Background: Mismanaged prescribing and use of medication among elderly puts major pressure on current healthcare systems. Performing a medication review, a structured critical examination of a patient's medications, during hospital stay with active follow-up into primary care could optimise treatment benefit and minimise harm. However, a lack of high quality evidence inhibits widespread implementation. This manuscript describes the rationale and design of a pragmatic cluster-randomised, crossover trial to fulfil this need for evidence.

Aim: To study the effects of hospital-initiated comprehensive medication reviews, including active follow-up, on elderly patients' healthcare utilisation compared to 1) usual care and 2) solely hospital based reviews.

Design: Multicentre, three-treatment, replicated, cluster-randomised, crossover trial.

Setting: 8 wards with a multidisciplinary team within 4 hospitals in 3 Swedish counties.

Participants: Patients aged 65 years or older, admitted to one of the study wards. Exclusion criteria: Palliative stage; residing in other than the hospital's county; medication review within the last 30 days; one-day admission.

Interventions: 1, comprehensive medication review during hospital stay; 2, same as 1 with the addition of active follow-up into primary care; 3, usual care.

Primary outcome measure: Incidence of unplanned hospital visits during a 12-month follow-up period.

Data collection and analyses: Extraction and collection from the counties' medical record system into a GCP compliant electronic data capture system. Intention-to-treat-analyses using log-linear Poisson generalized linear mixed models and frailty models.

Relevance: This study has a high potential to show a reduction in elderly patients' morbidity, contributing to more sustainable healthcare in the long run.

Background:

Mismanaged use of multiple medications is one of the greatest risks for healthcare-related harm in the elderly and puts major pressure on current healthcare systems [1,2]. Identifying effective interventions to optimise treatment benefit and minimise harm is an international public health priority [3]. Comprehensive medication review, a structured and critical examination of an individual patient's medications in relation to the patient's conditions, aims to accomplish these goals [4]. A recently published Cochrane meta-analysis examined whether medication reviews lead to improvement in health outcomes of hospitalised adult patients compared with standard care [5]. Ten randomised controlled trials (RCTs) were eventually used for analysis. The authors stated that they "found no evidence that medication review reduces mortality or hospital readmissions, although we did find evidence that medication review may reduce emergency department contacts."[5] A beneficial or detrimental effect on mortality or hospital admissions could be ruled out because estimates were uncertain and follow-up was short. The authors stated that there is a strong need for RCTs of high quality with at least one year follow-up and which are randomised at a cluster level to minimise contamination bias [5]. In addition, a cluster randomised crossover design in which each cluster serves as its own control would increase statistical power [6].

One of the included RCTs in this meta-analysis was conducted by our research group at Uppsala University Hospital in 2005-2006 [7]. We demonstrated in this study that patients, aged 80 years or older, who received a comprehensive medication review including follow-up after hospital discharge, performed by ward based clinical pharmacist, had 16% fewer hospital revisits in the following year. The costs of hospital based care were approximately €200 lower per patient in the intervention group compared to the control group after the intervention costs had been included. The study was conducted on two internal medicine wards with 400 enrolled patients, all 80 years or older, which limits the generalisability of its results.

Today, ten years after our previous RCT, several counties in Sweden have employed clinical pharmacists who perform medication reviews in hospital settings. However, their way of working has changed over time. For this reason it is important to identify the activities that generate the greatest benefits to the patients, which can be done by performing a pragmatic clinical trial, specifically designed to show the real-world effects of such interventions [8]. Therefore we propose this pragmatic cluster-randomised, three-treatment, crossover trial to study the effects of multidisciplinary medication reviews with active follow-up after hospital discharge on elderly patients' healthcare utilisation, compared with solely hospital based reviews and usual care. This large study will generate more robust results and high external validity, with the potential to show effects on hard outcomes such as healthcare utilisation. A similar study has, to our knowledge, not been undertaken anywhere else in the world.

Aim:

To study the effects of hospital-initiated comprehensive medication reviews, including active follow-up, on elderly patients' healthcare utilisation compared to 1) usual care and 2) solely hospital based reviews.

Primary objectives:

1. The first primary objective is to test the hypothesis that the incidence of unplanned hospital visits (admissions plus visits to the emergency department) among elderly patients during a one year follow-up is lower, if they receive a comprehensive medication review with active follow-up after discharge, than if they receive usual care.
2. The second primary objective is to test the hypothesis that a comprehensive medication review with active follow-up after discharge reduces the incidence of unplanned hospital visits more than only a medication review during hospital stay compared to usual care.

Methods:

This study protocol has been developed by using the applicable recommendations of the SPIRIT 2013 Guidance for protocols of clinical trials, the Consort 2010 extension to cluster randomised trials and the Consort 2010 extension to randomized trials of non-pharmacologic treatment [9-11]. The full study protocol is attached to this trial registration.

Setting and clusters:

The study will be conducted in three counties in Sweden: Västmanland, Uppsala and Gävleborg. Within these counties there will be four hospitals taking part in the study: Uppsala University Hospital and the hospitals of Västerås, Enköping and Gävle. At these hospitals clinical pharmacy, including the performance of medication reviews, is an established practice or is planned to be implemented prior to the study. The intervention components of the study will be performed by the existing workforce at two wards within each hospital. The wards differ in terms of medical specialty: geriatric, internal medicine and stroke. All wards are staffed with a multidisciplinary team consisting of physicians, nurses and clinical pharmacists. The pharmacists have either followed a full-time one year post-graduate programme in clinical pharmacy, in which the performance of medication reviews plays a central role, or have followed undergraduate courses in clinical pharmacy and advanced pharmacotherapy. Next to that, all pharmacists have at least six months working experience with performing medication reviews in a multidisciplinary team. To assess clinical skill performance related to medication reviews, all pharmacists participated in an objective structured clinical examination (OSCE), prior to the start of the study. All pharmacists have also participated in a training day with patient case discussions, to assure common practice across all study sites. Other members of the ward team did not receive additional training.

In total eight wards will be included, with each ward acting as a cluster. The study will be carried out as far as possible identically at the eight wards.

Inclusion Criteria:

• Admitted to one of the study wards

Exclusion Criteria:

• Has been subject to a medication review within the last 30 days as stated within their medical record;
• Residing in another than the hospital's county
• Being in a palliative stage as stated in their medical record
• Admitted for only one day