An adverse drug event (ADE) is defined as “an injury resulting from medical intervention related to a drug” [1]. The term encompasses harms that occur in any health care setting that are directly due to the drug including but not limited to medication errors, adverse drug reactions (ADRs), allergic reactions, and overdoses [2].

The clinical and economic burdens of ADEs are significant. Thus, it is critical to minimize the potential consequences of ADEs. Although a large majority of medical errors and ADRs are preventable, numerous studies have reported that ADRs are associated with clinically significant morbidity and mortality, and are a serious threat to public health [3–5]. A review of 25 studies including 106,586 hospitalized patients found that up to 15.7% of hospitalized patients experienced ADRs [3]. A study focused on more vulnerable populations reported that the overall incidence of ADRs was 9.5% and 1.5% in hospitalized and outpatient children, respectively [4]. Another study reviewed ADEs in the elderly, and showed that 23.1% of emergency department admissions were found to be ‘probably’ or ‘possibly’ medication-related (13.1% and 10.0%, respectively) [5]. Therefore, medication-related adverse events leading people to seek medical care are common in all populations, including special populations.

To reduce potential ADEs and their consequences, many types of quality assurance programs have been developed and introduced [6–8]. In South Korea, a prospective Drug Utilization Review (DUR) program, a systematic review program integrated with electronic medical records (EMRs) and electronic insurance claims submission systems, has been in use since December 2010 to improve the quality and safety of medication use [9, 10]. It is reported that 99.4% of South Korean outpatient health care facilities are currently utilizing the program to alert preventable ADRs (pADRs) [10]. However, despite the program’s purpose, no study has evaluated its influence in reducing the incidence of pADRs since its implementation.

We utilized the national health insurance claims database to evaluate the influence of the DUR program in reducing pADR incidence by quantitatively studying trends in ADE episodes leading people to seek medical care.

Data extraction from the HIRA database covering the years 2009 through 2014 identified 3,927,662 records with a primary diagnosis of an ADE. The incidence rates of first-time ADEs were 58.9, 58.8, 58.5, 59.1 and 59.8 per 10,000 population in 2010, 2011, 2012, 2013, and 2014, respectively. On the other hand, 5.4, 5.6, 5.1, 5.2 and 5.1 repeat ADEs occurred in every 10,000 population.

Demographic data and clinical characteristics are presented in Table 1. pADRs represented 634,324 of the first-time episodes (43.3%) that occurred during the 5-year period (2010–2014). Of these, 43.1% were male patients. The mean age of these patients was 47.0 years (standard deviation (SD) = 20.2) and the cohort aged ≥65 years represented 19.8% of the study population. A total of 525,412 pADRs (51.6%) events caused primary care provider visits, while 96,413 events (15.2%) led to treatment at tertiary hospitals.

The repeat/first-time pADR event ratio was 9.8. Among the people who experienced first-time pADRs, the same types of ADR occurred in 64,816 cases (43.9% male; mean [SD] age, 52.6 [18.6] years). Among these people, 27,900 (43.0%) sought medical care from primary care physicians while 15,958 (24.6%) were treated at tertiary hospitals.

Fig 1 shows the quarterly incidence rates of total ADEs, allergic reactions, and pADRs with seasonal variation. First-time pADR rates did not decrease immediately. Rather, they decreased gradually after implementation of the DUR program (change in slope: -0.016, p = 0.02). The DUR program had a similar influence on repeat pADR rates (change in slope: -0.006, p≤0.01). On the other hand, the program did not decrease rates of first-time or repeat allergic reactions (change in slope: 0.018, p = 0.07 and 0.003, p = 0.04, respectively).

Table 2 provides a comparison of pADR rates during pre- and post-DUR program implementation according to sex, age group, and type of health care system. The relative reduction of first-time pADRs in both male and female populations (16.7% [95% CI: 15.1–18.2] and 17.2% [15.6–18.9] were significant. In the population aged ≤65 years, first-time pADR rate reductions were significant (28.2% [27.1–29.3] in ≤18 years and 19.8% [18.1–21.5] in 19–64 years). By contrast, first-time pADR rates increased by 0.6% [-0.7–1.9] in the population ≥65 years. The relative reductions of repeat pADR rates were 23.1% [22.5–23.6], 20.8% [19.8–21.8], and 1.6% [0.8–2.4] in ≤18, 19–64, and ≥65 years, respectively. Among the different types of health care system, primary care providers were the most significantly influenced by DUR program implementation, with first-time and repeat pADRs reduced by 28.9% [27.3–30.5] and 34.8% [33.9–35.7], respectively.

Table 3 reports the five most frequently observed ICD-10 codes related to pADRs and the relative reduction of each diagnosis code after DUR program implementation. In first-time pADRs, K71 [Drug-induced idiosyncratic liver disease] was the most frequent diagnosis (36.5%), followed by L279 [Dermatitis due to unspecified substances taken internally] (13.0%) and L278 [Dermatitis due to other substances taken internally] (7.6%). K71 accounted for 42.8% of repeat pADRs, followed by L279 (8.5%), and G253 [Drug-induced myoclonus] (5.2%). Both first-time and repeat pADR rates related to K71 were significantly reduced after implementation of the DUR program (relative reduction: 25.2% [23.7–26.7] and 19.6% [18.7–20.5], respectively. The highest relative reduction of pADR rates was related to L279: 31.9% [30.7–33.0] for first-time events and 65.7% [65.1–66.3] for repeat events.

The present study provides a comprehensive, population-based evaluation of the influence of DUR program implementation on the incidence of first-time and repeat pADRs. Our data demonstrate that 59 out of every 10,000 individuals experience adverse events due to medications at least once each year, and of those, 26 individuals experience preventable ones. The DUR program had a significant impact on healthcare as demonstrated by decreased rates of pADRs while rates of allergic reactions unchanged or trended up. Since the DUR program does not include a module that alerts drug allergy history, this was as expected. The HIRA agency is currently making an effort to establish a module related to allergy alerts which requires a complex algorithm. Instead, hospitals with a pharmacovigilance center currently have an institution-level DUR program to alert the ADR risk for patients with allergy history using an ADR database.

A few studies have evaluated the impact of the DUR program on clinical outcomes, although results have been heterogeneous [7, 13]. Hennessy and colleagues retrospectively studied the effect of DUR implementation on the rate of exceptions, which were defined as a violation of criteria, and clinical outcomes for patients with exceptions using Medicaid data [7]. They found no reduction in the rate of exceptions coincident with DUR implementation (rate increase, 0.064 exceptions per 1,000 prescriptions per month; 95%, -0.006–0.133). Implementation of the DUR program also had no effect on the incidence of hospitalization for all causes (odd ratio (OR), 0.99; 95% CI, 0.98–1.00). Yet, these results were not comprehensive, since the analysis was limited to three criteria (drug-drug or drug-disease interactions, and therapeutic duplication) and other criteria such as excessive dose, insufficient dose, and excessive medication duration were purposely omitted.

A case-controlled retrospective study evaluating the impact of DUR implementation on physician spillover effect on future prescription following pharmacist’s intervention reported that a physician in a case group was eight times less likely to receive repeated interventions than a physician in a control group (2.2% and 18.2%, p<0.001, respectively) [13]. The shortcoming of this study was that the results were restricted to its impact on subsequent physician prescribing patterns, rather than directly correlating their interventions with clinical outcomes.

There are also a few studies evaluating effects of the DUR program in Korea since implementation. However, previous studies have focused on its effectiveness in cost-saving or in reducing the number of inappropriately prescribed medications [9, 14–16] rather than its consequences such as hospitalization due to medication misuse.

In contrast, we evaluated the DUR program’s direct effects on reducing specific negative clinical outcomes; the incidence of preventable adverse events due to medications. Since the program is not designed to capture non-preventable ADEs such as allergic reactions, we used rates of total ADEs and of allergic reactions as controls. As shown in Fig 1A, first-time incidence rates of total ADEs and allergic reactions trended up (change in slopes: 0.004, p = 0.81 and 0.018, p = 0.07) despite implementation of the DUR program. The rate of repeat allergic reactions was not reduced (change in slope: 0.003, p = 0.04) (Fig 1B). The most likely reason that first-time and repeat allergic reaction rates were increased is that there have been increased awareness and improved recording of drug allergies and consumption of drugs while no action has been taken to reduce the risk of allergic reaction. Thus, a marked rise in the incidence rates of allergic reaction appears unrelated to the implementation of the DUR program. Our study results strongly support the government agency to include the allergy alert module in the DUR program.

Conversely, both first-time and repeat pADR rates were significantly decreased (change in slopes: -0.016, p = 0.02 and -0.006, p≤0.001, respectively) upon DUR program implementation. In addition, when comparing incidence rates during pre- and post-DUR periods (Tables 2 and 3), post-DUR rate reductions remain significant (17.0% [15.2–18.8] for first-time pADRs, and 16.2% [15.1–17.3] for repeat pADRs).

ADRs are recognized as a major cause of morbidity, especially in the elderly. It has been reported that 36.7% of total prescriptions to elderly patients visiting ambulatory care were inappropriately prescribed [14]. This was confirmed by a regional pharmacovigilance center of the Korean Pharmaceutical Association, as one-third of reported ADRs were experienced by elderly patients [17]. Unfortunately, we found that elderly patients were the least benefitted by the DUR program’s effect on pADR rates. In fact, the rate of first-time pADRs in the population ≥65 years remained unchanged. The most plausible reason that the program was not effective in reducing pADRs in this population is that the criterion specifically designed to prevent inappropriate medication use in the elderly was absent at the time of program implementation. Despite the well-known fact that the elderly are at higher risk of experiencing ADRs because of multiple morbidities and polypharmacy than the general population, the criterion “precautions for use in the elderly” was not introduced until October 2015. Thus, the observed pADR rate reductions did not reflect the addition of this new criterion. Currently, the criterion has nineteen medications on its list, and most of them are known to be sedating and to increase risk of cognitive impairment (S1 Table). While it is clear that these medications should be avoided in the elderly, the list also needs to be expanded, as many researchers have suggested a wide range of potentially inappropriate medication uses in this population [18–20].

Liver damage was one of the disease manifestations most frequently identified as medication-induced in many studies [21, 22]. In the present analysis, the most commonly observed diagnoses were associated with liver damage, consistent with previous findings. We found that implementation of the DUR program effectively reduced the incidence of both first-time and repeat pADRs related to liver symptoms (relative reduction: 25.2% [23.7–26.7] and 19.6% [18.7–20.5], respectively).

To our knowledge, this is the first study to evaluate the effectiveness of implementation of the nationwide, prospective DUR program in reducing first-time and repeat pADRs. While recognizing its financial benefits by reducing total health care system and medication usage is important, our analyses demonstrated that the DUR program is able to detect pADRs before medication is dispensed and prevent potentially fatal medical consequences.

However, our study had several limitations. First, although pharmacists are encouraged to enter the over-the-counter medications into the DUR program for comprehensive medication review, it is not mandatory. Thus, it is possible that the DUR is limited to prescription medications. Second, when pharmacists’ are dispensing medications, they are unable to review the appropriateness of prescribed medications since the program does not provide clinical information. Therefore, the effect of the DUR program may have been underestimated in preventing adverse medical results.

In conclusion, implementation of the prospective DUR program was effective in reducing the incidence of pADRs. Continuous updates of criteria in the DUR program is encouraged to minimize pADRs. In addition, in order to reduce non-preventable adverse drug reactions, such as allergic reactions, providing clinical information including allergy history should be established in the DUR program.