Overview of Included Studies
The total number of citations identified was 22,082. After removing duplicates, this number fell to 16,571. The PRISMA flow diagram (Fig. 1) illustrates the citation review stages. All included studies are summarised in one table in Appendix 4 of the ESM, followed by tables in Appendixes 5–8 of the ESM, which summarise these studies based on the medication safety measure (ME, ADE, ADR, UMD).
In total, 54 studies were included in the systematic review, including 20,895 hospital discharges across 26 countries. The included studies consisted of 41 published papers [23, 24, 48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86] and 13 conference abstracts [87,88,89,90,91,92,93,94,95,96,97,98,99]. One of the included conference abstracts [88] was combined with one letter to the editor [100]. All included studies were published in English.
The majority of included studies were conducted in the United States of America (USA) (17/54, 31.5%) [52, 54,55,56,57, 61, 70, 74, 76, 78, 79, 82, 89, 90, 94, 96, 97], followed by the United Kingdom (UK) (7/54, 13%) [24, 49, 50, 59, 87, 95, 98]. Forty-three (79.6%) studies were published from the year 2010 onwards [23, 24, 51,52,53, 56,57,58,59,60,61, 64,65,66,67,68,69,70, 72, 73, 75,76,77,78,79,80,81,82, 84, 85, 87,88,89,90,91,92,93,94,95,96,97,98,99]. Of the 54 studies, 28 (51.8%) included adult patients, 18 (33.3%) focused specifically on elderly patients. Three studies (5.5%) were exclusively conducted in paediatric patients [75, 86, 95]. Most studies (85.2%, 46/54) were prospective in design [23, 24, 48,49,50,51,52, 54, 55, 57,58,59,60, 63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78, 80, 81, 83, 85, 86, 89,90,91,92,93, 95,96,97,98,99].
Seventy six percent of studies (41/54) included patients who were discharged home [24, 49,50,51,52,53,54, 56,57,58,59, 61, 62, 64, 65, 67,68,69,70,71,72, 74,75,76,77,78,79,80,81,82, 85,86,87,88, 92, 94,95,96,97,98,99], with three (5.5%) including patients discharged to nursing homes [60, 66, 98]. The most frequent data collection method was screening case summaries [e.g. discharge medical record and discharge summary] (43/54, 79.6%), followed by telephone follow-up interviews with the patient (25/54, 46.2%). Data collectors were mostly pharmacists (27/54, 50%). Almost a quarter of included studies (13/54, 24%) utilised a follow-up period post-discharge of 1 month, with the next most common time period being 1 week (7/54, 12.9%). The shortest follow-up period was 2 days and the longest was 180 days. Table 2 summarises key study characteristics.
Table 2 Characteristics of included studies Quality Assessment of Included Studies
A summary of the quality assessment of included studies is provided in Table 3. The quality assessment score was low (score = 1–4) in 14.8% of studies (8/54), moderate (score = 5–8) in 72.2% (39/54) and high (score = 9–12) in 12.9% (7/54). The aim and objectives were clearly described in all but one paper [96] and the outcome definition was clearly mentioned in 27 papers [24, 49, 50, 53, 54, 56, 58,59,60,61,62, 64, 68,69,70, 72, 75, 76, 79,80,81,82,83,84,85,86, 88]. In studies that measured drug-related problems (DRPs) but also reported data on MEs/ADEs, reported definitions of DRPs were accepted. The definition of a DRP was provided in six studies [53, 56, 58, 76, 79, 81] out of the cohort of 27 studies that mentioned outcome definitions. Error categories were mentioned in 14 studies [23, 24, 60, 61, 65, 70,71,72, 75, 81, 85, 87, 90, 97] but were only defined in five studies [60, 72, 75, 85, 87]. The outcome denominator was clearly defined in all papers and the data collection method was described clearly in all but one study [91]. The study setting was clearly described in all but six studies [73, 80, 90, 91, 93, 98]. Validity measures, to assess if independent personnel or an expert panel evaluated the event other than the data collector, were applied in 29 studies [23, 24, 48, 50, 54,55,56,57,58,59, 61, 62, 64,65,66,67, 69, 70, 72, 74, 77,78,79,80, 83, 84, 86, 94, 95] to confirm the occurrence of medication safety outcomes. Reliability measures to evaluate if a formal test/evaluation (e.g. Kappa test or consensus) was completed to assess inter-rater reliability were applied in 12 studies [24, 50, 54, 61, 65, 66, 70, 74, 78,79,80, 83]. Nearly two thirds of the included papers reported their limitations with 16 papers (including 11 conference abstracts [49, 58, 67, 68, 86, 89,90,91,92,93,94,95,96,97,98,99]) not reporting this information. Only nine studies [24, 59, 60, 63, 75, 80, 81, 83, 98] calculated sample size, with five studies [60, 75, 77, 83, 98] describing any assumptions made.
Table 3 Quality assessment Medication Error Studies
In total, 12 studies [23, 65, 71, 72, 75, 85, 87, 89, 90, 96, 97, 99] reported data concerning the frequency of MEs. Six studies used established definitions of MEs [23, 71, 72, 75, 85, 87], with one study developing their own definition [90], and five not reporting any definition [65, 89, 96, 97, 99]. Five studies [71, 72, 87, 90, 97] reported data specifically concerning prescribing errors, of which two [72, 87] used the prescribing error definition proposed by Dean et al. [101].
All studies explicitly used the number of discharged patients as their denominator. Seven studies that used patients affected by at least one ME as their numerator are summarised below [23, 72, 75, 87, 89, 96, 99]. Across five studies from three settings that reported ME rates per discharged patient [23, 87, 89, 96, 99], a median of 53% [IQR 33–60.5%] of adult and elderly patients experienced MEs post-discharge. Two prospective studies [96, 99] out of these five reported ME rates for patients discharged home as 47–53% of discharged patients. A range of 19–53% of elderly discharged patients (n = 2) experienced at least one ME post-discharge [23, 96].
One study [72] reported that one or more prescribing errors affected 43% of discharged patients. Another study [87] reported that 3.5% of discharge medications were affected by at least one monitoring error post-discharge. One study [61] reported ME and medication administration error rates for infants as 66.3% and 54.0% of discharged patients, respectively.
Unintentional Medication Discrepancy Studies
In total, 14 studies reported data concerning the frequency of UMDs [49, 50, 57, 59, 60, 66, 70, 74, 83, 84, 88, 93, 95, 98]. Three studies [83, 84, 93] used an established UMD definition, seven [49, 50, 59, 60, 70, 74, 95] developed their own and four [57, 66, 88, 98] did not report any definition.
The majority of included studies explicitly used the number of discharged patients affected by at least one event as their numerator, except two studies that used the number of discharge medications affected by one or more UMDs [49, 50]. These latter studies [49, 50] reported that 11–52.7% of individual prescribed medications had at least one UMD post-discharge. One study [95] reported that at least one UMD affected 12% of discharged paediatric patients. Across 11 studies [57, 59, 60, 66, 70, 74, 83, 84, 88, 93, 98], a median rate of 50% (IQR 39–76) of adult and elderly patients experienced at least one UMD post-discharge (range 14–93.5%). Four studies [59, 70, 74, 93] that used a telephone follow-up among data collection methods, and five studies using case note screening [60, 66, 83, 84, 98] reported the rate of UMD to be 65–93.5% and 14–76%, respectively, per adult and elderly patient discharged. A range of 36.5–93.5% of discharged elderly patients (n = 5) experienced UMDs post-discharge [60, 66, 83, 88, 93].
Adverse Drug Events
Seventeen studies [24, 48, 54,55,56, 61, 67, 69, 70, 74, 78, 80, 82, 86, 92, 94, 97] reported ADE rates post-hospital discharge, 17 studies [24, 51,52,53, 58, 62,63,64, 68, 71, 73, 76, 77, 79, 81, 82, 91] reported non-preventable ADE rates (ADRs) post-discharge, one study [24] reported both.
Non-preventable Adverse Drug Events (Adverse Drug Reactions)
Three studies [62, 64, 68] used the ADR definition proposed by the WHO in 1972, nine studies [51, 53, 58, 63, 71, 76, 79, 81, 82] used a broader DRP definition that included ADRs, and three [52, 77, 91] did not state a definition.
All studies explicitly used the number of discharged patients as their denominator. Across five studies [24, 58, 64, 73, 91] that used patients affected by events as their numerator, a median of 27% (IQR 18–40.5) of adult and elderly patients experienced one or more ADRs post-hospital discharge. Two studies [24, 73] that used a telephone follow-up as the most common data collection method reported the rate of ADRs post-discharge to be 20.4–27% of discharged patients. A range of 27–51% of elderly discharged patients (n = 3) experienced ADRs post-discharge [24, 58, 64].
Adverse Drug Events
Four studies [61, 74, 80, 86] used the ADE definition proposed by Bates et al. [32]. Seven studies [48, 55, 67, 78, 92, 94, 97] did not formally define ADEs. All studies explicitly used the number of discharged patients as their denominator. One study [86] reported the rate of post-discharge ADEs as 9% of paediatric patient hospital discharges. One study [82] reported the mean number of ADEs per discharged patient as 3. Across seven studies [24, 54, 55, 61, 69, 74, 94] that used patients affected by at least one event as their numerator, the median ADE rate was found to be 19% [IQR 16–24%] of adult and elderly patients experiencing one or more ADEs post-discharge. Two studies [74, 80] reported that between 11 and 16% of discharged patients experienced one or more preventable ADEs.
Five studies [24, 54, 55, 69, 74] that used telephone follow-up interviews among data collection methods reported 11–37% (median 20.3%, IQR 13.5–30.5) of adult and elderly patients discharged experienced one or more ADEs. Two studies [61, 94] that used case note screening among data collection methods reported that 18.7–18.9% of discharged patients were affected by ADEs post-hospital discharge. Two studies [54, 78] that adapted Bates definition of ADEs and used the same data collection method reported that 11–16% of adult and elderly patients had at least one ADE after hospital discharge. The highest reported ADE rate was 37% of patients using a telephone interview method in one study [24] in the UK. A range of 18.7–37% of elderly discharged patients (n = 4) experienced ADEs post-discharge [24, 55, 61, 94]. Table 4 summarises outcome rates of the included studies per patient population.
Table 4 Outcome rate summary Severity of Events
Eighteen [24, 54,55,56, 59, 61, 62, 64, 66, 69, 70, 72, 78, 80, 88, 91, 94, 95] (18/54, 33.3%) studies reported severity data of identified outcome measures, including one ME study [72], three ADR studies [62, 64, 91], nine ADE studies [24, 54,55,56, 61, 69, 78, 80, 94] and five UMD studies [59, 66, 70, 88, 95]. Seven studies [54, 61, 62, 64, 72, 78, 80] reported severity assessment based on existing rating scales published in the literature. Of these, three studies [54, 61, 78] used the severity rating proposed by Bates et al. [32], with various other scales being used by remaining studies.
Comparability of the severity of events was limited because of heterogeneity across studies in presenting severity of event data (e.g. number of patients affected by one or more serious incidents, or number of serious incidents), severity rating scale, and the small number of included studies particularly when divided across patient populations. One study reported that 86% of adult patients affected by MEs were considered to be moderate harm events [72]. Among patients affected by ADRs, three studies reported that serious ADRs affected 6.9%, 47% and 60% of elderly, adult and all age groups patients, respectively [62, 64, 91]. Among patients affected by ADEs post-hospital discharge, serious ADEs were reported to affect 13.3% of adult patients, and 81% of elderly patients in two studies [24, 54]. Four studies reported that the median rate of serious ADEs was found to be 29% (IQR 21–38.5%) of adult and elderly patients experiencing one or more ADEs post-discharge [61, 69, 80, 94]. Among patients affected by UMDs, three studies reported that between 25 and 34% of elderly patients [66, 88], and 63.3% of paediatric patients were affected by moderate harm events [95]. Two studies reported that 33–38% of UMDs identified post-hospital discharge as associated with a high potential of harm in adult patients [59, 70]. Appendix 9 of the ESM includes a summary of severity data of the included studies.
Medication Involved in Unintentional Medication Discrepancies/Adverse Drug Events
Fourteen studies [24, 53,54,55,56, 61, 62, 64, 70, 71, 78, 79, 82, 91] reported data regarding individual medications or drug classes associated with UMDs (n = 1) and ADEs (n = 14). Studies evaluating MEs did not report data regarding medications involved. The most common drug classes that were reported to lead to post-discharge ADEs across 14 studies [24, 53,54,55,56, 61, 62, 64, 70, 71, 78, 79, 82, 91] were antibiotics, antidiabetics, analgesics and cardiovascular drugs (common subclasses were anti-hypertensive and anticoagulant medications). Only one study [64] reported a statistical method to formally associate the prescription of warfarin with ADEs. Appendix 10 of the ESM summarises medications and medication classes that were reported to be involved in UMDs/ADEs, classified according to the British National Formulary system [102].