Research Article: Incidence, causes, and consequences of preventable adverse drug reactions occurring in inpatients: A systematic review of systematic reviews

Date Published: October 11, 2018

Publisher: Public Library of Science

Author(s): Dianna Wolfe, Fatemeh Yazdi, Salmaan Kanji, Lisa Burry, Andrew Beck, Claire Butler, Leila Esmaeilisaraji, Candyce Hamel, Mona Hersi, Becky Skidmore, David Moher, Brian Hutton, Adam Todd.


Preventable adverse drug reactions (PADRs) in inpatients are associated with harm, including increased length of stay and potential loss of life, and result in elevated costs of care. We conducted an overview of reviews (i.e., a systematic review of systematic reviews) to determine the incidence of PADRs experienced by inpatients. Secondary review objectives were related to assessment of the effects of patient age, setting, and clinical specialty on PADR incidence.

The protocol was registered in PROSPERO (CRD42016043220). We performed a search of Medline, Embase, and the Cochrane Library, limiting languages of publication to English and French. We included published systematic reviews that reported quantitative data on the incidence of PADRs in patients receiving acute or ambulatory care in a hospital setting. The full texts of all primary studies for which PADR data were reported in the included reviews were obtained and data relevant to review objectives were extracted. Quality of the included reviews was assessed using the AMSTAR-2 tool. Both narrative summaries of findings and meta-analyses of primary study data were undertaken.

Thirteen systematic reviews encompassing 37 unique primary studies were included. Across primary studies, the PADR incidence was highly varied, ranging from 0.006 to 13.3 PADRs per 100 patients, with a pooled incidence estimate of 0.59 PADRs per 100 patients. Substantial heterogeneity was present across both reviews and primary studies with respect to review/study objectives, patient age, hospital setting, medical discipline, definitions and assessment tools used, event detection methods, endpoints of interest, and units of measure. Thirteen primary studies used prospective event detection methods and had a pooled PADR incidence of 3.13 (2.87–3.38) PADRs per 100 patients; however, extreme statistical heterogeneity (I2 = 97%) indicated this finding should be considered with caution. Subgroup meta-analyses demonstrated that PADR incidence varied significantly with event detection method (prospective > retrospective > voluntary reporting methods), hospital setting (ICU > wards), and medical discipline (medical > surgical). High statistical heterogeneity (I2 > 80%) was present across all analyses, indicating results should be interpreted with caution. Effects of patient age could not be assessed due to poor reporting of age groups used in primary studies.

The method of event detection appeared to significantly influence PADR incidence, with prospective methods having the highest reported PADR rate. This finding is in agreement with the background literature. High methodological and statistical heterogeneity across primary studies evaluating adverse drug events reduces the validity of the overall PADR incidence derived from the meta-analyses of the pooled data. Data pooled from studies using only prospective methods of event detection should provide an overall estimate closest to the true PADR incidence; however, our estimate should be considered with caution due to the statistical heterogeneity found in this group of studies. Future studies should employ prospective methods of detection. This review demonstrates that the true overall incidence of PADRs is likely much greater than the overall pooled incidence estimate of 0.59 PADRs per 100 patients obtained when event detection method was not taken into consideration.

Partial Text

Medical errors are the third leading cause of death in the United States [1]. In the year 2000, an estimated 70,000 Canadian patients experienced at least one highly preventable adverse event (AE) due to health care management, resulting in an estimated 9,250 to 23,750 preventable deaths [2]. Medication errors (MEs)—failures in the treatment process that lead to, or have the potential to lead to, harm to the patient [3]—accounted for almost a quarter of all AEs [2]. Adverse events caused by medication errors are generally considered to be preventable [4], and are referred to as preventable adverse drug events (PADEs). Adverse drug events (ADEs), by definition [5], occur after administration of a medication at any dosage level and may or may not incur harm to the patient (e.g., over-dosage of a drug that caused increased monitoring of a patient but no resultant harm). Adverse drug reactions (ADRs) are, by definition [6], a subset of ADEs (Fig 1) in that they only occur following drug administration within normal dose ranges and they result in “noxious and unintended” consequences to the patient. Preventable adverse drug reactions (PADRs) include ADRs caused by medication errors, whether they be acts of omission or commission, incorrect medication/dose/timing, administration of a medication to a patient with a known allergy, inadequate monitoring, or other errors.

Preliminary scoping of the literature identified several existing systematic reviews on the topic of ADRs. Therefore, we used an “overview of reviews” approach to identify relevant data [11,12]. Methods were developed in consultation with both the Cochrane Handbook’s chapter on overviews of reviews [11] and recent work by Smith [12]. A review protocol [13] was drafted prior to review initiation and registered with PROSPERO (CRD42016043220). Amendments were made to this protocol after completion of the overview of reviews, when we recognized that limitations in reporting of PADR data within the included systematic reviews had precluded answering of many of our secondary review questions. In this manuscript, the term “reviews” refers to the systematic reviews included under the original protocol, while “studies” refers to the primary studies found within those reviews.

Evidence identified from the review is presented in two stages. The findings from the overview of reviews have been presented first, followed by the more substantive evidence obtained from the primary studies that were reported in our included reviews.

Spontaneous adverse drug reaction reporting programs provide important information on adverse events that may not have been detected during the pre-market clinical trial process. However, spontaneous reporting is limited by factors such as under-reporting and a lack of data on the population exposed to the drug that precludes the estimation of incidence rates. Research conducted outside of this system is necessary to acquire a better understanding of the occurrence of PADRs in specific populations or settings, such as hospitals. With this objective in mind, we undertook an overview of reviews, identifying 13 systematic reviews that reported in-hospital PADR data from 37 primary studies. However, obtaining a summary estimate of PADR incidence that could be generalized to all populations and settings was not possible due to heterogeneity of several sources within the primary studies. These included intra-study variability in the elements of the PADR definition, patient age, hospital setting, medical discipline, event detection methods, and others.

More well-conducted, well-reported primary studies that use accepted definitions and causality assessment tools need to be conducted in the Canadian context to address the lack of Canadian PADR data in the published literature. Globally, while several systematic reviews and a broad range of primary research studies exist that have sought to assess the occurrence of preventable adverse drug reactions (and related outcomes), there remains considerable diversity in methods and other factors that complicate the ability to establish a single overall estimate of PADR incidence. Rather than using an incidence estimate pooled from multiple heterogenous studies, readers may want to consider using incidence estimates reported in individual primary studies that incorporated prospective event detection methods and that were conducted in a similar context to the one of interest (i.e., country and hospital setting). Our findings from our secondary review questions and their general concordance with the existing literature suggest that interventions to reduce PADRs may be most effective when targeted at the use of specific drug classes in medical and ICU patients. However, substantial reductions in adverse events may be unlikely to occur without complex, multi-component interventions, including intensive institutional cultural change.




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