in the primary ADEsED study (n = 2856 patients with an ADE). Thus, extrapolating our results to the total population of the ADEsED study, we estimated that 658 and 798 ADEs would have been detected and better detected through the BPMHs of the clinical pharmacy team, respectively. The BPMHs of the ED pharmacists could be considered complete and reliable, given the mean number of different information sources (2.9 per BPMH), which were cross-referenced. To obtain an accurate medication history, crossreferencing information sources is crucial [START_REF] Breuker | Medication Errors at Hospital Admission and Discharge: Risk Factors and Impact of Medication Reconciliation Process to Improve Healthcare[END_REF]. Moreover, considering the ED's large influx of patients and the limited time to establish a medication history, the most relevant sources should be prioritized. Personal communication with the community pharmacist was identified as the most reliable, available and complete source of information [START_REF] Fitzsimons | Sources of pre-admission medication information: Observational study of accuracy and availability[END_REF][START_REF] Balon | Comparison of hospital admission medication lists with primary care physician and outpatient pharmacy lists[END_REF]. This is consistent with our results showing that general practitioners were contacted in only 10.5% of the BPMHs, whereas community pharmacists were contacted in 77.0% of the histories. In this study, we highlighted a traceability problem concerning ADEs detected in the ED. Indeed, only 41.0% of the ADEs were mentioned in the ED discharge report, and the medication involved was mentioned in only 30.5%. The community-hospital link is essential to guarantee continuous and consistent care. The emergency physician intervenes in an acute situation, but is not the patient's referring physician. Medical guidance and patient follow-up are responsibilities of the general practitioner, sometimes accompanied by the community pharmacist. Therefore, it is very important that the relevant information detected in the ED is transmitted to the patient's referring healthcare professionals, who can review and adapt the treatment involved in the ADE. Other studies have shown that most discharge reports are incomplete [START_REF] Marvin | Applying quality improvement methods to address gaps in medicines reconciliation at transfers of care from an acute UK hospital[END_REF][START_REF] Uitvlugt | Quality of medication related information in discharge letters: A prospective cohort study[END_REF] in terms of the ADEs. However, this information is essential to initiate a process of therapeutic revision that will prevent recidivism and readmission to the ED. Indeed, according to the ADE definitions (only adverse drug effect or any problem related to drug treatment) and methodologies used (detection during patient management or during retrospective analysis of the database), the rate of readmission to the ED after an initial admission related to an ADE is between 3.6% and 18.7% [START_REF] Zhang | Comorbidity and repeat admission to hospital for adverse drug reactions in older adults: Retrospective cohort study[END_REF][START_REF] Lopez-Aguila | Predictive model for emergency hospital admission and 6-month readmission[END_REF].

Our study has some limitations, mainly with its monocentric design. The lack of a control arm without pharmacist intervention does not allow us to make conclusions about the specific role of pharmacists to improve ADE detection. Thus, we only know that at least 23.1% of the ADEs would not have been detected by the physician without the intervention of the pharmacist. Our study also has strengths, primarily its prospective design, the large population, the specificity of our population (population with ADEs), and the number of observations of the outcome of interest. We should also note the rigorous approach we used in obtaining medication histories and detecting ADEs.

Conclusions

Our study demonstrates that medication histories retrieved by pharmacists in an ED are more complete than those made by ED physicians. Nearly all medication histories made by the ED physicians contained an error, compared to the pharmacists' BPMHs. Reliable medication histories are an essential part of medication safety and ADE detection. A common computerized medical record with all drug prescriptions, educating patients to always have a copy of their prescription and an updated medical report with them, can save time and improve the quality of patient management and ADE detection. Our study shows that the intervention of a pharmacist can improve the detection of ADEs, and may well reduce the risk of readmission. We also point out a problem of information transmission to the community healthcare professionals concerning ADEs retrieved within the ED. Transition points in a patient's care path are points of risk for medication errors, and the lack of communication between various health professionals increases the risk of these errors. To optimize and secure the care information between the ED and community healthcare professionals, clinical pharmacist should be an essential member of the ED team [START_REF] Breuker | Impact of a medicopharmaceutical follow-up and an optimized communication between hospital and community on the readmission to the emergency department for an adverse drug event: URGEIM, study protocol for a randomized controlled trial[END_REF]. Since this study was conducted, we have changed our practices; we leave only the pharmacist's medication history in the ED report in those cases where a pharmacist was present. Moreover, the pharmacist's inclusion in the ED team for this study has been implemented permanently, and is now part of routine practice.

Figure 1 .

 1 Figure 1. Principle of pharmacist medication history and detection of adverse drug events in the emergency department.

Figure 2 .

 2 Figure 2. Flow chart of the study population. ADE, adverse drug event; ADEsED, adverse drug event detection at ED.

Acknowledgments:

The authors acknowledge the pharmacy residents and students of the clinical pharmacy department, the emergency physicians and nurses and the Emergency Department at Montpellier University Hospital for their ongoing support throughout the study.

Funding:

This research received no external funding.

Institutional Review Board Statement:

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of University Hospital of Montpellier (n•2018_IRB-MTP_04-02, approved on 6 March 2018).

Data Availability Statement:

The data analyzed during the current study are not publicly available due ethical restrictions, but are available from the corresponding author on reasonable request.

Informed Consent Statement:

Oral consent was obtained by a clinical pharmacist from all participants, or from a member of their family (written informed consent for participation was not required for this study in accordance with Montpellier University Hospital Institutional Review Board).

Conflicts of Interest:

The authors declare no conflict of interest.