RESEARCH IN

FOCUSAdverse Drug Events and

Patient Safety

Peter J. Zed, BSc, BSc(Pharm), ACPR, PharmD, FCSHP

ISSUE SEVEN: AUGUST 2015

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INTRODUCTION

ADVERSE DRUG EVENTS (ADES) ARE UNFAVOURABLE OCCURRENCES RELATED TO THE USE AND MISUSE OF MEDICATIONS. It has been estimated that ADREs account for over 17 million emergency department (ED) visits and

8.7 million hospital admissions annually in the United States (US). It has been estimated the annual cost associated with morbidity and mortality secondary to ADEs in Canada exceeds $21 billion.

Establishing the epidemiology and impact of ADEs in Canada has been a challenge. Until recently, most research evaluating medication-related ED visits or hospitalizations has involved retrospective medical record reviews or analysis from admin-istrative databases, primarily from the United States. Data from retrospective studies or from administrative databases estimate that the incidence of ADEs among ED visits ranges from 0.86-10.6%, of which 14-24% result in hospital admission. Unfortunately, retrospective studies and administrative databases will underestimate the true incidence of medication-relat-ed ED visits because important information may be missing or inaccurately documented. Limitations of the use of adminis-trative databases also include the risk of misclassification bias and, in the case of voluntary reporting systems, selection bias. In addition, it is difficult to characterize the nature of an ED visit and any medication-related association from retrospective review or from an administrative database.

Data from prospective studies have estimated that the incidence of ADEs among ED visits to be 4.3-28% with rates of hospitalization 9-27%. These studies vary significantly in the reported rate of medication-related ED visits, in part due to the variations in study design and patient population studied, but also related to the heterogeneous definition of what consti-tutes a “drug-related event.” This variability between studies limits both comparative evaluation and result generalizability. In most studies a “drug-related event” is limited to “adverse drug reactions” (ADR) defined by the World Health Organization (WHO) as “any noxious, unintended, or undesired effect of a drug which occurs at doses used in humans for prophylaxis, diagnosis or treatment.” This definition excludes many other classes of drug-related events which may result in ED visits or hospitalization including untreated indication, improper drug selection, subtherapeutic dosage, supratherapeutic dosage, nonadherence, drug interaction and drug use without an indication. Most recently the definition of “drug-related event” has expanded to “adverse drug event” (ADE) or “adverse drug-related event” (ADRE) defined as any ADR, as defined by the WHO, and/or drug interactions and medications errors (i.e. errors in prescribing, dispensing, patient adherence and moni-toring). This definition also has limitations, in that it excludes therapeutic failures, insufficient dosing and untreated indica-tions. A more comprehensive and reproducible definition of a “drug-related event” is the classification of Hepler and Strand which includes eight potential classes of ADREs and includes ADR, drug interaction, improper drug selection, untreated indication, subtherapeutic dosage, supratherapeutic dosage, nonadherence, and drug use without indication. This taxonomy of ADREs allows evaluation of drug-related morbidity to be more comprehensive and inclusive all clinically important defini-tions, providing a more accurate and meaningful characterization of medication-related visits to the ED.

This program of research has focused for over a decade on using prospective primary data collection methods by a pharma-cist with expertise in the identification of ADEs and the best available causality tools to better understand the epidemiology and impact of ADEs on ED visits and hospitalization in Canada. The general research questions of the selected research

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Image: Martin Dee

projects described below include:

1. What is the frequency, severity, preventability and classification of medication-related ED visits/hospitalization?

2. What are the patient, prescriber, drug and system factors associated with medication-related ED visits/hospitalization?

3. What are the short-term disposition and health care utilization patterns of patients who present to the ED with medica tion-related events compared to these outcomes of patients who present to the ED without medication-related problems?

SELECTED PROJECTSDRUG-RELATED HOSPITALIZATION

One of the earliest studies performed by this program was and evaluation of the impact of ADE on hospital admissions. This study was performed at Vancouver General Hospital over a 12-week period in which all patients admitted to the internal medicine service were enrolled to determine the rate of drug-related hospitalization (DRH). During the study period 565 pa-tients were enrolled (mean age 69.3 years, 50.6% were female). The incidence of DRH was found to be 24.1% (95% CI 20.6-27.8%) of which 72.1% (95% CI 63.7-79.4%) were deemed preventable. Severity was classified as mild, moderate, severe and fatal in 8.1% (95% CI 4.1-14.0%), 83.8% (95% CI 76.5-89.6%), 7.4% (95% CI 3.6-13.1%) and 0.7% (95% CI 0.0-4.0%) of cases, respectively. Adverse drug reactions (35.3%: 95% CI 27.3-43.9%), wrong/suboptimal drug (17.6%: 95% CI 11.6-25.1%) and non-adherence (16.2%: 95% CI 10.4-23.5%) were the most common classes of DRH. Overall, there were a total of 167 implicated drugs. In 105 (77.2%) patients a single drug was associated with hospitalization while 31 (22.8%) patients had admissions associated with multiple drugs. The most common drug classes associated with DRH included cardiovas-cular agents (27.5%), antibiotics (23.4%), non-steroidal anti-inflammatory drugs (13.2%), central nervous system agents (7.8%), anticoagulants (5.4%) and hypoglycemic agents (4.8%).

ADVERSE DRUG-RELATED EMERGENCY DEPARTMENT VISITS IN ADULTS

Our team performed the first prospective study in Canada evaluating the impact of medication-related ED visits. Over a 12-week period, 1017 adult patients were randomly selected and enrolled (mean age 49.3 years, 50.7% female) at Van-couver General Hospital. A drug-related visit was found in 122 patients (12.0%, 95%CI 10.1-14.2%) of which 83 (68.0%, 95%CI 59.0-76.2%) were deemed preventable. Severity was classified as mild, moderate and severe in 15.6% (95%CI 9.6-23.2%), 74.6% (95%CI 65.4-82.0%), and 9.8% (95%CI 5.2-16.6%) of cases, respectively. The most common ADEs were ADRs 39.3% (95%CI 30.6-48.6%), nonadherence 27.9% (95%CI 20.1-36.7%) and wrong/suboptimal drug 11.5% (95%CI 6.4-18.5%). The most common drug classes were antibiotics (11.2%), opioid-containing analgesics (11.2%), antipsychotics (9.5%), and benzodiazepines (6.1%). The number of comorbidities, number of medications and the use of multiple pre-scribers were found to be significantly associated with drug-related visits. Overall, 233 patients (22.9%) were admitted to hospital during the study period. This included 45/122 (36.9%, 95%CI 28.3-46.1%) patients with a drug-related visit and

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188/895 (21.0%, 95%CI 18.4-23.8%) patients without. The probability of admission for patients who presented with a med-ication-related visit compared to those whose visit was not medication-related, was significantly higher at 36.9% and 21.0%, respectively (OR 2.18, 95% CI 1.46-3.27), and if admitted, the median (IQR) length of stay was longer (8.0 (23.5) days vs. 5.5 (10.0) days, p=0.06).

MEDICATION-RELATED EMERGENCY DEPARTMENT VISITS IN PEDIATRICS

The majority of research performed has provided data for medication-related hospital visits in adults, but this issue has been poorly studied in pediatric patients. In the majority of studies published to-date, pediatric patients were either excluded or significantly under-represented among the study population. Those studies that have been performed in pediatric patients have used retrospective design or significantly limited prospective methodologies which preclude accurate determination of the magnitude of this issue. The incidence and classifications of medication-related ADEs in pediatrics cannot be expected to be the same as adults due in large part to the age-related prevalence of disease as well as the spectrum and scope of med-ication use. As a result, approaches to identify and prevent ADEs in pediatric patients will also be unique. Thus, our team performed the first and only prospective study to evaluate magnitude and impact of medication-related ED visits in pediatric patients.

We performed a prospective observational study of pediatric patients presenting to the ED over a 12-month period at the IWK Health Centre in Halifax, NS. 2028 patients were randomly selected and enrolled (mean age 6.1 years, 47.4% female). A medication-related visit (MRV) was found in 163 patients (8.0%, 95%CI 7.0-9.3%) of which 106 (65.0%, 95%CI 57.2-72.3%) were deemed preventable. Severity was classified as mild in 14 cases (8.6%, 95%CI 4.8-14.0%), moderate in 140 cases (85.9%, 95%CI 79.6-90.8%) and severe in 9 cases (5.5%, 95%CI 2.6-10.2%). The most common events were related to adverse drug reactions 26.4% (95%CI 19.8-33.8%), subtherapeutic dosage 19.0% (95%CI 13.3-25.9%) and nonadherence 17.2% (95%CI 11.7-23.9%). A total of 201 drugs (78 different agents), were implicated in the 163 MRVs (Table 3); 136 pa-tients (83.4%) had one drug implicated, 16 patients (9.8%) had two drugs implicated, and 11 patients (6.8%) had three drugs implicated. The most common drug classes were anti-infectives (27.4%), respiratory agents (22.4%), central nervous system agents (20.4%), immunosuppressants (7.5%) and gastrointestinal agents (6.0%). Age, the number of comorbidities, number of medications, the use of multiple pharmacies and the use of multiple prescribers were found to be significantly associated with MRVs. The probability of hospital admission was significantly higher among patients with a MRV compared to those without a MRV (OR 6.5, 95%CI 4.3-9.6) and, if admitted, the median (IQR) length of stay was longer (3.0 (5.0) days vs. 1.5 (2.5) days, p=0.02).

FUTURE DIRECTIONSOur work to-date reveals the significant impact ADEs have on patients and result in an ED visits and hospitalization. Future research should focus on a number of areas to further our understanding of the burden of ADEs and improve patient safety. Due to the heterogeneous nature of adverse medication-related events, interventions should focus on those that are most prevalent and where evidence exists to support a preventative strategy. The optimal strategy may involve interventions out-

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side the hospital to improve prescribing practices and monitoring, particularly in high-risk patients or high-risk medications. Interventions that target multiple levels (patients, health care providers, health care system) to optimize communication between acute and ambulatory settings and improve adherence should also be evaluated. Finally, further research is required to explore the higher admission rate and determine if ADEs that result in a visit to the ED are a marker of sicker patients or an independent factor leading to an increased likelihood of hospital admission.

FUNDING SUPPORTVancouver Coastal Health Research Institute Canadian Institutes of Health Research Izaak Walton Killam Research Fund Nova Scotia Health Research Foundation

TEAM MEMBERS/COLLABORATORSDr. Riyad B. Abu-Laban Dr. Stacy Ackroyd-Stolarz Crystal J. Anthony Dr. Robert M. Balen Dr. Karen T.L. Black Dr. Jeff R. Brubacher Dr. Janet Curran Eleanor A. Fitzpatrick Amy Fry Dr. Corinne Hohl Saleema Karim Katie Lacaria Dr. Peter S. Loewen Dr. Neil J. MacKinnon

Dr. Nancy G. Murphy Dr. Roy Purssell Dr. Mark Roberts Leslie Jo Samoy Dr. Doug Sinclair Jennifer Turple Dr. Matthew O. Wiens Dr. Kerry Wilbur

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SELECTED REFERENCES1. Samoy LJ, Zed PJ, Wilbur K, Balen RM, Abu-Laban RB, Roberts M. Drug-related hospitalizations in a tertiary care internal medicine service of a Canadian hospital: a prospective study. Pharmacotherapy 2006;26;1578-86.

2. Zed PJ, Abu-Laban RB, Balen RM, Loewen PS, Hohl CM, Brubacher JR, Wilbur K, Wiens MO, Samoy LJ, Lacaria K, Purssell RA. Incidence, severity and preventability of medication-related visits to the emergency department: a prospective study. CMAJ 2008;178:1563-9.

3. Hohl CM, Zed PJ, Brubacher JR, Abu-Laban RB, Loewen PS, Purssell RA. Do emergency physicians attribute drug-related emergency department visits to medication-related problems? Ann Emerg Med 2010;52:493-502.

4. Ackroyd-Stolarz S, MacKinnon NJ, Zed PJ, Murphy NG. Use of an electronic information system to identify adverse events resulting in an emergency department visit. Qual Saf Health Care 2010;19:1-5.

5. Ackroyd-Stolarz S, MacKinnon NJ, Murphy N, Gillespie E, Zed PJ. Adverse events related to medications identified by a Canadian poison centre. J Popul Ther Clin Pharmacol 2011;18:e250-6.

6. Hohl CM, Nosyk B, Kuramoto L, Zed PJ, Brubacher JR, Abu-Laban RB, Sheps SB, Sobolev B. Outcomes of emergency department patients who present with adverse drug events. Ann Emerg Med 2011;58:270-9.

7. Anthony CJ, Karim S, Ackroyd-Stolarz S, Fry A, Murphy NG, Christie R, Zed PJ. Intensity of anticoagulation with warfarin and risk of adverse events in patients presenting to the emergency department. Ann Pharmacother 2011;45:881-7.

8. Zed PJ, Haughn C, Black KTL, Fitzpatrick EA, Ackroyd-Stolarz S, Murphy NG, MacKinnon NJ, Curran J, Sinclair D. Medica tion-related emergency department visits in pediatrics: a qualitative systematic review. J Pediatrics 2013;163:477-83.

9. Zed PJ, Black KTL, Fitzpatrick EA, Ackroyd-Stolarz S, Murphy NG, Curran J, MacKinnon NJ, Sinclair D. Medication-related emergency department visits in pediatrics: a prospective observational study. Pediatrics 2015;135:435-43.

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