OPTImization of Medication by Transdisciplinary Assessment of Drug Treatment in Elderly Hospitalized Patients

Background:

Recurrent hospitalization and unplanned emergency department (ED) attendance resulting from potentially inappropriate medication is an increasingly common phenomenon in older people with multi-morbidity and associated polypharmacy. With a growing older population with multi-morbidity/polypharmacy, there is a pressing need to address the increasing challenge of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) and associated problems that accentuate adverse drug reactions/events and avoidable excess morbidity. There is also an imperative to curb excess healthcare expenditure related to preventable medication-related problems.

Objective:

To test the clinical and economic impact of a multi-faceted medication optimization definitive intervention on avoidable rehospitalization and unscheduled ED attendance in multi-morbid patients aged ≥ 70 years hospitalized with acute illness.To test the clinical and economic impact of a multi-faceted medication optimization definitive intervention (DI) on avoidable rehospitalization and unscheduled ED attendance in multi-morbid patients aged ≥ 70 years hospitalized with acute illness.

Design:

A randomized controlled clinical trial is proposed in which it is anticipated to randomize 3 x 463 patients to one of 3 groups: (a) standard pharmaceutical care, or (b) trained physician-implemented DI, or (c) clinical pharmacist-implemented DI.

Setting: Acute care environment in 3 large tertiary referral teaching hospitals with similar custom and practice relating to management of older people with acute illness.

Participants: Patients aged ≥ 70 years with multi-morbid illness i.e. ≥ 3 chronic medical conditions and associated polypharmacy i.e. ≥ 5 daily prescription medications admitted with acute unselected illness.

Intervention:

The definitive multi-faceted intervention will consist of the following components:modified structured history of medication (SHiM), Screening Tool of Older Persons' Prescriptions (STOPP) and Screening Tool to Alert to Right Treatment (START) screening for PIMs and PPOs using STOPP/START version 3.0, drug-drug interaction screening using Stockley's Drug Interaction Checker, face-to-face consultation with attending hospital physicians to discuss PIMs, PPOs, interactions and other issues, pre-discharge medication review and adjustment, detailed medication adjustment discharge report to patients' general practitioners (GPs), post-discharge follow-up contact with patients' GPs and community pharmacists at 1 week and 1 and 3-6 months post-discharge.

Study Population:

OPTIMATE will focus on patients admitted with acute medical or surgical illness to Cork University Hospital, University Hospital Waterford and Ghent University Hospital. Patients to be screened for enrolment are those admitted primarily under the care of specialist departments other than geriatric medicine.

Data Collection:

All OPTIMATE trial data will be collected electronically and entered on a bespoke trial proforma. Once verified as fully correct and complete, all individual participant trial data will be stored on a fully secure clinical trial database.

Statistical Analysis:

Treatment effects for each of the two active intervention arms (versus control) in terms of binary outcomes (e.g. readmission) will be estimated using logistic regression, while Health Related QoL (EQ-5D 5L) will be analyzed using ordinal regression with a logit link function (i.e. a proportional odds model). We will report two models for each outcome: one adjusted for centre and admitting service type; and another further adjusted for centre, age (years), sex, number of comorbidities at baseline, and number of prescribed medications at baseline. Effect estimates will be reported as odds-ratios with 95% confidence intervals and exact p-values. There will be no correction for multiplicity, but we will report results for all outcomes regardless of the result and provide enough information for the reader to make whatever corrections they may consider appropriate. Equivalence tests comparing the two active arms (for each outcome) will be done using a "two one-sided tests" procedure based on a 90% confidence interval (which equates to a 5% type 1 error rate). All analyses will be conducted on an intention-to-treat basis and will be conducted under the quality system and SOPs of the HRB CRF-C Statistics and Data Analysis Unit. A complete statistical analysis plan (SAP) will be pre-registered on the Open Science Framework prior to patient recruitment database lock. Any necessary deviations from this SAP will be documented and explained in the trial report. There will be only one single trial data analysis at the end of the project. All reporting will be carried out in accordance with CONSORT guidelines for clinical trials.

• Definitive multi-faceted intervention consisting of several components (Other), also known as STOPP/START criteria, Face to face consultation with attending physician, medication adjustment report to patient's general practitioner, post discharge follow up with GP and community pharmacist, follow up with patient at 30 and 90-180 days post discharge, the Structured History of Medication (SHiM) questionnaire, Stockley's Drug Interaction Checker: The definitive intervention will consist of the following components: structured history of medication (SHiM), Screening Tool of Older Persons' Prescriptions (STOPP) and Screening Tool to Alert to Right Treatment (START) screening for PIMs and PPOs, drug-drug and drug-disease interactions screening, face-to-face consultation with attending hospital physicians to discuss PIMs, PPOs, interactions and other issues, pre-discharge medication review and adjustment, detailed medication adjustment discharge report to patients' general practitioners (GPs), post-discharge follow-up contact with patients' GPs and community pharmacists at 1 week, 1 month and 3-6 months post -discharge. The interventions will be applied by a trained physician or pharmacist.
• Sham Intervention (Other), also known as Control: Sham intervention in the form of the modified Medication Adherence Rating Scale (MARS) questionnaire in addition to standard care.

Primary outcomes

• Unscheduled readmission to hospital. [At day 30 post-discharge.]: All-cause re-hospitalization in multi-morbid older people exposed to polypharmacy. Computerized hospital admission records will be inspected. If hospital readmission has occurred dates of admission and discharge will be recorded in the electronic case report form.
• Emergency Department attendance. [At day 30 post-discharge.]: Unscheduled emergency department attendance at in multi-morbid older people exposed to polypharmacy. Computerized hospital emergency department attendance records will be inspected. The primary researcher will record on the electronic case report form whether there has there been an unscheduled emergency department attendance since the first follow-up post discharge.
• Composite endpoint 1 [At day 30 post-discharge.]: Composite endpoint of readmission to hospital or emergency department attendance within 30 days of discharge from the index admission.
• Unscheduled readmission to hospital. [At between days 90 and 180 post-discharge.]: Unscheduled readmission at 180 days post-discharge in multi-morbid older people exposed to polypharmacy. This will be ascertained during the follow-up interview within 180 (+/-14) days post-discharge. Computerized hospital emergency department attendance records will be inspected. The primary researcher will record on the electronic case report form whether there has there been an unscheduled readmission at 180 days since discharge from the index hospital admission.
• Emergency Department attendance. [At between days 90 and 180 post-discharge.]: Unscheduled emergency department attendance at in multi-morbid older people exposed to polypharmacy. This will be ascertained during the follow-up interview within 180 (+/-14) days post-discharge. Computerized hospital emergency department attendance records will be inspected. The primary researcher will record on the electronic case report form whether there has there been an unscheduled emergency department attendance at 180 days since discharge from the index hospital admission.
• Composite endpoint 2 [At between days 90 and 180 post-discharge.]: Composite endpoint of readmission to hospital or emergency department attendance within 180 days of discharge from the index admission.

Secondary outcomes

• Quality of life measured by EuroQol quality of life 5 dimensional 5 level instrument (incorporating pain control) [At day 30 post-discharge.]: The EuroQol quality of life 5 dimensional 5 level instrument (EQ5D-5L) is a self-reported quality of life questionnaire comprised of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each of the five dimensions is divided into five levels: level 1 (no problem), level 2 (slight problems), level 3 (moderate problems), level 4 (severe problems) and level 5 (unable to/extreme problems).The results are used to calculate a five digit score that describes the patient's health state. This value is the converted into an index value, on a range between 0 and 1, where 0 represents "a state as bad as being dead" and 1 represents "full health".In addition, the questionnaire has a Visual Analogue Scale question which asks the patient to indicate their overall health on the day of questionnaire completion. This is a 0 -100 scale where 100 represents "The best health you can imagine' and 0 'The worst health you can imagine'.
• Quality of life measured by EuroQol quality of life 5 dimensional 5 level instrument [At between days 90 and 180 post-discharge.]: The EQ5D-5L is a self-reported quality of life questionnaire comprised of five dimensions. The questionnaire gives a score in the range between 0 and 1, where 0 represents "a state as bad as being dead" and 1 represents "full health".In addition, the questionnaire has a Visual Analogue Scale question which asks the patient to indicate their overall health on the day of questionnaire completion. This is a 0 -100 scale where 100 represents "The best health you can imagine' and 0 'The worst health you can imagine'.
• All-cause mortality [At day 30 post-discharge.]: secondary outcome
• All-cause mortality [At between days 90 and 180 post-discharge.]: secondary outcome
• Occurrence of first admission to residential care facility for long-term nursing care [At day 30 post-discharge.]: secondary outcome
• Occurrence of first admission to residential care facility for long-term nursing care [At between days 90 and 180 post-discharge.]: secondary outcome

Other outcomes

• Quality Life Adjusted Year (QALY) [At between days 90 and 180 post-discharge.]: The study proposes to examine the DI cost-effectiveness from the wider public health services perspective including possible costs and benefits accrued via the community services and rehospitalizations. The study aims to assess the following cost-effectiveness measures of the DI as delivered by a trained physician and by a trained pharmacist
• Cost per hospital readmission avoided [At between days 90 and 180 post-discharge.]: The cost-effectiveness analysis will be performed by combining quality of life data and data from hospital records (the number of days in hospital if readmitted) and health resource utilization costs.
• Cost per ED attendance avoided [At between days 90 and 180 post-discharge.]: The cost-effectiveness analysis will be performed by combining quality of life data and data from hospital records (the number of emergency department attendances and health resource utilization costs.
• Unscheduled readmission to hospital within 180 days of discharge [At between days 90 and 180 post-discharge.]: All-cause re-hospitalization in multi-morbid older people exposed to polypharmacy. This will be ascertained during the follow-up interview within 180 (+/-14) days post-discharge. The primary researcher will record on the electronic case report form whether there has there been an unscheduled hospital admission. Computerized hospital admission records will be inspected. If hospital readmission has occurred dates of admission and discharge will be recorded in the electronic case report form.
• Composite endpoint of readmission to hospital or emergency department attendance within 180 days of discharge [At between days 90 and 180 post-discharge.]: All-cause re-hospitalization (outcome 2) will be ascertained as described. The number of days in hospital will be calculated for each visit and from these figures, the total days in hospital will be calculated. Unscheduled emergency department attendance (outcome 3) will also be ascertained as described. Computerized admission and emergency department attendance records will be used. The composite endpoint will be calculated from outcomes 2 and 3.

Sex: All, ages: 70 Years to any

Inclusion Criteria:

1. Age ≥ 70years
2. 3 or more chronic conditions.
3. ≥ 5 daily medications pre-admission, all medications taken for at least 4 weeks continuously.
4. Can speak and understand English (in the two Irish medical centres), and Dutch or French in Ghent University Hospital (Ghent is predominantly Dutch-speaking).
5. Can give informed consent or give witnessed verbal consent or have a suitable proxy who can give informed assent on the patient's behalf.
6. Agrees to follow-up contact post-discharge up to 180 days post-randomization.
7. Agrees to primary researcher contacting the GP and community pharmacist post-discharge.

Exclusion Criteria:

1. Terminal illness.
2. Severe dementia and clearly unable to understand the purpose of the trial or give consent to participation.
3. Severe communication disorder, making informed consent impossible.
4. Likely to be discharged from hospital within 48 hours of arrival.
5. Intensive Care Unit (ICU) admission.
6. Primary psychiatric presenting illness.
7. Unavailable for post-discharge follow-up for any reason.
8. Non-accidental poisoning.
9. Previous participation in medication optimization trials.
10. Active participation in another clinical trial
11. Infectious illness requiring strict isolation (including COVID-19 infection) blocking access of the primary researcher to the patient for enrolment.
12. End-stage renal, liver or lung disease requiring organ replacement therapy.
13. Admitted under the care of specialists in Clinical Pharmacology, Palliative Medicine, Clinical Oncology or Haematology.
14. Admitted under the care of specialists in Geriatric Medicine in Ghent University Hospital.
15. Trial participation refusal.

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• Study Protocol and Statistical Analysis Plan (PDF, 2023-06-13)

• Denis O'Mahony, Professor, Principal investigator, University College Cork