OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly: a cluster randomised controlled trial

Global life expectancy at birth has increased by a further 6 years from 1990
until 2012, and average life expectancy in the EU is projected to further
increase to 89.1 years for females and 84.6 years for males by 2060. The
population aged >=65 years is growing rapidly in the EU region. Multimorbidity
is the coexistence of several chronic diseases . Multimorbidity is associated
with increased mortality, decreased QoL, increased healthcare utilisation,
hospital admissions, and higher rates of drug prescriptions. Two-thirds of the
overall healthcare expenditures are spent for multimorbid patients, because
these patients are usually older, have more activity limitations, and present
with more complex clinical pictures.Despite the large number of multimorbid
patients, they were excluded in more than 60% of the RCTs published in high
impact journals during the last 15 years. Only 2% of RCTs explicitly included
multimorbid patients.

Polypharmacy may have detrimental effects in the elderly
Polypharmacy can be defined as the concurrent use of multiple drugs. A clear
and consistent definition is lacking, but >=5 chronic medications is a commonly
used approach to defining polypharmacy. Appropriate polypharmacy can improve
QoL and prevent consequences of diseases, whereas inappropriate polypharmacy is
often harmful.16 Inappropriate polypharmacy can have detrimental effects
especially in elderly patients for several reasons. Age-related changes in
pharmacokinetics and pharmacodynamics increase the risk of adverse drug events
(ADEs) in elderly. With polypharmacy, there is also an increased risk of
drug-drug and drug-disease interactions. In addition to its relation with
adverse drug reactions (ADRs) and ADEs, polypharmacy is associated with poor
drug compliance and other negative health outcomes, such as drug-related
hospital admissions (DRAs), cognitive decline, falls, and an increased risk of
hip fractures. Awareness of the related problems of polypharmacy and
inappropriate drug treatment in resource-rich countries is increasing.

Drug-related hospital admissions are common and costly
Drug-related morbidity and mortality is an increasing problem in European
healthcare systems. In the US, the overall costs of drug related morbidity and
mortality have been estimated to more than 170 billion dollars every year, of
which nearly 70 % are due to DRAs.

Overall Objective
The objective of this RCT is to evaluate whether the Systematic Tool to Reduce
Inappropriate Prescribing (STRIP) including STRIP assistant (STRIPA)
implemented by an appropriately qualified team will lead to an improvement in
clinical and economic outcomes among patients aged 70 years and more with
multimorbidity and polypharmacy.

Primary Objective
The primary objective is to assess the effect of pharmacotherapy optimisation,
using STRIP, on DRAs.

Secondary Objectives
Secondary objectives is to assess the impact of pharmacotherapy optimisation by
STRIP on parameters listed below (objectives 1-12) as well as to asssess the
patient*s acceptance of the STRIPA recommendations (objective 13):

1. Number of inpatient re-hospitalisations for any cause
2. Mortality
3. Number of falls and fractures
4. Health economics parameters, including direct costs of the intervention and
overall cost-effectiveness
5. Quality of life, including pain/discomfort
6. Degree of polypharmacy
7. Activities of daily living
8. Drug compliance
9. Clinically significant drug-drug interaction (DDI)
10. Unnecessary drug use
11. Drug underuse
12. Use of potentially inappropriate medications
13. Acceptance of the STRIPA recommendations

General study design and justification of design

OPERAM is a European multi-centre, cluster randomised, controlled trial of
people aged 70 years or older, with multimorbidity and polypharmacy, being on
an ambulatory visit or on a hospital stay in one of the four participating
centres in Ireland, Belgium, Switzerland, and the Netherlands. The primary
objective is to assess the effect of pharmacotherapy optimisation on DRAs over
one year of follow-up. Clusters will be randomised 1;1 to either the
intervention arm receiving STRIP or to the control arm undergoing usual
clinical care. The cluster is defined by one or two prescribing physicians,
i.e. physicians that are responsible for the pharmacotherapy of the participant
at the time of inclusion in the trial (cluster-defining physician). The
patients assigned to a cluster which was allocated to the intervention arm will
undergo a systematic pharmacotherapy optimisation by a research physician and a
pharmacist using the STRIP, including the STRIPA software. Patients assigned to
a cluster allocated to the control arm will receive usual care. Patients will
be followed for 1 year with follow-up phone calls to either the patient or his
or her carer(s) at 2, 6, and 12 months after inclusion. For the purpose of this
trial, all hospitalisations during follow-up of the participants will be
adjudicated at each site, based on common guidelines, to assess their
relationship to drugs. To assess the occurrence of selection bias, data on a
negative control outcome will be analysed. Assessment of the time needed for
the intervention will be collected in a subsample of patients.

The intervention will take place during the initial hospital stay
(corresponding to the index hospitalisation) or an equivalent situation for
outpatients (i.e. a visit at an ambulatory clinic). STRIP is a structured
method to perform pharmacotherapy optimisation. The STRIP-intervention consists
of 9 steps:
1. Structured history taking of medication (SHIM): Conducted by any trained
member of the trial team
2. Recording medication and diagnoses in STRIPA: Conducted by any trained
member of the trial team
3. Structured drug review based on the STRIPA with the integrated STOPP/START
criteria: Conducted by the research pharmacist and the research physician
4. Communication and discussion of the structured drug review with prescribing
physician with possible adaptation of the recommendation: Between the research
pharmacist and/or the research physician and the prescribing physician
5. Shared decision-making with the patient with possible adaptation of the
recommendation: To be conducted by the prescribing physician, the research
physician, or the research pharmacist
6. Optional revision based on new accumulating data during hospitalisation
(e.g. new diagnoses, ADRs): Adapted by the research pharmacist and the research
physician
7. Generation of medication report for patient*s GP: Conducted by the research
pharmacist and the research physician
8. Delivery of the report to the GP (optional additional direct communication):
Conducted by any trained member of the trial team
9. Follow-up: Conducted by any trained member of the trial team

Changes in therapy will be implemented according to discussions between the
research physician, the research pharmacist, and the prescribing hospital
physician. The prescribing hospital physician must determine the ultimate
potential net risk and benefit associated with any such management change in
the context of the individual patient*s circumstances and it is thus the
clinician who exclusively determines the most appropriate course of action for
the patient and who remains responsible for it. Changes will only be performed
after shared decision-making with the patient. The GP will be provided with the
STRIP suggestions including reasons for suggested changes..

Control Intervention (standard / routine / comparator treatment / medical
device)
Participants in the control group will receive medication review by the
prescribing physicians in accordance with usual care.

Changing medication may also lead to disadvantages or risk for patients.
Changes in medication will only be recommended after a careful review of all
drugs and weighing of all potential benefits and risks according to guidelines
about polypharmacy in elderly. Changes will be implemented only if agreed with
the patient and the treating physician at the hospital. He or she remains
responsible for these changes. Therefore, the risk is equal to that of patients
in the usual care group.