Cost-Effectiveness Analysis of Implementing a Secondary Prevention Programme in Those Patients Who Visited an Emergency Department for Drug-Related Problems

Background: To evaluate the cost-effectiveness of a secondary prevention programme in patients admitted to the Emergency department due drug-related problems (DRPs) Methods: A decision model compared costs and outcomes of patients admitted to the Emergency department with drug-related problems included in Anatomical Therapeutic Classication (ATC) groups A, B or C was designed, based on the results of a randomized clinical trial (NCT03607097). Model variables and costs, along with their distributions, were obtained from the trial results and the literature. The study was performed from the perspective of the National Health System including only direct costs. The Incremental Cost-Effectiveness ratio (ICER) was analysed regarding the ability of the programme to reduce emergency department revisits. Uncertainty in ICERs was evaluated with probabilistic sensitivity analyses. Results: According to the results of the proposed model, the implementation of a secondary prevention programme for DRPs reduces the cost associated with Emergency Department revisits, with an annual net benet of €87,639. Considering a mortality rate attributable to readmission for DRPs of 4.7%, the cost per life-years gained (LYG) with the implementation of this program was €2,205. In the short term, the reduction in the number of revisits due to the implementation of the programme was the variable that most affected the model, with the benet threshold value corresponding to a relative reduction of 12.4% of the number of revisits in patients with DRPs to obtain benets with the implementation of this type of programme. Conclusions: Implementing a secondary prevention programme is cost-effective on patients admitted to the emergency department with DRPs. Implementation costs will be exceeded by reducing revisits to the emergency department.


Introduction
Drug-related problems (DRPs), de ned as pharmacotherapy failure in patients owing to drug e cacy, safety, or availability problems, are a major public health issue. It is estimated that approximately 5-10% of hospital admissions and 30% of Emergency Department (ED) visits result from DRPs, and most are considered preventable [1][2][3][4].
Several studies published over the last decade have demonstrated that the implementation of multidisciplinary programmes focused on the primary prevention of DRPs can be effective strategies to reduce the risk of hospital admission [5][6][7]. However, the available evidence on the e cacy of secondary prevention programmes in patients who suffer a rst DRPs episode is limited. Therefore, we designed a clinical trial (Clinical Trials.gov: NCT03607097) in a public tertiary hospital to determine the impact of a multidisciplinary action on patients who visit the ED with DRPs, whose results have been published recently [8]. Despite the high number of studies that show the healthcare impact of these programmes, there is limited information on the e ciency of this type of intervention. The reduction in the number of hospital assistances secondary to the implementation of these programs implies a lower cost for the public health system. Cost-effectiveness analyses are a useful tool to guide on the selection of e cient strategies for health institutions and healthcare administrators. The aim of our study was to determine the cost-effectiveness of the implementation of a secondary prevention programme for DRPs in patients attended in an ED by extrapolating the patient-level data collected from the Medication Code trial

Methods
In the present study, we conducted a cost-effectiveness analysis of the implementation of a multidisciplinary healthcare programme for the secondary prevention of DRPs in patients attending an ED from a Catalan healthcare payer perspective. Speci cally, the programme developed a set of interventions at different levels of healthcare (collectively referred to as 'Medication Code') with the objective of reducing the 30-day revisits of patients attended in the ED for DRPs caused by medicines from the Anatomical Therapeutic Chemical (ATC) categories A (Alimentary tract and metabolism), B (Blood and blood forming organs) or C (Cardiovascular system). These interventions included actions aimed at improving the patient's chronic prescriptions (interview with the patient and a review of their chronic medication treatment), therapeutic adherence (including the delivery of written information on the medication treatment plan and a telephone consultation 48 h after discharge), and coordination between different levels of healthcare (including sending an email to the next healthcare provider explaining the reason for the consultation any changes in the medication treatment). Patients in the control group received the standard care in ED, consisting of medication review and prescriptions validation.  A decision tree was developed to simulate the clinical progression of patients attended in the ED (Fig. 1), according to which patients attended for DRPs for medicines in groups A, B, or C could be either treated or not by the 'Medication Code' programme. To simplify the model, the DRPs were considered mutually exclusive. As the study determined the effect of the intervention programme after hospital discharge, the possible reduction in the patient's length of hospital stay after the initial intervention programme was not considered in the model.
An incremental cost-effectiveness ratio (ICER) analysis was performed on the ability of the programme to reduce ED attendance. The ICER was calculated based on the costs assumed for the implementation of the programme in relation to the ED revisit cases with and without the implementation of the programme.
The cost per life year gained (LYG) was calculated based on the prevention of death after a revisit due to DRPs, considering a mortality attributable to the admission for DRPs of 4.7% and a mean age of ED attendance of 80.3 years according to the results of the clinical trial 7 , being the life expectancy of 83.8 years in Spain [10].
The nal model was calculated using Microsoft Excel v.14.5.9. A univariate sensitivity analysis (tornado diagram) was performed to establish the short-term robustness of the model to variables with uncertainty, including the risk of revisit and readmission (50%), costs associated with revisits (20%), number of annual ED visits (5%), patient identi cation loss rate (50%), as well as the percentage of visits caused by DRPs in A, B, or C groups (20%).
In addition, a probabilistic sensitivity analysis was performed to analyse the cost per prevented DRPs and per LYG. The variables included in the analysis were the risk of revisit and readmission (50%), the costs associated with these (20%), the number of annual ED visits (5%), the patient identi cation loss rate (50%), as well as the percentage of visits caused by DRPs in groups A, B, or C (20%). The variation in mortality related to DRPs was considered to be 20%. The analysis was performed using a Monte-Carlo simulation on the included uncertainty variables, simulating a cohort of 1,000 patients admitted to the ED unit, either after the implementation of the program or without it. Each point estimate contains random values within the considered range. All variable distributions were considered to represent beta distributions. The considered distribution values are presented in Table 2.

Results
According to the results of the proposed model, the implementation of a secondary prevention programme for DRPs reduces the cost associated with ED revisits, with an annual net bene t of €87,639 (CI95%:80,258 − 94,021) thus, representing the most signi cant option. Considering a mortality attributable to readmission for DRPs of 4.7%, the cost per LYG with the implementation of this program was €2,055 (CI95%:1,403-2,927).
The results of the univariate analysis are shown in Fig. 3. In the short term, the reduction in the number of revisits due to the implementation of the intervention programme was the variable that most affected the model, with the bene t threshold value corresponding to a relative reduction of 12.4% of the number of revisits in patients with DRPs to obtain bene ts with the implementation of this type of programme. The results of the probabilistic sensitivity analysis are shown in Fig. 3 (cost per prevented revisit) and Fig. 4 (Cost per LYG).

Discussion
According to the proposed model, the implementation of a multidisciplinary team action programme to prevent revisits in patients attended in the ED for DRPs is a cost-effective strategy.
DRPs is a growing public health concern in an environment of increasingly polymedicated patients [11], with a signi cant impact both in terms of health and consumption of healthcare resources. Several studies conducted over the last decade have shown that DRPs prevention programmes can reduce both the number of hospital admissions and healthcare costs [12]. The results of our clinical trial support these ndings, demonstrating that a secondary DRPs prevention programme reduces both the number of ED revisits and hospital readmissions. However, as with any health intervention, cost-effectiveness analysis is an important aspect to be considered in the decision-making process of DRPs prevention programme implementation.
The economic bene t of the implementation of primary DRPs prevention programmes has been con rmed by many published reports [13][14][15][16]. These studies have shown that these types of programmes have the potential that do not require additional resources. However, to date there are no published studies with complete pharmacoeconomic models of these types of interventions, often considering only costs associated with reducing the treatment cost and without appropriate sensitivity analyses. However, there are also no reports on the bene ts of the implementation of a secondary DRPs prevention programme that is coordinated by an ED.
Our study demonstrates that a set of measures at different levels of care provide a signi cant economic bene t. It should be noted that the potential bene ts of the implementation of this type of programme include not only a reduction in the number of ED revisits to the emergency room, but also an improvement in the quality of life of patients. Several studies have shown an improvement in the quality of life with an intervention programme for chronic treatments [14][15][16][17], which is a bene t to be considered after the investment made. However, the results of the clinical trial did not include this aspect in this group of patients, not allowing to perform a quality-adjusted year's analysis.
According to the proposed model, the higher the number of patients attending the ED for DRPs, the more likely is that the programme will be cost-effective; therefore, the implementation of this programme would be especially bene cial in those EDs with a high rate of DRPs, resulting from a high-risk population or a poor health care at other levels of care.
We identi ed several limitations in our study. First, there is an important variability in the frequency of ED visits caused by DRPs [4], affecting the e ciency of the model presented. Secondly, the model was designed based on the results of one clinical trial conducted in a single centre. It has been published a wide variability in the results obtained with the implementation of DRPs prevention programmes in terms of hospital revisits and readmissions [18]. However, it should be noted that the results obtained in the reference clinical trial are similar to those obtained by Ravn-Nielsen et al [4]. with a similar intervention model. Therefore, we consider that the proposed economic model has su cient clinical evidence.
Nevertheless, it should be considered that the interventions performed at discharge for pharmacotherapy optimisation programmes are very heterogeneous in the different hospitals; therefore, the results of other types of interventions that do not t to the model used in this clinical trial require their own economic analysis. Moreover, the phenomenon of ED revisits is a complex issue that is affected by the structure of the healthcare system. To account for this variability, we included a wide range of cases in the sensitivity analysis, considering a variation in the reduction in hospital revisits and readmissions, as well as a 50% loss in patient identi cation. With this variation, we have included a range of values in which most cases could be found.
Owing to the context used to calculate the cost (Catalan Health System) and considering the high variability in the salaries of clinical pharmacists and the cost of healthcare between countries, the economic results obtained in our study cannot be directly extrapolated to other contexts and should be adjusted to each particular healthcare system. It should also be considered that our model included a tertiary hospital, with sizeable ED attendance and an ageing population. Therefore, its extrapolation to smaller hospitals, as well as to those attending a younger population, could also be inappropriate. However, the results of the present study are enough consistent to ensure that the implementation of this type of programme is a highly e cient strategy.

Conclusions
DRPs are an emerging health problem given the increase in the number of polymedicated patients. Therefore, it is necessary to develop interventions that minimise their impact on patients and healthcare systems. The results of our study strongly support investing in a secondary DRPs prevention programme acting at different levels of healthcare is a cost-effective strategy. Cost of the intervention programme per re-visit avoided Figure 4 Cost of the intervention programme per life-year gained (LYG)