Eur J Clin Pharmacol (2014) 70:361–367 DOI 10.1007/s00228-013-1630-5
PHARMACOEPIDEMIOLOGY AND PRESCRIPTION
Prevalence, risk factors and main features of adverse drug reactions leading to hospital admission Consuelo Pedrós & Beatriz Quintana & Mireia Rebolledo & Núria Porta & Antoni Vallano & Josep Maria Arnau
Received: 11 October 2013 / Accepted: 8 December 2013 / Published online: 21 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose To assess the prevalence of hospital admission related to adverse drug reactions (ADRs) in a third-level hospital, to analyse the associated factors, and to describe the reactions and the drugs involved. Methods A cross-sectional study was conducted for a 120-day period. Patients that were urgently hospitalized entered the study. The primary endpoint was the ADR-related urgent admission. A descriptive analysis of demographic, clinical, and drug-related variables was performed. The association between the likelihood of urgent admission due to ADRs and age, gender, and number of drugs used was analysed. A descriptive analysis of the suspected drugs and the reactions in ADR-related admissions was performed. Results Overall, 186 out of 4,403 hospital admissions were due to ADRs (prevalence: 4.2 % [95 % CI 3.7–4.8 %]). Age
(≥65 years: OR 1.59 [95 % CI 1.10–2.29]) and number of drugs used at the time of admission (3–5 drugs: OR 5.07 [95 % CI 2.71–9.59]; 6–9 drugs: OR 5.90 [95 % CI 3.16– 11.0]; ≥10 drugs: OR 8.94 [95 % CI 4.73–16.89]), but not gender, were identified as independent factors associated with ADR-related hospitalization. The overall in-hospital stay for patients admitted with ADRs amounted to 1,785 days. The ADRs were mainly type A reactions (92 %). Acute renal failure related to renin-angiotensin system inhibitors, haemorrhage due to anticoagulants, and upper gastrointestinal bleeding related to antiplatelet drugs and/or non-steroidal antiinflammatory drugs were the most frequent. Conclusion Over 4 % of urgent hospitalizations are caused by ADRs, which are dose-related and predictable in more than 90 % of cases. The main risk factors are advanced age and polypharmacy.
Electronic supplementary material The online version of this article (doi:10.1007/s00228-013-1630-5) contains supplementary material, which is available to authorized users.
Keywords Pharmacovigilance . Adverse drug reaction reporting systems . Drug toxicity . Hospitalization . Risk factors
C. Pedrós (*) : B. Quintana : M. Rebolledo : A. Vallano : J. M. Arnau Clinical Pharmacology Service, Bellvitge University Hospital, c/Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain e-mail: [email protected] C. Pedrós : B. Quintana : M. Rebolledo : N. Porta : A. Vallano : J. M. Arnau Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain N. Porta : J. M. Arnau Clinical Trials Unit (UCICEC-CAIBER), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain A. Vallano : J. M. Arnau Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Spain
Introduction Adverse drug reactions (ADRs) are a major public health problem because of their impact in terms of morbidity, mortality and economic cost. Meta-analyses of studies on the frequency of ADRs as a cause of hospitalization in Western countries provide figures that range between 3.7 and 5.3 % [1–3]. The variability between the studies included in those meta-analyses can be explained, at least in part, by differences in study designs, type of events studied, definition of ADR applied, methods of identifying cases, methods of assessment of causality, length of periods of study and wards included [4]. Although most published studies of ADRs have applied the
362
WHO definition [5], the new European pharmacovigilance legislation has put into force a wider definition [6]. In our hospital, with a Service of Clinical Pharmacology and a prospective pharmacovigilance programme (PhvP) recently set up (i.e. in 2007 and 2008, respectively), the information currently available in the scientific literature on frequency and characteristics of ADR-related hospital admissions did not allow us to properly size up the problem and to plan actions in this regard based on reliable and updated local data. The aim of this study was therefore: (i) to assess the prevalence of ADRrelated hospital admission in a third-level teaching hospital, taking into account the current European definition of ADR, (ii) to analyse the factors associated, (iii) to characterize the ADRs, and (iv) to describe the drugs involved.
Methods Study design A cross-sectional study was carried out at Bellvitge University Hospital, a Spanish tertiary care teaching hospital. It has approximately 800 beds, covers a population of approximately 1.3 million inhabitants and provides all medical and surgical specialities except for obstetrics, gynaecology, paediatrics, and oncology. The period of study was 120 days. All patients admitted through the emergency room during the first 10 days of each month during a period of 12 consecutive months (from July 2009 to June 2010) were included. The study was approved by the Clinical Research Ethics Committee of Bellvitge University Hospital. All identified cases of ADRs were reported to the Spanish Pharmacovigilance System (SPhVS). Data collection and variables studied The source of identification of patients was the daily list of urgent admissions provided by the Admissions Unit. For each patient, demographic data (age and sex), clinical information (admission diagnosis, medical ward and length of hospital stay), as well as information on the number of different drugs used at the time of arrival at the hospital were gathered. The information was obtained from the medical electronic records. Definition and ascertainment of cases of ADR The primary endpoint was urgent admission caused by an ADR. We used the definition of ADR utilized by the SPhVS [7] that corresponds with the one currently in force in the regulatory framework of the European Union, which considers as an ADR any response to a drug which is noxious and unintended [6].
Eur J Clin Pharmacol (2014) 70:361–367
Cases of ADRs included in the present study are a sample of those identified within the context of the prospective PhVP that we have been running in our hospital since 2008. Our PhVP collects cases of ADRs identified by a systematic daily review of admission diagnoses. Patients admitted with diagnoses included in a pre-defined list of diseases or syndromes potentially caused by drugs (see Supplementary Material, Figure 1) are selected for further review. Their medical records are reviewed by a clinical pharmacologist in order to make a clinical judgement about the possibility of an ADR by applying the causality assessment methods and the algorithm of the SPhVS (a modification of the algorithm of Karch-Lassagna) [8], which categorises imputability as improbable, conditional, possible, probable or definite (see Supplementary Material). When an ADR is initially suspected, a trained nurse collects information on the drugs taken and the reaction from the medical record or by direct patient interview. Each case is followed up until discharge to gather enough information to discard or retain it as a case of suspected ADR. A clinical pharmacologist makes a final causality assessment in those cases retained as suspected ADRs. Admissions with insufficient information for a reliable assessment, as well as improbable ADR cases are excluded. The information regarding each individual ADR case is incorporated into a database. Drugs are coded as suspected, not suspected, or suspected of pharmacological interaction. The Anatomical Therapeutic Chemical Classification (ATC) [9] and the Medical Dictionary for Regulatory Activities (MedDRA) version 11.0. are used to code active principles and reactions, respectively. The outcome of the ADR is categorised into recovered, recovered with sequelae, not yet recovered, death from the ADR, death from other causes, or outcome unknown. For the purposes of this study, cases of ADRs with date of admission within the study period were retrieved from the PhVP database. Additionally, the reactions were classified according to their mechanism of production into type A or type B [10]. Sample size calculation We calculated that 4,098 patients were needed for inclusion in the study in order to estimate the proportion of patients admitted for an ADR with 95 % confidence interval (CI), and with a CI width of 1.2 % (margin of error: 0.6 %), taking into account an expected frequency of 4 % based on the results of published meta-analyses and previous studies performed in Spain [1–3, 11–13]. Statistical analysis The prevalence of ADR-related admission was calculated by dividing the number of patients admitted for ADRs and the total number of admissions through the emergency room
Eur J Clin Pharmacol (2014) 70:361–367
during the study period. We calculated the 95 % CI for this estimate. We performed a descriptive analysis of demographic, clinical, and drug-related variables stratified by the condition of interest (ADR-related admission). We calculated absolute and relative frequencies for qualitative variables (gender, age group, number of drugs used at admission categorised, and stay in special units —Intensive Care Unit and Recovery Unit), as well as median, interquartile range (IQR) and range for continuous variables (age, number of medications, total length of hospital stay, and length of stay in special units). The chi-squared test was used to compare the distribution of categorical variables. Continuous variables were tested for normality; the t test or the Mann–Whitney test (when appropriate) was used to compare the distribution of continuous variables. In the subset of patients admitted for ADRs, we performed a descriptive analysis of suspected drugs, type of reactions, mechanism of production, and outcome. Absolute and relative frequencies were calculated. The association between the likelihood of urgent hospital admission due to ADR and age, gender, and number of drugs being taken at admission—which were defined as covariates a priori—was analysed in a logistic regression model. Covariates that were significant in a Wald test at a p-value of decision 0.1 were selected for the final model. Statistical analysis was performed with SPSS version 15.0 (Chicago, Illinois, USA).
Results During the study period, 4,403 patients were urgently admitted to our hospital. There were 1,352 patients with admission diagnoses included on the list of syndromes and diseases suggestive of ADRs. ADRs were actually suspected as the reasons for hospitalization in 186 of these patients, resulting in an estimated prevalence of ADR-related hospital admission of 4.2 % (95 % CI 3.7–4.8 %). Patients admitted for ADRs were older and were taking a greater number of drugs than those admitted for other reasons. No differences in gender distribution were seen between both groups (Table 1). The length of hospital stay of ADR-related hospital admissions was shorter, but the proportion of patients requiring stay in special units was higher in those admitted for ADRs. Overall, ADR-related hospital admissions resulted in 1,785 days of hospital stay, 150 of them in special units (Table 1). The logistic regression analysis identified the age and the number of drugs being taken at admission as independent factors associated with hospitalization due to ADR (Table 2). The 186 cases included 201 ADRs and 382 suspected drugs. The most common reactions were renal and urinary disorders (29.4 %; n=59) followed by gastrointestinal and nervous system disorders (26.4 % [n=53] and 10.4 % [n=
363 Table 1 Patient characteristics and comparison between ADR- and nonADR-related hospital admissions ADR-related
Non-ADR-related
Total number of hospital N=186 N=4,217 admissions Gender, N (%) Female 82 (44.1) 1,660 (39.4) Male 104 (55.9) 2,557 (60.6) Age (years) Median (IQR) 75.0 (17.0) 66.0 (26.0) Range 28-97 16-102 Age, categorised, N (%)
PHARMACOEPIDEMIOLOGY AND PRESCRIPTION
Prevalence, risk factors and main features of adverse drug reactions leading to hospital admission Consuelo Pedrós & Beatriz Quintana & Mireia Rebolledo & Núria Porta & Antoni Vallano & Josep Maria Arnau
Received: 11 October 2013 / Accepted: 8 December 2013 / Published online: 21 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose To assess the prevalence of hospital admission related to adverse drug reactions (ADRs) in a third-level hospital, to analyse the associated factors, and to describe the reactions and the drugs involved. Methods A cross-sectional study was conducted for a 120-day period. Patients that were urgently hospitalized entered the study. The primary endpoint was the ADR-related urgent admission. A descriptive analysis of demographic, clinical, and drug-related variables was performed. The association between the likelihood of urgent admission due to ADRs and age, gender, and number of drugs used was analysed. A descriptive analysis of the suspected drugs and the reactions in ADR-related admissions was performed. Results Overall, 186 out of 4,403 hospital admissions were due to ADRs (prevalence: 4.2 % [95 % CI 3.7–4.8 %]). Age
(≥65 years: OR 1.59 [95 % CI 1.10–2.29]) and number of drugs used at the time of admission (3–5 drugs: OR 5.07 [95 % CI 2.71–9.59]; 6–9 drugs: OR 5.90 [95 % CI 3.16– 11.0]; ≥10 drugs: OR 8.94 [95 % CI 4.73–16.89]), but not gender, were identified as independent factors associated with ADR-related hospitalization. The overall in-hospital stay for patients admitted with ADRs amounted to 1,785 days. The ADRs were mainly type A reactions (92 %). Acute renal failure related to renin-angiotensin system inhibitors, haemorrhage due to anticoagulants, and upper gastrointestinal bleeding related to antiplatelet drugs and/or non-steroidal antiinflammatory drugs were the most frequent. Conclusion Over 4 % of urgent hospitalizations are caused by ADRs, which are dose-related and predictable in more than 90 % of cases. The main risk factors are advanced age and polypharmacy.
Electronic supplementary material The online version of this article (doi:10.1007/s00228-013-1630-5) contains supplementary material, which is available to authorized users.
Keywords Pharmacovigilance . Adverse drug reaction reporting systems . Drug toxicity . Hospitalization . Risk factors
C. Pedrós (*) : B. Quintana : M. Rebolledo : A. Vallano : J. M. Arnau Clinical Pharmacology Service, Bellvitge University Hospital, c/Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain e-mail: [email protected] C. Pedrós : B. Quintana : M. Rebolledo : N. Porta : A. Vallano : J. M. Arnau Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain N. Porta : J. M. Arnau Clinical Trials Unit (UCICEC-CAIBER), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain A. Vallano : J. M. Arnau Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Spain
Introduction Adverse drug reactions (ADRs) are a major public health problem because of their impact in terms of morbidity, mortality and economic cost. Meta-analyses of studies on the frequency of ADRs as a cause of hospitalization in Western countries provide figures that range between 3.7 and 5.3 % [1–3]. The variability between the studies included in those meta-analyses can be explained, at least in part, by differences in study designs, type of events studied, definition of ADR applied, methods of identifying cases, methods of assessment of causality, length of periods of study and wards included [4]. Although most published studies of ADRs have applied the
362
WHO definition [5], the new European pharmacovigilance legislation has put into force a wider definition [6]. In our hospital, with a Service of Clinical Pharmacology and a prospective pharmacovigilance programme (PhvP) recently set up (i.e. in 2007 and 2008, respectively), the information currently available in the scientific literature on frequency and characteristics of ADR-related hospital admissions did not allow us to properly size up the problem and to plan actions in this regard based on reliable and updated local data. The aim of this study was therefore: (i) to assess the prevalence of ADRrelated hospital admission in a third-level teaching hospital, taking into account the current European definition of ADR, (ii) to analyse the factors associated, (iii) to characterize the ADRs, and (iv) to describe the drugs involved.
Methods Study design A cross-sectional study was carried out at Bellvitge University Hospital, a Spanish tertiary care teaching hospital. It has approximately 800 beds, covers a population of approximately 1.3 million inhabitants and provides all medical and surgical specialities except for obstetrics, gynaecology, paediatrics, and oncology. The period of study was 120 days. All patients admitted through the emergency room during the first 10 days of each month during a period of 12 consecutive months (from July 2009 to June 2010) were included. The study was approved by the Clinical Research Ethics Committee of Bellvitge University Hospital. All identified cases of ADRs were reported to the Spanish Pharmacovigilance System (SPhVS). Data collection and variables studied The source of identification of patients was the daily list of urgent admissions provided by the Admissions Unit. For each patient, demographic data (age and sex), clinical information (admission diagnosis, medical ward and length of hospital stay), as well as information on the number of different drugs used at the time of arrival at the hospital were gathered. The information was obtained from the medical electronic records. Definition and ascertainment of cases of ADR The primary endpoint was urgent admission caused by an ADR. We used the definition of ADR utilized by the SPhVS [7] that corresponds with the one currently in force in the regulatory framework of the European Union, which considers as an ADR any response to a drug which is noxious and unintended [6].
Eur J Clin Pharmacol (2014) 70:361–367
Cases of ADRs included in the present study are a sample of those identified within the context of the prospective PhVP that we have been running in our hospital since 2008. Our PhVP collects cases of ADRs identified by a systematic daily review of admission diagnoses. Patients admitted with diagnoses included in a pre-defined list of diseases or syndromes potentially caused by drugs (see Supplementary Material, Figure 1) are selected for further review. Their medical records are reviewed by a clinical pharmacologist in order to make a clinical judgement about the possibility of an ADR by applying the causality assessment methods and the algorithm of the SPhVS (a modification of the algorithm of Karch-Lassagna) [8], which categorises imputability as improbable, conditional, possible, probable or definite (see Supplementary Material). When an ADR is initially suspected, a trained nurse collects information on the drugs taken and the reaction from the medical record or by direct patient interview. Each case is followed up until discharge to gather enough information to discard or retain it as a case of suspected ADR. A clinical pharmacologist makes a final causality assessment in those cases retained as suspected ADRs. Admissions with insufficient information for a reliable assessment, as well as improbable ADR cases are excluded. The information regarding each individual ADR case is incorporated into a database. Drugs are coded as suspected, not suspected, or suspected of pharmacological interaction. The Anatomical Therapeutic Chemical Classification (ATC) [9] and the Medical Dictionary for Regulatory Activities (MedDRA) version 11.0. are used to code active principles and reactions, respectively. The outcome of the ADR is categorised into recovered, recovered with sequelae, not yet recovered, death from the ADR, death from other causes, or outcome unknown. For the purposes of this study, cases of ADRs with date of admission within the study period were retrieved from the PhVP database. Additionally, the reactions were classified according to their mechanism of production into type A or type B [10]. Sample size calculation We calculated that 4,098 patients were needed for inclusion in the study in order to estimate the proportion of patients admitted for an ADR with 95 % confidence interval (CI), and with a CI width of 1.2 % (margin of error: 0.6 %), taking into account an expected frequency of 4 % based on the results of published meta-analyses and previous studies performed in Spain [1–3, 11–13]. Statistical analysis The prevalence of ADR-related admission was calculated by dividing the number of patients admitted for ADRs and the total number of admissions through the emergency room
Eur J Clin Pharmacol (2014) 70:361–367
during the study period. We calculated the 95 % CI for this estimate. We performed a descriptive analysis of demographic, clinical, and drug-related variables stratified by the condition of interest (ADR-related admission). We calculated absolute and relative frequencies for qualitative variables (gender, age group, number of drugs used at admission categorised, and stay in special units —Intensive Care Unit and Recovery Unit), as well as median, interquartile range (IQR) and range for continuous variables (age, number of medications, total length of hospital stay, and length of stay in special units). The chi-squared test was used to compare the distribution of categorical variables. Continuous variables were tested for normality; the t test or the Mann–Whitney test (when appropriate) was used to compare the distribution of continuous variables. In the subset of patients admitted for ADRs, we performed a descriptive analysis of suspected drugs, type of reactions, mechanism of production, and outcome. Absolute and relative frequencies were calculated. The association between the likelihood of urgent hospital admission due to ADR and age, gender, and number of drugs being taken at admission—which were defined as covariates a priori—was analysed in a logistic regression model. Covariates that were significant in a Wald test at a p-value of decision 0.1 were selected for the final model. Statistical analysis was performed with SPSS version 15.0 (Chicago, Illinois, USA).
Results During the study period, 4,403 patients were urgently admitted to our hospital. There were 1,352 patients with admission diagnoses included on the list of syndromes and diseases suggestive of ADRs. ADRs were actually suspected as the reasons for hospitalization in 186 of these patients, resulting in an estimated prevalence of ADR-related hospital admission of 4.2 % (95 % CI 3.7–4.8 %). Patients admitted for ADRs were older and were taking a greater number of drugs than those admitted for other reasons. No differences in gender distribution were seen between both groups (Table 1). The length of hospital stay of ADR-related hospital admissions was shorter, but the proportion of patients requiring stay in special units was higher in those admitted for ADRs. Overall, ADR-related hospital admissions resulted in 1,785 days of hospital stay, 150 of them in special units (Table 1). The logistic regression analysis identified the age and the number of drugs being taken at admission as independent factors associated with hospitalization due to ADR (Table 2). The 186 cases included 201 ADRs and 382 suspected drugs. The most common reactions were renal and urinary disorders (29.4 %; n=59) followed by gastrointestinal and nervous system disorders (26.4 % [n=53] and 10.4 % [n=
363 Table 1 Patient characteristics and comparison between ADR- and nonADR-related hospital admissions ADR-related
Non-ADR-related
Total number of hospital N=186 N=4,217 admissions Gender, N (%) Female 82 (44.1) 1,660 (39.4) Male 104 (55.9) 2,557 (60.6) Age (years) Median (IQR) 75.0 (17.0) 66.0 (26.0) Range 28-97 16-102 Age, categorised, N (%)
