Medication Reviews Bridging Healthcare: a Cluster-randomised Crossover Trial to Study the Effects of Hospital-initiated Comprehensive Medication Reviews, Including Active Follow-up, on Elderly Patients' Healthcare Utilisation
Phase: NA
Conditions: Medication Review
Sponsor: Uppsala County Council, Sweden

Study Protocol 
Protocol ID: MedBridge 
Version: 19-02-20 
 
Study protocol 
Medication Reviews Bridging Healthcare (MedBridge):  
a cluster-randomised crossover trial  
 
Swedish titel: Läkemedelsgenomgångar som överbryggande sjukvård: en klusterrandomiserad 
crossoverstudie 
Protocol ID: MedBridge  
Version: 19-02-20 (previous version: 17-02-22) 
Principal investigator: Region Uppsala (RU), Sweden 
Collaborators: Region Gävleborg (RG) and Region Västmanland (RV), Sweden 
MedBridge research group: 
Region Uppsala 
 
Ulrika Gillespie (project leader), Uppsala University Hospital 
 
Thomas Kempen (project coordinator), Uppsala University Hospital 
 
Håkan Melhus, Uppsala University Hospital and Uppsala University 
 
Maria Bertilsson, Uppsala Clinical Research Center 
 
Elisabet Nielsen, Uppsala University 
 
Region Gävleborg 
 
Johanna Sulku, Gävle Hospital 
 
Johanna Carlsson, Gävle Hospital 
 
Region Västmanland 
 
Karl-Johan Lindner, Västerås Hospital 
 
Åke Tenerz, Västerås Hospital 
 
Trial registry: Clinicaltrials.gov: NCT02999412 
Official website: www.akademiska.se/medbridge 
Ethical approval: Swedish Central Ethical Review Board (CEPN; registration number: Ö 21-2016) 
and Regional Ethical Review Board in Uppsala (EPN Uppsala; registration number: 2016-251-1) 
Internal project number: 1011393 (account nr. 90100, reference nr. AS9010001) 
 
Funding: Uppsala-Örebro Regional Research Council [grant RFR-555601, RFR-641791 and RFR-
735911], Region Uppsala [grant LUL-527721, LUL-614061 and LUL-716201], Region Gävleborg 
[grant CFUG-658451 and CFUG-698771] and Region Västmanland [grant LTV-675921, LTV-712341, 
LTV-736641 and LTV-821261], the Swedish Pharmacists Association [Sveriges Farmaceuter], the 
Thuréus Fund for Geriatric Research [Thuréus stiftelse för främjande av geriatrisk forskning], the 
Geriatric Fund [Geriatriska fonden] and the Swedish Heart and Lung Association [Riksförbundet 
HjärtLung; grant FA 2017:38 and FA 2018:43]. 
 

2 
 
 
 
Content 
1. Abstract ......................................................................................................................................................... 3 
2. Background .................................................................................................................................................... 3 
3. Aim ................................................................................................................................................................. 4 
3.1 Primary objectives ................................................................................................................................... 4 
4. Methods......................................................................................................................................................... 4 
4.1 Setting and clusters ................................................................................................................................. 4 
4.2 Participants .............................................................................................................................................. 5 
4.3 Interventions ........................................................................................................................................... 5 
4.4 Study design ............................................................................................................................................ 7 
4.5 Randomisation ......................................................................................................................................... 7 
4.6 Outcomes ................................................................................................................................................ 8 
4.7 Sample size and power calculation ......................................................................................................... 9 
4.8 Data collection ....................................................................................................................................... 10 
4.9 Statistical analyses ................................................................................................................................. 10 
5. Process evaluation and quality assurance ................................................................................................... 11 
5.1 Protocol fidelity ..................................................................................................................................... 11 
5.2 Quantitative intervention analysis ........................................................................................................ 11 
5.3 Qualitative intervention analysis ........................................................................................................... 11 
6. Ethical considerations .................................................................................................................................. 12 
7. Declaration of interests ............................................................................................................................... 12 
8. Organisation structure and publication policy ............................................................................................ 12 
9. References ................................................................................................................................................... 13 
10. List of appendices ...................................................................................................................................... 15 
 
 
 

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1. Abstract 
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 study 
protocol 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. Process evaluation using qualitative and mixed-method analyses. 
Relevance: This study has a high potential to show a reduction in elderly patients’ morbidity, contributing to 
more sustainable healthcare in the long run. 
2. 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 reported to find no evidence that medication reviews reduce mortality or hospital 
admissions, although evidence that medication reviews may reduce emergency department contacts was 
found. 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 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 pharmacists, 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 at two internal medicine wards with 400 
enrolled patients, all 80 years or older; factors that limit the generalisability and applicability of the results.  

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Today, ten years after our previous RCT, several counties in Sweden have employed clinical pharmacists who 
perform medication reviews in hospital settings. However, there are not enough resources allocated to 
structurally provide an intervention as extensive as the one performed in the previous study. There is thus a 
risk that precisely those parts of the intervention which contributed the most to the positive results, are 
currently not carried out in practice. For this reason it is important to identify the activities that generate the 
greatest benefits to the patients, something that can be done by performing a pragmatic clinical trial, 
specifically designed to show real-world effects of such interventions [8]. Hence 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 have 
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. 
3. 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. 
3.1 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. 
4. Methods 
This study protocol has been developed in accordance with 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]. A more condensed 
version of this study protocol has been published in the peer-reviewed journal Contemporary Clinical Trials 
[12]. 
4.1 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 (internal medicine and/or 
geriatrics) within each hospital. The eligibility of the included wards has been based on the presence of a 
multidisciplinary ward staff consisting of physicians, nurses and clinical pharmacists. Next to that, the patient 
population within these wards consist mostly of multimorbid elderly patients who are not in the need for 
intensive or critical care. The clinical pharmacists have either followed a fulltime one year postgraduate 
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. Prior to the start 

5 
 
of the study, a pilot study with a minimum duration of two weeks was performed at each ward to get 
familiarised with the study procedures. 
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, following Standard Operating Procedures (SOPs), see appendix 1-
4. However, statistical analysis will account for differences between wards, see 4.9 Statistical analyses. 
Randomisation will take place at cluster level, see 4.4 Study design and 4.5 Randomisation. 
4.2 Participants 
All patients who are eligible for inclusion according to the in- and exclusion criteria will be asked for informed 
consent. 
Inclusion criteria 
• 
Patients aged 65 years or older who have been admitted to one of the study wards  
Exclusion criteria  
• 
Patients who have been subject to a medication review by a clinical pharmacist within the last 30 
days as stated within their electronic medical record (EMR) 
• 
Patients residing in another than the hospital’s county 
• 
Patients in a palliative stage as stated in their EMR 
• 
Patients admitted for only one day (maximum one overnight stay) 
4.3 Interventions 
Two different interventions will be compared with each other and with usual care. Detailed SOPs will serve 
as checklists for the clinical pharmacists’ work, see appendix 2-4. The different interventions pertain to 
individual patients. The participant flow from a patient perspective is graphically presented in Fig. 1. The 
participants’ schedule of enrolment including post-inclusion assessments is shown in appendix 5. 
Figure 1: Participant flow from an individual patient perspective including expected number of included patients.  
Med. rec. = medication reconciliation 
 
Intervention 1 (I1) ‘comprehensive medication review’ 
• 
A thorough medication reconciliation within 24 hours after admission, including a patient or carer 
interview, by a clinical pharmacist to ensure the hospital list of medication is consistent with what 
Record data extraction
Intervention after hospital 
discharge
Intervention during 
hospitalisation
Enrolment
Admission to one of the 
study wards
Included as study 
participant (n = 2 310)
Patient's ward allocated to 
control (n = 770)
Usual care
1 year follow-up
Patient's ward allocated to 
intervention 1 (n = 770)
Comprehensive 
medication review
Med. rec. before discharge
Usual care
1 year follow-up
Patient's ward allocated to 
intervention 2 (n = 770)
Comprehensive 
medication review
Med. rec. before discharge
Electronic medication 
referral
Phone call after 2-7 days
Phone call after 1-2 
months
1 year follow-up
Exclusion criteria met 
or no informed 
consent provided 

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medications the patient used at home. The start of the intervention may be delayed to the 
pharmacist’s discretion in case the patient’s acute condition does not allow for an interview. 
• 
Directly after the medication reconciliation, the clinical pharmacist performs a comprehensive 
medication review in collaboration with the ward physician and patient, similar to a level three 
clinical medication review as earlier described in the literature [4]. This includes a structured, critical 
examination of all of the patient’s medications in relation to the patient’s conditions, based on 
information from the patient and the EMR. The objective is to reach an agreement about the 
continued appropriateness and effectiveness of the treatment, optimising the impact of medications 
and minimising the number of medication related problems. Other issues, such as adherence, 
practical use of the medications (e.g. how to use an inhaler), dosage forms, adverse effects, 
interactions, and the patient’s understanding of the condition and its treatment are considered when 
appropriate. The outcome of the review will be a decision about the continuation (or otherwise) of 
the treatment. The effects of medication changes will be monitored during the hospital stay by the 
physician or pharmacist, depending on the specific situation. If deemed necessary, additional contact 
between the physician, pharmacist and/or patient may take place during the admission to optimise 
medication treatment. 
• 
Before discharge, the clinical pharmacist performs another medication reconciliation to check if the 
patient’s medication list and prescriptions for medications to be used after hospital stay are 
consistent with the patient’s EMR. This medication reconciliation does not necessarily involve patient 
contact. The pharmacist also supports the physician in making sure that the information in the EMR 
system is consistent with the national automated drug dispensing system, for patients enrolled in 
that scheme. 
Intervention 2 (I2) ‘comprehensive medication review with active follow-up’ 
The same as I1 but with the following additions: 
• 
In case of any monitoring needs or necessary subsequent actions to be taken after hospital discharge, 
the clinical pharmacist and the ward physician send an electronic medication review referral to the 
patient’s primary care physician (or any other relevant healthcare provider) upon discharge. This 
referral contains specific proposals and instructions regarding the patient’s medication treatment for 
monitoring needs and necessary follow-up actions within primary care. Additional actions by the 
primary care physician or other clinicians are not considered a part of the intervention, but may result 
from this electronic referral. 
• 
A first phone call to the patient or carer is made by the clinical pharmacist 2-7 days after discharge 
depending on the patient’s health condition and the pharmacist’s availability. All pharmacists follow 
a checklist to assure that the conversation addresses the same questions and topics. Within the 
phone call, the patient or carer will be asked to describe the current medication treatment to ensure 
that all information has been understood correctly. Next to that, this phone call aims to find out if 
any problems, concerns or questions have arisen after discharge. If necessary, the clinical pharmacist 
provides counselling during the phone call to solve the problems and allay concerns. Additional 
actions may be taken at the clinical pharmacist’s discretion as a result of this phone call (e.g. sending 
a new medication list to the patient or carer if it is missing). Examples of situations and how to act 
on them will be provided and discussed with the pharmacists. 
• 
A second phone call will be made by the clinical pharmacist approximately 30 days after hospital 
discharge. In case the patient has been living in a short-term stay residence after hospital discharge, 
this period can be extended to maximum 60 days. This phone call is primarily designed to find out 
how the patient is managing the medication and if any problems, concerns or questions have arisen. 
With decreasing treatment adherence over time, this phone call also aims to provide the patient with 
a motivational “boost”. Subsequent contact between the clinical pharmacist and the primary care 
physician is not considered a mandatory part of the intervention, but may occur and will then be 
documented in the patient’s EMR. 

7 
 
Control ‘usual care’ 
• 
The control group will receive usual hospital care. According to Swedish legislation, usual care 
includes medication reconciliation upon admission. Next to that, the law requires a medication 
report addressing the patient’s medication treatment to be given to the patient or carer upon 
hospital discharge and to be attached to the electronic discharge letter. This report contains a 
motivation for the changes in medication treatment that have been made during hospital stay, as 
well as the patient’s updated medication list. These mandatory activities are currently carried out to 
various degree within the different hospitals and wards. Other activities as described in the 
interventions above may be carried out to a certain degree as well, but no clinical pharmacist will be 
involved. 
4.4 Study design 
A pilot study has been performed which suggested that a traditional RCT design (randomisation at patient 
level) was unsuitable due to practical reasons and the risk of contamination bias. For example, ward staff had 
to wait for informed consent and randomisation before starting the intervention and clinical pharmacists 
were frequently asked to review the medications of patients allocated to receive only usual care. To minimise 
the risk of contamination bias, it has been proposed that new RCTs on medication reviews should be 
randomised at a cluster level [5]. In addition, a cluster randomised crossover design in which each cluster 
serves as its own control increases statistical power compared to a cluster randomised parallel design [6]. 
Such a design produces high level evidence which forms the basis of meta-analyses and systematic reviews. 
The approach with two intervention groups is chosen to be able to distinguish between medication review 
activities during hospital stay and those after discharge. We therefore propose a cluster-randomised, three-
treatment, replicated, crossover design with study periods of 8 weeks.  
Crossover and randomisation will take place at ward level within each hospital, so that one ward is one 
cluster. This means that each ward will be allocated to one intervention (I1, I2 or control) during three 
consecutive periods of eight weeks. Changes over time, such as seasonal differences, and any significant 
changes to the cluster setting during the study’s inclusion period, such as an outbreak of multi-resistant 
bacteria at one of the study wards, can also influence the study outcomes. To account for any of these 
temporal effects, the three consecutive 8-week periods will be rotated twice and randomisation of 
intervention sequences will be performed (see below). Contamination risk monitoring, in terms of ward 
personnel covering several study wards at the same time, will be performed as well. The total study duration 
will consist of six consecutive periods of eight weeks per ward. This means that each ward will perform each 
intervention for 16 active study weeks. 
4.5 Randomisation 
To assure that each ward performs each intervention twice, randomisation will take place at hospital level in 
two blocks of three periods. This within-hospital block randomisation has been chosen to spread out the 
different intervention periods more equally over the full study period, to account for period effects. Due to 
logistical, staffing reasons the method of block randomisation also prevents a particular intervention being 
concurrently performed on both wards within the same hospital. The randomised sequence will be generated 
by an independent statistician at Uppsala Clinical Research Center (UCR) using SAS© software (SAS Institute 
Inc., Cary, NC, USA). The computer generated codes will be held by the statistician to assure allocation 
concealment at the moment of randomisation. Allocation concealment will not be possible during the rest of 
the study. However, we regard the lack of concealment as being of minor importance due to the crossover 
aspect of the trial (all wards will perform each intervention twice). To minimise the possibility of selection 
bias within the wards, all eligible patients will be asked for informed consent to be included in the study. It 
will be explained to the patients that they will receive the particular intervention whether or not they provide 
informed consent. By this measure we aim to minimise the risk of consent bias. Any included patient that 
gets readmitted to one of the study wards will receive the intervention that is being performed at that 
particular moment. A hypothetical randomisation chart to visualise the block randomisation is shown in Fig. 
2.  

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Figure 2: Chart with a hypothetical result of the block randomisation based on 6 periods of 8 weeks per ward. Each 
randomisation block of three periods is marked in dashed lines. 
4.6 Outcomes 
Primary outcome 
• 
Incidence of unplanned hospital visits (admissions plus visits to the emergency department) during 
a 12-month follow-up period 
An unplanned visit is defined as a visit which has not been part of the patient’s treatment plan (scheduled 
visit), but results from an acute health problem. 
Secondary outcomes 
• 
Separate incidences of unplanned hospital admissions and emergency department visits after 30 
days, 3, 6 and 12 months 
• 
Incidences of unplanned hospital visits after 30 days, 3 and 6 months 
• 
Separate incidences of unplanned medication related hospital admissions and unplanned primary 
care physician visits after 30 days, 3, 6 and 12 months 
• 
Time from hospital discharge to first unplanned hospital visit during 12 months 
• 
Costs of hospital based care (costs of healthcare utilisation including the costs of the intervention) 
after 6 and 12 months 
• 
All-cause mortality rates after 30 days, 3, 6 and 12 months 
Secondary outcomes include the primary outcome applied to the following subgroups according to baseline 
characteristics: 
• 
Age: 65-74 years vs. ≥75 years 
• 
Number of unplanned hospital visits within 12 months before admission: 0-1 vs. >1 visits 
• 
Number of prescribed medications upon admission: <5 vs. 5-9 vs. ≥10 medications 
• 
Using an automated drug dispensing system in the home care situation vs. no automated drug 
dispensing system 
• 
Previously diagnosed diseases according to the patient’s EMR: congestive heart failure (HF) vs. no 
HF; chronic obstructive pulmonary disease (COPD) vs. no COPD; diabetes mellitus (DM) vs. no DM 
Choice of outcome measures 
All primary and secondary outcomes are measurements of patients’ healthcare utilisation. Unplanned 
hospital visits is an objective and clinically important outcome measure reflecting the patients’ morbidity. 
Any statistical difference in the primary outcome measure is therefore considered clinically relevant. The 
study interventions are expected to only influence medication related hospital visits instead of all-cause 
hospital visits. However, due to the subjective nature of this outcome measure, we have chosen this as a 
secondary outcome measure. Because of a lack of available diagnostic information, it was deemed impossible 
to assess to what extent emergency department visits were medication related. Unplanned medication 
related hospital admissions was therefore chosen as an outcome measure. Next to that, unplanned primary 
care physician visits has been added as a relevant outcome measure for primary care practices. As this 
Ward 1
Ward 2
Ward 1
Ward 2
Ward 1
Ward 2
Ward 1
Ward 2
= Control
= Intervention 1
= Intervention 2
 = Block randomisation
Month number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Hospital 1
C
I1
I2
C
I2
I1
I1
I2
C
I2
I1
C
I2
C
I2
I1
C
C
I1
I2
Hospital 2
I1
C
I2
I1
Hospital 4
I2
C
I1
C
I1
C
C
I2
I1
I1
C
I2
Hospital 3
I2
I1
C
I2
C
I1
I2
I1
I2
C
I1
I2
I2
C
I1

9 
 
endpoint is not of similar clinical and economical importance as hospital visits, we considered it unsuitable 
to combine both into one composite primary endpoint. With the time to first unplanned hospital visit we will 
be able to study effectiveness without the risk of contamination in terms of interventions provided to 
individual study participants; e.g. a study patient included as a control group patient later receiving I1 and I2 
during the follow-up period. Based on data from our previous RCT and pilot study, we expect that 
approximately 20% of all study participants will be readmitted to one of the study wards within 12 months 
after discharge. Hence, there is a high risk of contamination. We have accounted for this contamination in 
the power calculation by lowering the expected difference in the primary outcome measure and we will 
perform sensitivity analyses using per-protocol (PP) analyses to investigate the effect of contamination. 
Nevertheless, time to first unplanned hospital visit allows for an intention-to-treat (ITT) analysis without such 
contamination, which justifies this additional outcome measure. We have included costs of hospital based 
care as a cost-effectiveness component in order to be able to value the interventions economically. Finally, 
all-cause mortality is added as our clinically most relevant endpoint, taking into account that our study might 
not be sufficiently powered to show a significant difference. 
We have chosen the 30 days and 12 month follow-up periods in both the primary and secondary outcome 
measures to investigate the effectiveness on a short and mid-long term. These cut-off points are frequently 
used in clinical trials, for example in our previous RCT, which allows for between study comparisons [5,13]. 
Next to that, 30-day hospital readmissions is an important measure for the quality of healthcare in many 
countries, e.g. Sweden and the United States [13,14]. In addition, we consider three and six months as logical 
follow-up periods in order to be able to show trends from 30 days to 12 months follow-up. 
Choice of subgroups 
We have defined different subgroups based on participants’ baseline characteristics in order to be able to 
investigate which patients benefit the most from the study interventions. According to Swedish legislation, 
all patients aged 75 years or older with five or more prescribed drugs in use should receive a medication 
reconciliation with every hospital visit and, if deemed necessary, a comprehensive medication review [15]. 
We therefore want to investigate whether there is a difference between patients aged 65-74 years and 75 or 
older in terms of effectiveness. The lower cut off point for the number of prescribed medications (<5 vs. 5-9) 
is also based on this legislation, whereas the other cut off point (≥10) is arbitrarily chosen based on our pilot 
study data: approximately 50% of the included patients used ten or more medications upon admission. Next 
to that, the number of previous unplanned hospital visits is considered an important predictor of our primary 
outcome (unplanned hospital visits). Based on our previous RCT and pilot study, the median number of 
previous unplanned hospital visits is expected to be one, motivating our cut off point (>1 visits). Lastly, HF, 
COPD and DM are seen as indications for which medication treatment plays such an essential role that any 
hospital admission related to these diseases are classified as preventable medication related hospital 
admissions in Sweden [16]. As the interventions in this study aim to optimise medication treatment, we 
expect to see different effectiveness in participants who have previously been diagnosed with specifically 
these diseases. 
4.7 Sample size and power calculation 
The proposed cluster-randomised crossover design will result in an approximately 1:1:1 ratio of study 
participants in I1, I2 and in the control group. In our previous study in which we compared a comprehensive 
medication review with usual care at two hospital wards, the reduction in hospital visits was 16% [7]. Due to 
the multicentre nature of the current study, as well as an expected 20% of the patients revisiting study wards 
and receiving one or more additional study interventions (possibly diluting the estimated difference between 
groups), the expected reduction in this study is approximately 10%. Based on our previous RCT and data from 
our pilot study, we expect an incidence of two hospital visits (per patient year) in the control group. This 
means that a 10% reduction would result in Number Needed to Treat (NNT) of five to prevent one hospital 
visit during the 12 months follow-up, which we consider highly clinically relevant. 
Power simulations were performed using the R package clusterPower version 0.5 [17,18]. The power 
simulations were based on a fixed effects Poisson regression with a between cluster variance of 0.5. Analyses 

10 
 
at the cluster level was assumed, even though the subsequent analyses will be performed at the individual 
level. We used anticipated cluster sizes from the pilot study (i.e. varying cluster sizes), with eight clusters and 
six periods per cluster in total. The expected mean number of at-risk days per patient was 290 and we 
assumed seven hospital visits per 1000 patient-days in the control group. With these assumptions, 2310 study 
participants in total would be needed to show a 10% reduction of hospital visits between I2 and the control 
group with a power of approximately 83% (α=5%). The corresponding power for an expected 3% difference 
between I1 and I2 would be approximately 48%. 
No compensation for withdrawals has been accounted for in the sample size estimation, since the primary 
analysis will be based on the ITT principle. We plan for an inclusion period of 12 months within each hospital 
which, based on the pilot study, will be sufficient to include enough patients. 
4.8 Data collection 
Information on patient characteristics, hospital visits and primary care physician visits will be extracted from 
the counties’ EMR system (e.g. COSMIC®, Cambio Healthcare Systems AB, Stockholm, Sweden). The 
extraction will take place on a daily basis during the first hospital admission upon study inclusion and then 
after the pre-specified follow-up moments 30 days, 3, 6 and 12 months after hospital discharge. In case the 
patient is registered at a private healthcare centre without shared EMR system, the centre in question will 
be contacted directly to retrieve data. Data regarding mortality will be extracted from the EMR system and 
the national death registry. Costs of hospital based healthcare will be retrieved from the counties’ costs per 
patient (CPP) system, and average costs of clinical pharmacist employment will be calculated to account for 
the intervention costs. During the inclusion phase of this study, a separate research project will focus on what 
the average costs of the pharmacist employment are. 
Two final-year undergraduate pharmacy students will independently assess whether the hospital admissions 
are either unlikely to be or possibly medication related. The Assessment Tool for identifying Hospital 
Admissions Related to Medications (AT-HARM10) will be used for these assessments [19]. AT-HARM10 is a 
practical tool to identify medication related hospital admissions which is valid for use in older patients by 
final-year undergraduate and postgraduate pharmacy students. For an admission to be classified as 
medication related, consensus needs to be reached between the two students, and where this is not possible, 
a clinical expert will have the deciding vote. All three assessors will be blinded to study allocation and are not 
involved in any other part of the MedBridge trial.  
Data management will follow a detailed Data Management Plan, see appendix 6. All data will be anonymised, 
captured in CRFs by local research assistants and saved within a protected Electronic Data Capture (EDC) 
system, Castor EDC©, 2016 Ciwit B.V., Amsterdam, the Netherlands. All analyses will be based on these CRF 
data, see appendix 7-9. 
4.9 Statistical analyses 
Statisticians from UCR will be responsible for the statistical analyses. Statistical analyses will primarily be 
performed using the ITT principle. In addition, supportive analyses will be performed using PP analyses, i.e. 
excluding patients and/or clusters where protocol violation had occurred, and as-treated analyses on a per-
patient basis. The two primary objectives will be tested using a closed testing procedure. Patient 
characteristics will be presented with descriptive statistics per study group (control, I1 and I2). Rates of 
healthcare contacts (admissions, emergency department visits and primary care) and number of days spent 
in hospital will be analysed using log-linear models with Poisson variance function in the framework of 
Generalized Linear Mixed Models (with fixed-treatment, random-cluster and patient-within-cluster effects). 
The number of out-of-hospital days will be used as an offset. We will use estimated rate ratios with 95% 
confidence intervals (CIs) for comparison between groups. Time-to-event outcomes will be analysed using 
frailty models. The three groups will be compared with hazard ratios and 95%-CIs. Costs of hospital based 
care will be presented with descriptive statistics and the nonparametric bootstrap method will be used to 
compare costs and estimate confidence intervals. 

11 
 
No imputation for missing data will be performed. Patients that drop out will be censored at that time-point. 
Reasons for, and number of, drop-outs per intervention group will be reported and analysed descriptively. 
Tests of significance will be two-tailed and a p-value less than 0.05 will be considered significant. All statistical 
analyses will be performed with SAS© software (SAS Institute Inc., Cary, NC, USA) or R software (R Foundation 
for Statistical Computing, Vienna, Austria). 
5. Process evaluation and quality assurance 
Within the MedBridge study, a process evaluation consisting of continuous monitoring and several projects 
and sub-studies will be performed. Such a process evaluation within an RCT can provide detailed information 
about the different components of the interventions, for example the implementation, the mechanism of 
impact and the context [20]. The purpose of process evaluations is to provide a deeper understanding of the 
study results, which is often needed to inform policy decisions and further integration of the interventions in 
daily practice [21].  
5.1 Protocol fidelity 
Participant inclusion and informed consent rates will be updated on a daily basis. The performed intervention 
components (as defined by the bullet points in 4.3 Interventions) will be recorded by the clinical pharmacists 
as notes in the patients’ EMR as currently part of their daily clinical routine. Data about the performed 
intervention components, to be used as protocol fidelity measures for daily monitoring and sensitivity 
analyses, will be extracted from the physicians’ and pharmacists’ notes within the EMR system during the full 
12-month follow-up period. 
Deviations from the protocol will be captured in the EDC system. Regular meetings will be held at each study 
site, to share progress on the inclusion of study participants and the performance of the study interventions 
among the involved researchers and clinical pharmacists. Problems and proposals for improvement will be 
discussed during this meeting. Beside the regular meetings, the full research group will have monthly 
meetings to discuss any problems that arise and to ensure that the study is progressing as planned.  
5.2 Quantitative intervention analysis  
As a quality measurement for I1 (comprehensive medication review) and I2 (comprehensive medication 
review with active follow-up), the number and type of identified medication related problems will be 
extracted from the EMR. For these assessments, one-third of all intervention patients will be randomly 
selected within each cluster and study period. Categorisation of the problems will be performed using an 
adjusted version of the Hepler and Strand classification of drug related problems [22]. For each problem, the 
proposal to solve the problem and whether this action was finally taken will be noted down based on the 
information within the EMR. The mean number of medication related problems per intervention and the 
percentage of implemented proposals will be presented. 
5.3 Qualitative intervention analysis 
Physicians and clinical pharmacists 
A nested qualitative analysis will be performed to evaluate the implementation process of the study 
interventions and to promote the understanding of why the interventions within the study may or may not 
have been effective. Specific objectives are to identify existing barriers and facilitators to the implementation 
and performance of the study interventions and to investigate the attitudes and beliefs of the physicians and 
pharmacists towards these interventions. The qualitative analysis will use semi-structured interviews with 
physicians and clinical pharmacists. A similar analysis within the Pharmacists in Practice Study where 
researchers investigated the experience of practice staff, pharmacists and patients with pharmacist services 
in Australian general practice clinics, will be used as an example to draw up questions and discussion topics 
[23]. The interviews will also be informed by widely used frameworks such as the Structuration Model of 
Collaboration and the Normalization Process Theory focussing on interprofessional collaboration and the 
implementation of complex interventions [24,25]. We aim to involve as many different pharmacists and 
physicians from all study wards as possible. The interviews will be recorded and then transcribed verbatim. 

12 
 
The transcripts from the interviews will be analysed using thematic analysis. Finally, a mixed method analysis 
will be performed combining both quantitative and qualitative data. 
Patients 
Knowledge about the patient perspective is needed to support the understanding of the effects of 
comprehensive medication reviews on patients’ health outcomes and to improve clinical practice. We 
therefore aim to explore older patients’ experiences with, and views on, hospital-initiated comprehensive 
medication reviews and follow-up telephone calls by ward-based clinical pharmacists within the MedBridge 
trial. In-depth semi-structured interviews will be conducted with study participants (and/or their carers)  who 
received one of the two active study interventions (I1 or I2). Purposive sampling will be used to be able to 
identify themes which cut across a variety of patients [26]. In this approach, patients will be sampled to 
ensure coverage across hospital wards and heterogeneity in terms of age, gender, intervention (I1 or I2), 
clinical pharmacist involved, and the number (high or low) of medication related problems identified during 
the comprehensive medication review. Sampling will be continued to the point of data saturation, defined 
as the point when no new additional data are found that develop a conceptual category or theme [27]. In 
our approach, 12 initial interviews will be conducted and analysed, to identify key, recurring themes. After 
12 interviews, three consecutive interviews with no new themes emerging are needed to reach the point of 
data saturation [27]. Discussion topics include communication, information, decision-making, and effects on 
the patient. Interviews will take place after discharge, and will be audio-recorded, transcribed verbatim, and 
thematically analysed using a framework approach as proposed by Ritchie and Spencer [26]. 
6. Ethical considerations 
This study has received ethical approval from the Swedish Central Ethical Review Board (CEPN; registration 
number: Ö 21-2016) and additional ethical approval from the Regional Ethical Review Board in Uppsala for 
the patient interviews (EPN Uppsala; registration number: 2016-251-1). Due to the nature of the study 
design, written informed consent is not needed prior to the start of the intervention, but only for collection 
of individual patient data. All participants and their data will be handled according to the ethical principles 
as stated in the WMA Declaration of Helsinki [28]. Next to that, this study complies with all applicable 
recommendations of the ICH-GCP standards [29]. With this trial we aim to gain essential knowledge about 
which medication review activities generate the most benefit on clinically relevant outcomes and when 
during the care process these effects are the greatest. We will only include study sites where clinical 
pharmacists, who perform medication reviews on a daily basis, are already integrated in the ward team. The 
two interventions within this study consist of activities which are in line with current Swedish guidelines 
regarding medication reviews, with the addition of extra patient consultation and follow-up communication 
with patients and primary care physicians. The control group will receive usual hospital care. As there are 
currently not enough pharmacist resources to provide medication reviews to all elderly patients, we consider 
the use of a control group receiving usual care to be justifiable. Next to that, the performance of medication 
reviews within a hospital setting is currently (still) not common practice in most hospitals in Sweden. No 
patient will be at increased risk of harm in relation to standard hospital care. 
7. Declaration of interests 
All research group members declare to have no conflict of interest. 
8. Organisation structure and publication policy 
Our research group consists of representatives from Region Uppsala, Region Gävleborg and Region 
Västmanland, which are all part of the Uppsala-Örebro healthcare region. Within this region there is a long 
history of strong collaboration when it comes to innovations in healthcare. Specifically, the current 
medication review activities of the three different project partners result from close collaboration between 
healthcare professionals within this region. The MedBridge research group decides on matters regarding 
authorship and contribution. The research group will follow the recommendations of the International 
Committee of Medical Journal Editors (ICMJE) [30]. A reference group has been formed to advice the research 

13 
 
group on study related matters. The reference group consists of experienced clinicians, managers and 
researchers from Sweden as well as Norway, see the Study Contact List (appendix 10). The reference group 
receives important documents, such as the updated version of the study protocol, and all minutes from 
research group meetings. The group members are invited to give advice to the research group and will be 
actively approached in case of important decisions.  
9. References  
1) The Swedish National Board of Health and Welfare. Current developments in care of the elderly in Sweden. 
Stockholm: Socialstyrelsen, 2007. Article nr: 2007-131-40. 
2) Chiatti C, Bustacchini S, Furneri G, Mantovani L, Cristiani M, Misuraca C, et al. The economic burden of inappropriate 
drug prescribing, lack of adherence and compliance, adverse drug events in older people: a systematic review. Drug 
Saf. 2012 Jan;35 Suppl 1:73-87. 
3) The WHO Research Priority Setting Working Group. Global Priorities for Research in Patient Safety (first edition): 
World Health Organization, 2008. 
4) Blekinsopp A, Bond C, Raynor DK. Medication reviews. Br J Clin Pharmacol 2012; 74: 573–80. 
5) Christensen M, Lundh A. Medication review in hospitalised patients to reduce morbidity and mortality. Cochrane 
Database of Systematic Reviews 2016, Issue 2. Art. No.: CD008986. 
6) Rietbergen C, Moerbeek M. 2011. The design of cluster randomized crossover trials. J. Educ. Behav. Stat. 36:472–90. 
7) Gillespie U, Alassaad A, Henrohn D, Garmo H, Hammarlund-Udenaes M, Toss H, Melhus H, Mörlin C. A 
comprehensive pharmacist intervention to Reduce morbidity in patient 80 Years or Older: a randomized controlled 
trial. Arch Intern Med. 2009 May 11; 169 (9): 894-900. 
8) Ford I, Norrie J. Pragmatic Trials. N Engl J Med. 2016 Aug 4;375(5):454-63. doi: 10.1056/NEJMra1510059. 
9) Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: 
guidance for protocols of clinical trials. BMJ. 2013 Jan 8;346:e7586. 
10) Campbell MK, Piaggio G, Elbourne DR, Altman DG; CONSORT Group. Consort 2010 statement: extension to cluster 
randomised trials. BMJ. 2012 Sep 4;345:e5661. 
11) Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P; CONSORT Group. Extending the CONSORT statement to 
randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med. 2008 Feb 
19;148(4):295-309.  
12) Kempen TGH, Bertilsson M, Lindner KJ, Sulku J, Nielsen EI, Högberg A, et al. Medication Reviews Bridging Healthcare 
(MedBridge): Study protocol for a pragmatic cluster-randomised crossover trial. Contemp Clin Trials. 2017 
Oct;61:126-132. doi: 10.1016/j.cct.2017.07.019. Epub 2017 Jul 21 
13) Renaudin P, Boyer L, Esteve MA, Bertault-Peres P, Auquier P, Honore S. Do pharmacist-led medication reviews in 
hospitals help reduce hospital readmissions? A systematic review and meta-analysis. Br J Clin Pharmacol. 2016 Aug 
11.  
14) Leppin AL, Gionfriddo MR, Kessler M, Brito JP, Mair FS, Gallacher K, et al. Preventing 30-day hospital readmissions: 
a systematic review and meta-analysis of randomized trials. JAMA Intern Med. 2014 Jul;174(7):1095-107.  
15) The Swedish National Board of Health and Welfare. Changes in regulations and general guidelines (SOSFS 2000:1) of 
medication use in healthcare [in Swedish]. SOSFS 2012:9 (M). Västerås: Socialstyrelsen, 2012. ISSN 0346-6000; 
Artikelnr.2012-6-43. 
16) The Swedish National Board of Health and Welfare. Development of indicators for avoidable hospital care and 
unplanned readmissions [in Swedish]. Stockholm: Socialstyrelsen, 2014. Article nr: 2014-2-12. 
17) Reich NG, Obeng D. clusterPower: Power calculations for cluster-randomized and cluster-randomized crossover 
trials. R package version 0.5. CRAN.Rproject.org/package=clusterPower (2013). 
18) Reich NG, Myers JA, Obeng D, Milstone AM, Perl TM. Empirical power and sample size calculations for cluster-
randomized and cluster-randomized crossover studies. PLoS One 2012, 7(4):e355-64. 
19) Kempen TGH, Hedström M, Olsson H, Johansson A, Ottosson S, Al-Sammak Y, et al. Assessment tool for hospital 
admissions related to medications: development and validation in older patients. Int J Clin Pharm. 2019 
Feb;41(1):198-206. doi: 10.1007/s11096-018-0768-8. Epub 2018 Dec 26. 
20) Oakley A, Strange V, Bonell C, Allen E, Stephenson J, RIPPLE Study Team. Process evaluation in randomised controlled 
trials of complex interventions. BMJ. 2006 Feb 18;332(7538):413–6.  
21) Moore GF, Audrey S, Barker M, Bond L, Bonell C, Hardeman W, et al. Process evaluation of complex interventions: 
Medical Research Council guidance. BMJ. 2015 Mar 19;350:h1258. 
22) Hepler CD, Strand LM. Opportunities and responsibilities in pharmaceutical care. Am J Hosp Pharm 1990;47(3):533-
43. 

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23) Tan ECK, Stewart K, Elliott RA, George J. Stakeholder experiences with general practice pharmacist services: a 
qualitative study. BMJ Open. 2013 Sep 1;3(9):e003214. 
24) May, C., Rapley, T., Mair, F.S., Treweek, S., Murray, E., Ballini, L., Macfarlane, A. Girling, M. and Finch, T.L. (2015) 
Normalization Process Theory On-line Users’ Manual, Toolkit and NoMAD instrument. Available from 
http://www.normalizationprocess.org. 
25) D'Amour D, Goulet L, Labadie JF, Martín-Rodriguez LS, Pineault R. A model and typology of collaboration between 
professionals in healthcare organizations. BMC Health Serv Res. 2008 Sep 21;8:188. 
26) Ritchie J, Lewis J. Qualitative research practice: a guide for social science students and researchers. Sage Publications; 
2003. 336 p. 
27) Francis JJ, Johnston M, Robertson C, Glidewell L, Entwistle V, Eccles MP, et al. What is an adequate sample size? 
Operationalising data saturation for theory-based interview studies. Psychol Heal. 2010;25:1229-45. 
28) World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research 
involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. 
29) ICH. ICH harmonised tripartite guideline for good clinical practice E6(R1), International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use [Internet]. ICH; 1996. Current Step 4 
version; dated 10 June 1996 [Cited 08-09-2016]. Available from: www.ich.org.  
30) ICMJE. Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in Medical Journals 
[Internet]. ICMJE; 2015 [Cited 08-09-2016]. Available from: www.icmje.org. 
 
 

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10. List of appendices 
Nr. 
Item 
1 
Standard Operating Procedure – Clinical Pharmacists 
2 
Standard Operating Procedure – Coordinator Uppsala/Enköping 
3 
Standard Operating Procedure – Coordinator Gävle 
4 
Standard Operating Procedure – Coordinator Västerås 
5 
Schedule of Enrolment, Interventions and Assessments 
6 
MedBridge Data Management Plan 
7 
Electronic Case Report Form: General part 
8 
Electronic Case Report Form: Reports 
9 
Electronic Case Report Form: Variable lists and field options 
10 
MedBridge Study contact list