Effects of Hospital-Based Comprehensive Medication Reviews Including Postdischarge Follow-up on Older Patients’ Use of Health Care

Key Points Question What are the effects of hospital-based comprehensive medication reviews (CMRs) that include postdischarge follow-up of older patients’ use of health care resources? Findings In this cluster randomized crossover trial that included 2637 older hospitalized patients in Sweden, the incidence of unplanned hospital visits within 12 months did not differ between patients who received a CMR that included postdischarge follow-up compared with those who received either a hospital-based CMR alone or usual care. Meaning Hospital-based CMRs, including postdischarge follow-up as conducted in this trial, did not decrease the incidence of unplanned hospital visits in older patients.


Introduction
Suboptimal use of medications is a leading cause of avoidable harm in health care systems around the world. 1,2 Medication-related harm may often arise as a consequence of medication errors occurring at transitions of care. 3,4 In response, the World Health Organization established a global patient safety initiative to reduce severe, avoidable medication-related harm by 50% from 2017 to 2022. 5 One of the proposed actions is to perform medication reviews in patients who use multiple medications. 6 A medication review can be interpreted in different ways, but it is often defined as a structured, critical examination of a person's medications with the objective of reaching an agreement with the person about treatment, optimizing the impact of medications, and minimizing medication-related harm. 7 Medication reviews can range from a paper-based review of a patient's medication list by a single clinician to a more comprehensive, multiprofessional approach that directly involves patients and takes their underlying conditions and symptoms into account. 8 Medication reviews in hospitalized patients have been shown to decrease medication-related problems and inappropriate prescribing, but it is unclear whether these improvements in medication treatment also affect hard clinical end points after discharge. 9,10 A 2016 Cochrane review 10 expressed the need for high-quality trials that incorporate at least 1 year of follow-up and are randomized at a cluster level to minimize contamination bias. A cluster randomized crossover design, in which each cluster is randomly assigned to a sequence of interventions, could also improve statistical efficiency and reduce the required number of clusters. 11 In a previous randomized clinical trial (RCT) 12 conducted at Uppsala University Hospital, Sweden, in 2005-2006, patients 80 years or older who received a comprehensive medication review (CMR) that included follow-up after hospital discharge performed by a pharmacist as part of the ward team had a 16% reduction in hospital visits the following year. Medication-related readmissions were reduced by 80%. 12 In a recent multicenter RCT among older patients in Denmark, 13 hospital-based medication reviews with motivational interviewing on discharge and postdischarge follow-up performed by a ward-based pharmacist resulted in a 25% reduction in the risk of being readmitted within 6 months compared with usual care. In recent decades, Swedish health care authorities have taken various measures to improve the quality of care for older patients, such as developing quality indicators, educating health care professionals in geriatric pharmacology, and funding local initiatives. 14,15 In this context, numerous hospitals in Sweden have used ward-based pharmacists who perform daily medication reviews in older patients. However, the resources allocated for structured provision of CMRs-including postdischarge follow-up-are insufficient, as studied in previous trials. 12,13 It is currently unclear which forms of medication reviews are most beneficial to patients. Pragmatic trials, which are designed to show the real-world effectiveness of clinical interventions, may enable prioritization of interventions and patients in clinical practice. 16 The goal of this pragmatic cluster randomized crossover trial (the Medication Reviews Bridging postdischarge follow-up on older patients' use of health care resources, with those of hospital-based reviews only and usual care.

Study Design and Participants
The MedBridge trial is a pragmatic, multicenter, cluster randomized crossover trial that incorporated 3 treatments. The trial was performed and is reported in accordance with the Helsinki Declaration 17 and the applicable extensions of the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. [18][19][20] The trial received ethical approval from the Swedish Central Ethical Review Board. All participants provided written informed consent or verbal informed consent if written informed consent was not possible. The rationale and design of the trial have been described previously. 21 The study was prespecified in the trial protocol, which is provided in Supplement 1; the statistical analysis plan is provided in Supplement 2. A process evaluation was conducted alongside the trial to understand how the interventions were implemented and performed and which factors may have affected the trial's results. Findings from this process evaluation have been published elsewhere. [22][23][24] The trial was conducted from February 6, 2017, until October 19, 2018, at 4 hospitals in Sweden ( Figure 1). Two wards per hospital were included, with each ward acting as a cluster. The 8 wards differed in terms of medical specialty: internal medicine (n = 3), acute internal medicine (n = 1), acute stroke and neurology (n = 1), diabetes and nephrology (n = 1), geriatrics (n = 1), and stroke (n = 1). The selection of these wards was based on the high prevalence of older patients using multiple medications as well as the fact that the performance of medication reviews by ward-based pharmacists was an established practice or that pharmacists had been introduced at each ward at least 6 months before the start of the trial. The pharmacists (including T.G.H.K. and J.S.) had either completed a full-time, 1-year postgraduate program in clinical pharmacy or taken undergraduate courses in clinical pharmacy and advanced pharmacotherapy in Sweden. All pharmacists had at least 6 months of experience performing medication reviews in a multiprofessional ward team. To assess clinical skill performance in relation to medication reviews, all pharmacists participated in an objective structured clinical examination before the start of the trial. Two training days were held, one before and the other during the trial, with patient case discussions among the pharmacists to ensure common practice across all sites. Other ward staff did not receive additional training.
All patients who were eligible for inclusion during the trial were asked to provide informed consent to participate. Inclusion criteria were age 65 years or older and admission to one of the participating wards for at least one 24-hour period on regular weekdays. Patients were excluded if  AIM indicates acute internal medicine; ASN, acute stroke and neurology; DN, diabetes and nephrology; and IM, internal medicine. they had undergone a medication review by a clinical pharmacist within the last 30 days, as stated in their electronic health record (EHR), did not reside in the hospital's county, or were receiving palliative treatment, as stated in their EHR. Medication reconciliation (ie, the process of ensuring an accurate and complete medication list 25 ) by a pharmacist at the emergency department (ED) was not considered an exclusion criterion.

Randomization and Masking
Crossover and randomization took place at a cluster (ie, ward) level within each hospital. Each ward participated in the trial for 6 consecutive 8-week study periods, which were divided into 2 separate blocks of 3 study periods each. During each period, 1 of 3 treatments (intervention 1 or 2 or control) was provided at the ward, with permuted block randomization ensuring that each treatment was performed within each block ( Figure 1). Details of the block randomization are available in eMethods 1 in Supplement 3.
Participants and ward staff were not blinded to treatment allocation. All patients who were eligible for inclusion received the treatment that was being performed at the ward at that time, regardless of informed consent to participate in the trial. Individual patients could only be included in the trial once. Any participant who was readmitted to one of the study wards also received the intervention being performed at that time.

Interventions
The different interventions pertained to individual patients. Intervention 1, CMR, consisted of a medication reconciliation by a clinical pharmacist with the patient, next-of-kin, or caregiver within 24 hours after hospital admission to ensure a correct list of medications. This reconciliation was directly followed by a CMR in collaboration with the ward physician, the nurse if appropriate, and the patient, next-of-kin, or caregiver if possible, similar to a level 3 medication review as described in the literature. 8 A level 3 medication review includes a structured, critical examination of the patient's medications in relation to the patient's symptoms and conditions, based on information from the patient and the EHR. The objective was to reach an agreement about the continued appropriateness and effectiveness of the treatment, including treatment not related to the cause of admission and untreated indications. Other issues, such as adherence, practical use of medications (eg, how to use an inhaler), dosage forms, adverse effects, interactions, and the patient's understanding of their condition and its treatment, were considered when appropriate. The effects of medication changes resulting from the CMR were monitored during the hospital stay by the physician or pharmacist. On discharge, a medication reconciliation was performed by the pharmacist to ensure that the patient's medication list and prescriptions for medications to be used after the hospital stay were consistent with the patient's EHR. This medication reconciliation did not necessarily involve contact with the patient or other ward staff.
Intervention 2, a hospital-based CMR that included postdischarge follow-up (CMR plus follow-up), consisted of the same elements as intervention 1 with the following additions: a referral sent by the clinical pharmacist in consultation with the ward physician to the patient's primary care clinician with recommendations on monitoring needs or actions to be taken after hospital discharge, if deemed necessary. A first telephone call to the patient, next-of-kin, or caregiver by the pharmacist 2 to 7 days after discharge ensured that the information about the patient's current medication treatment had been understood correctly and addressed any related problems, concerns, or questions. A second telephone call by the pharmacist 1 to 2 months after discharge inquired how the patient was managing the medications and whether any problems, concerns, or questions had arisen. Counseling was provided, and any other necessary actions were taken by the pharmacist.
Control patients received usual hospital care. According to Swedish regulations, usual care should include medication reconciliation on admission for patients who are 75 years or older and are taking 5 or more medications, followed by a medication review if medication-related problems are present. 26 Adherence to these regulations in hospital practice seems generally low. 27 Some of the intervention components or related activities could thus be performed to a certain degree, but no pharmacist was involved at the ward. In contrast, approximately 1 full-time-equivalent clinical pharmacist was available per ward during each intervention period (CMR or CMR plus follow-up).

Outcomes, Data Collection, and Sample Size
The primary outcome measure was the incidence of all-cause unplanned hospital visits (admissions plus visits to the ED) within 12 months after the index admission. An unplanned visit was defined as a visit that had not been part of the patient's treatment plan but resulted from an acute health problem. Secondary outcomes were all-cause unplanned hospital admissions and separate ED visits, unplanned medication-related admissions, visits with a primary care clinician, time to first unplanned hospital visit, all-cause mortality, and costs of hospital-based care. The primary outcome was also applied to predefined subgroups based on characteristics at index admission (baseline).
Baseline and outcome data were extracted from county EHR systems and health care registries.
All primary and secondary outcome data collection and assessments were blinded to treatment allocation. A detailed description of the outcomes and data collection is provided in eMethods 1 in Supplement 3. According to previous power simulations 21

Statistical Analysis
Data from the modified intention-to-treat population were analyzed from December 10, 2019, to September 9, 2020. Primary and secondary outcome analyses were based on a modified intentionto-treat (ITT) population. The ITT population was defined as all patients who were eligible for inclusion in the trial. Patients who provided informed consent were considered part of the modified ITT population, thus representing all participants who could be included in the analyses. Patients who did not provide informed consent and those who withdrew before data collection were considered dropouts. The ITT population was used for sensitivity analysis of the primary outcome measure, because multiple imputation was needed for patients without consent to participate (see eMethods 2, eTable 1, and eTable 2 in Supplement 3 for detailed procedures and results).
The differences in incidence rates of visits and admissions between treatment groups were compared using log-linear models with Poisson variance function, with adjustments made for cluster and period effects. The number of unplanned hospital visits within 12 months before the index admission was used as a patient-level covariate, and the number of out-of-hospital days was used as an offset. Tukey adjusted P values and 95% CIs were calculated to prevent multiple testing problems.
Time to first unplanned hospital visit and mortality were analyzed with nested frailty models to account for the hierarchical clustering of the data (hospital ward

Results
In total, 6052 patients were admitted during the study periods (Figure 2 Participants in each treatment group were similar in terms of baseline characteristics (Table 1). 47,48 The median age was 81 (interquartile range, 74-87) years, 1357 (51.5%) were female and 1280 (48.5%) were male, and a median of 9 (interquartile range, 5-13) medications were prescribed. The treatment group sizes within each cluster ranged from 63 to 146 participants.

Primary Outcome
The incidence of unplanned hospital visits within 12 months did not differ in the intervention groups compared with usual care:   visit, all-cause mortality, or costs of hospital-based care for any of the follow-up periods (see Table 2 for 12-month follow-up and eTables 3 and 4 in Supplement 3 for 30-day, 3-month, and 6-month follow-up).

Subgroup Analyses
There were no differences in the incidence of unplanned hospital visits within 12 months (primary

Discussion
In this pragmatic cluster randomized crossover trial in older hospitalized patients, hospital-based CMR with and without postdischarge follow-up did not decrease the incidence of unplanned hospital visits within 12 months compared with usual care. Secondary and sensitivity analyses supported this finding, with consistent results within 30 days and 3 and 6 months. The analyses of secondary outcomes revealed an unexpected increase in the incidence of ED visits within 3, 6, and 12 months for    35 However, the increase in ED visits in our trial did not seem to lead to more hospital admissions or increased costs of hospital-based care, which may call into question the clinical relevance of this result.

JAMA Network Open | Geriatrics
In a recent trial in Denmark, hospital-based medication reviews that include postdischarge follow-up by pharmacists who had received a 3-day training in motivational interviewing reduced the risk of hospital readmissions in older patients. 13 Patient empowerment and shared decision-making, as with motivational interviewing, are key factors in discharge interventions to reduce readmissions. 36 Our process evaluation suggested that patients had a limited role in decision-making. 23 The pharmacists were not specifically trained in shared decision-making or to empower patients through discharge counseling and follow-up telephone calls.

Limitations
Overall, the trial was completed as planned, 22,24 but there are some limitations to the study. First, our randomized cluster design did not allow for patient recruitment before randomization, resulting in a risk of selection bias. 37 We mitigated this risk by screening all patients admitted to the study wards for eligibility and asking all eligible patients about participation. In the end, 356 of 2993 eligible patients (11.9%) were not included in the modified ITT analysis, indicating a low risk for a systematic between-group imbalance.
Second, there is a risk of contamination bias, despite cluster randomization. Unintended intervention components were received by 132 of the 892 control patients (14.7%) during index admission. 22 However, only 14 control patients (1.6%) received a CMR during the index admission, indicating a low risk of contamination bias due to CMRs.
Third, the outcome measures may not fully reflect the effects of our interventions. Although 77% of the CMRs resulted in at least 1 discrepancy in the patient's medication list or medicationrelated problem being resolved, 22 the incidence of unplanned hospital visits did not decrease.
Patient-reported outcomes, such as health-related quality of life, might have been more suitable for capturing effects of these treatment changes. However, subjective measurement tools, such as patient-reported outcomes, may introduce bias in trials in which ward staff and study participants cannot be blinded to treatment allocation. 38 Finally, our interventions may not have been sufficiently targeted at a specific patient population. Although medication-related problems are common in older hospitalized patients, their subsequent use of health care may be driven by factors other than the solution of medicationrelated problems, such as frailty or lack of social support. 39 We included all patients, regardless of their needs, reason for admission, condition, or medication use. Medication reviews and similar pharmacist interventions improve clinical outcomes in patients with cardiovascular disease, type 2 diabetes, chronic obstructive pulmonary disease, and cognitive impairment. [40][41][42] In our trial, CMR was not effective in patients with previously diagnosed chronic obstructive pulmonary disease, and CMR plus follow-up even increased unplanned hospital visits in patients with heart failure and type 2 diabetes. However, neither our interventions nor our outcome measures were developed to specifically address these conditions.