Drug Reduction in Older Patients: The DROP Trial
Phase: NA
Conditions: Geriatric Assessment, Frail Elderly, Skilled Nursing Facilities, Patient-centered Care
Sponsor: VA Office of Research and Development

 
Drug Reduction in Older Patients (The DROP Trial) 
 
 
 
 
 
 
 
Study Protocol 
 
Last Revised March 30, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Drug Reduction in Older Patients (The DROP Trial) 
 
 
 
 
Co-Principal Investigators: 
 
Amanda Mixon, MD, MPHS, MS, FHM 
Associate Professor of Medicine 
Section of Hospital Medicine 
Vanderbilt University Medical Center, and  
Geriatric Research Education and Clinical Center (GRECC) 
VA Tennessee Valley Healthcare System 
 
 
Sandra Simmons, PHD 
Paul V. Hamilton Chair in Geriatrics and Aging Research 
Director of the Vanderbilt Center for Quality Aging 
Professor of Medicine, Vanderbilt University Medical Center, Division of Geriatrics 
Professor, College of Arts and Sciences, Department of Psychology, Vanderbilt University 
VA Geriatric Research Education & Clinical Center (GRECC), Deputy Associate Director for Research 
Tennessee Valley, Senior Scholar for the VA Quality Scholar Program 
 
 
 
 
Supported by: 
 
VA Office of Research and Development 
 
 
ClinicalTrials.gov Identifier: NCT03722017 
 
 
 
 
 
 
 
 

Table of Contents 
PRÉCIS .......................................................................................................................................................................5 
Overview and Objectives ......................................................................................................................................5 
Study Design and Outcomes .................................................................................................................................6 
BACKGROUND AND SIGNIFICANCE ......................................................................................................................7 
Background on Condition, Disease, and Primary Study Focus..........................................................................7 
Study Rationale .....................................................................................................................................................8 
STUDY DESIGN ...................................................................................................................................................... 10 
PARTICIPANT RECRUITMENT AND ENROLLMENT ....................................................................................... 10 
Eligibility Screening and Recruitment ............................................................................................................. 10 
Enrollment Procedures ..................................................................................................................................... 11 
STUDY PROCEDURES ........................................................................................................................................... 11 
Schedule of Assessments ................................................................................................................................... 12 
Description of Assessments .............................................................................................................................. 13 
STUDY INTERVENTION ....................................................................................................................................... 16 
Conceptual Model .............................................................................................................................................. 16 
Pre-Review (Target Medications for Deprescribing) ...................................................................................... 16 
Incorporating Veteran Preferences .................................................................................................................. 17 
Inpatient Provider Communication .................................................................................................................. 17 
Final Deprescribing Actions .............................................................................................................................. 17 
SNF Handover .................................................................................................................................................... 18 
Post-Intervention Follow-Up ............................................................................................................................ 18 
SAFETY MONITORING AND ASSESSMENTS ..................................................................................................... 18 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ...................................... 18 
Adverse Event Reporting Procedures .............................................................................................................. 19 
STATISTICAL CONSIDERATIONS ....................................................................................................................... 19 
Sample Size and Randomization ....................................................................................................................... 19 
Interim Analysis and Stopping Rules ............................................................................................................... 20 
Outcomes ............................................................................................................................................................ 20 
Data Analyses ..................................................................................................................................................... 21 
DATA MANAGEMENT AND QUALITY ASSURANCE ......................................................................................... 22 
Data Collection Forms & Data Entry ................................................................................................................. 22 

Data Storage ....................................................................................................................................................... 22 
Quality Assurance .............................................................................................................................................. 22 
PARTICIPANT RIGHTS AND CONFIDENTIALITY ............................................................................................ 22 
Protection Against Risks ................................................................................................................................... 22 
Veteran Confidentiality ..................................................................................................................................... 23 
REFERENCES ......................................................................................................................................................... 23 
 
 
 

PRÉCIS 
Overview and Objectives 
Polypharmacy, defined as five or more medications,1, 2 is common in older patients discharged to skilled nursing 
facilities (SNFs) and is associated with adverse health outcomes.3-5 As part of a recent VA project, we 
prospectively collected medication data for 134 hospitalized, older Veterans. These data showed that, on average, 
14.2 medications were ordered for Veterans discharged to SNF, which included 2.5 medications newly prescribed 
in the hospital that met criteria for being potentially inappropriate medications (PIMs). Moreover, 75% of these 
Veterans had two or more geriatric syndromes. Geriatric syndromes are clinical conditions common in older 
adults such as cognitive impairment, unintentional weight loss and falls.6, 7 The co-occurrence of multiple 
syndromes is associated with loss of independence and higher healthcare utilization.8 All Veterans with 
polypharmacy also had one or more medications associated with geriatric syndromes. The prevalence of 
polypharmacy and multiple geriatric syndromes may partially explain why these patients often have poor health 
outcomes after SNF discharge. Recent data suggests that only 28% of patients discharged from SNF are living at 
home 100 days later, and 35% experience an adverse drug event.9  
 
There is a dearth of evidence related to the management of multiple co-existing geriatric syndromes, and few 
interventions have been implemented to reduce medications while also monitoring health outcomes. The 
relationship between polypharmacy, adverse drug events and geriatric syndromes in the VA population supports 
the rationale for an intervention focused on deprescribing medications before hospital discharge. We have pilot-
tested a multifaceted intervention (Drug Reduction in Older Patients, DROP) to engage patients and providers to 
reduce the number and/or dose of medications prior to hospital discharge. The proposed randomized, controlled 
trial is powered to evaluate the effect of this intervention on a reduction in medications as defined by the total 
number of prescribed medications, the number of PIMs, anticholinergic and sedative drug burden and the number 
of medications associated with geriatric syndromes. In addition, we will collect relevant data on the prevalence 
and severity of geriatric syndromes and other clinical outcomes. We also will use a hybrid research design to 
evaluate both effectiveness and implementation issues to better inform future adoption and sustainability.10 Our 
overarching hypothesis is that a hospital-based intervention to safely reduce the total number of medications 
represents the most feasible way to impact multiple health-related outcomes among older Veterans. Our Specific 
Aims reflect the primary outcomes that are the focus of the analyses, although we also will measure secondary 
outcomes related to VA healthcare utilization and patient safety: 
 
Specific Aim 1: Implement a patient-centered deprescribing intervention (DROP) in the hospital to reduce the 
total number of medications Veterans are prescribed at hospital discharge. 
Hypothesis 1a: DROP will result in a significant reduction in total medication exposure due to 
discontinuations and dose reductions at hospital discharge, SNF discharge and 90-days after SNF 
discharge. 
Hypothesis 1b: DROP will result in a significant reduction in the number of potentially inappropriate 
medications (PIMs) at hospital discharge, SNF discharge and 90-days after SNF discharge. 
Hypothesis 1c:  DROP will result in a significant reduction in the anticholinergic and sedative drug 
burden at hospital discharge, SNF discharge and 90-days after SNF discharge. 
Hypothesis 1d:  DROP will result in significantly fewer medications associated with geriatric syndromes 
at hospital discharge, SNF discharge and 90-days after SNF discharge. 
 
Specific Aim 2: Document the effects of a Veteran-centered deprescribing intervention (DROP) on medication 
adherence, health status, and geriatric syndromes. 
Hypothesis 2a: DROP will result in a significant improvement in medication adherence and self-rated 
health status at 7 and 90 days after SNF discharge. 
Hypothesis 2b: DROP will result in a lower prevalence and severity of geriatric syndromes at 7 and 90 
days after SNF discharge. 

 
Specific Aim 3: Evaluate intervention implementation to inform future adoption and sustainability. 
Aim 3a:  Identify patient-level barriers and facilitators of DROP. 
Aim 3b:  Identify VA and Non-VA provider-level barriers and facilitators of DROP. 
Aim 3c:  Identify system-level factors that influence sustainability after hospital discharge. 
 
Study Design and Outcomes 
Overview of Design 
Figure 1. Schematic of Study Design 
 
 
Study Setting 
The Nashville VA Medical Center is part of the Tennessee Valley Healthcare System (TVHS), which serves a 
diverse Veteran population in terms of income, geography and education level. We will target Veterans 
discharged from the Nashville VA hospital to any SNF, although the most common SNF locations include the 
TVHS York campus and 20 contract VA homes in surrounding areas. 
 
Interventions and Duration 
The intervention occurs during the Veteran’s hospital stay (Figure 1: Phase 2). This phase includes identification 
of medication for deprescribing, an interview to determine Veteran preference for deprescribing, and discussion 
with the Veteran’s inpatient treatment team. The inpatient treatment team incorporates the agreed upon final 
deprescribing actions in the Veteran’s hospital discharge orders. The intervention ends at the point of hospital 
discharge. 
 
Study Population and Sample Size 
Eligible Veterans are age ≥ 50 with polypharmacy as defined by ≥ 5 medications based on the pre-hospital 
admission; ability to provide consent (or proxy); speaks English; does not reside in long-term care or receive 
hospice services; have a recommendation or referral to a skilled nursing facility (SNF). All eligible Veterans will 
be approached for consent with an original enrollment goal of 540.  
 
The population and sample size were adjusted mid-study due to the significant enrollment and retention 
challenges caused by the COVID-19 pandemic. It was determined that a sample of 260 Veterans was sufficient to 
provide power greater than 93% for both the primary and secondary outcomes. Additionally, Veterans who were 
recommended SNF placement but ultimately discharged from hospital to home were approved to remain in study, 
which improved the study retention rate. 
 

BACKGROUND AND SIGNIFICANCE 
Background on Condition, Disease, and Primary Study Focus 
Geriatric Syndromes represent clinical conditions that share underlying causative factors and involve multiple 
organ systems.6, 7 The most commonly cited geriatric syndromes include: incontinence, depression, cognitive 
impairment, delirium, unintentional weight/appetite loss, mobility impairment, pressure ulcers and falls. However, 
no published studies include measures of all these conditions in one patient population. Multiple syndromes are 
common in older adults and predictive of poor health outcomes, even when controlling for age and illness 
severity.8 Approximately 50% of hospitalized patients aged 65 and older experience two or more syndromes,12 
with one or more syndromes either developing or worsening during the acute care episode.13-15 Patients discharged 
from the hospital to SNF are at higher risk for loss of independence relative to patients discharged home, and our 
preliminary data showed that 47% of hospitalized Veterans discharged to SNF had two or more geriatric 
syndromes. Moreover, each Veteran was prescribed an average of 5.4 medications associated with one or more 
geriatric syndromes (Preliminary Studies).  A separate study of community-dwelling Veterans aged 65 and older 
with polypharmacy, as defined by five or more medications, showed that 43% had one or more geriatric 
syndromes, and the strongest predictor of an adverse drug event was the number of medications added to their 
regimen during a 12-month timeframe.16 These data provide a strong rationale for our overarching hypothesis that 
reducing medications for older Veterans will favorably impact geriatric syndromes and other health-related 
outcomes, such as adverse drug events. 
 
Polypharmacy is common among older patients. Among hospitalized patients, polypharmacy has been most 
commonly defined as five or more medications1, 2 to as many as 10 or more, also described as, “hyper-
polypharmacy”.17 About 45% of older hospitalized patients are discharged on five or more medications.18, 19 Older 
patients have an increased prevalence of multi-morbidity; thus, it is not surprising polypharmacy is common. 
However, a substantial number of prescribed medications may be unnecessary.  Studies have found that > 90% of 
inpatients are taking at least one inappropriate medication.20, 21 Several studies have shown that up to 43%20 of 
medications taken by older patients lacked a clear indication, and 5%-11% of medications may be unintentionally 
prescribed for the same indication.20 Even when a clear indication exists, medications may be inappropriate when 
considering drug-drug or drug-disease interactions.22, 23 These medications, also known as potentially 
inappropriate medications (PIMs), have been defined by multiple criteria such as the Beers list24 and the 
Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP)25, 26 Beyond medical 
appropriateness, some medications may be costly or have inconvenient dosing that decreases adherence.20, 27 
Finally, prescribed medications may be inconsistent with a patient’s goals of care.28, 29  
 
Although most studies have been conducted in non-VA hospital settings, two studies reveal similar rates of 
polypharmacy and prescribing problems among VA patients. Most recently, a large study involving 462,405 
Veterans aged 65 and older examined prescribing quality using VA pharmacy data. Results showed that Veterans 
were prescribed a median of five medications, and 50% were identified as having one or more types of 
‘prescribing problems’ as defined by the following categories:  inappropriately high dose (12%), drug-drug 
interactions (30%), drug-disease interactions (3%), potentially inappropriate per the Beers list (26%) or other 
high-risk drugs (26%, e.g., warfarin, insulin, and/or digoxin). This study also showed that the total number of 
medications was the strongest predictor of each type of prescribing problem.30 Similarly, an earlier study with 196 
community-dwelling Veterans aged 65 and older prescribed 5 or more medications showed that 65% were taking 
one or more medications deemed clinically inappropriate and 57% were taking at least one medication deemed 
ineffective, not indicated or duplicative. Most importantly, however, the frequency of inappropriate medications 
increased as the total number of medications increased from a mean of 0.4 per Veteran among those taking five to 
six medications, to 1.1/Veteran among those taking seven to nine medications, and 1.9/Veteran among those 
taking 10 or more medications (i.e., hyper-polypharmacy). Underuse also occurred but was much less common, 
especially for those taking more than eight medications.31 
 

These studies demonstrate the prevalence and potential inappropriateness of polypharmacy among older patients 
in (non)VA healthcare settings.  Other studies have shown that polypharmacy can lead to multiple harmful 
outcomes among older community-dwelling and hospitalized populations. These outcomes include decreased 
medication adherence,32 increased adverse drug events,16, 32 and increased health care utilization and costs.3-5 
Polypharmacy and a variety of drug indices that quantify drug burden33, 34 also have been associated with the 
development of geriatric syndromes including long-term cognitive impairment,35, 36 delirium,37, 38 falls,1, 39-41 
frailty,42, 43 urinary incontinence,44 and weight loss.45 The number of syndromes related to polypharmacy supports 
our hypothesis that polypharmacy may be contributing to geriatric syndromes.  
 
Study Rationale 
Alignment with VA Priorities 
The study will examine the quality of care for hospitalized Veterans as they transition from acute to post-acute 
care and, subsequently, to home. The focus of this study is on polypharmacy among a vulnerable group of older 
Veterans who typically experience frequent care transitions and high healthcare utilization. The intent of the 
Veteran-centered intervention is to deprescribe unnecessary and potentially inappropriate medications to improve 
adherence and health status, which aligns with VA HSR&D research priority B, topic #3: assesses an intervention 
that encourages Veterans to be more actively engaged participants in their health care and decision-making by 
improving communication and interactions between providers and Veterans.  
 
Interventions to Deprescribe Medications and Knowledge Gaps 
     In recognition of the potential harms of polypharmacy, numerous studies have evaluated efforts to improve 
medication prescribing for older patients.46, 47 Most interventions have applied the use of explicit criteria to reduce 
inappropriate prescribing with tools such as the Beers or STOPP, while a few considered other patient-centered 
factors (e.g., cost, convenience, life expectancy). Trials commonly use pharmacists, physicians or inter-
disciplinary teams to implement deprescribing protocols.48 However, there are several important gaps in 
knowledge, which this proposal will address. First, few interventions have been initiated in the hospital setting, 
and no deprescribing interventions have targeted older patients transitioning from acute to post-acute care, which 
may be an opportune time to deprescribe. The few trials that have been conducted have been disease-focused on 
deprescribing specific types of medications.49, 50 Second, few trials have incorporated patient preferences into the 
decision-making process. A recent VA study implemented an electronic health record algorithm to identify 
medications for deprescribing; however, patients were not explicitly involved in the decision process.51  A recent 
qualitative study that included community-dwelling Veterans aged 65 and older with polypharmacy (mean = 13 
medications/Veteran) demonstrated that most Veterans expressed a desire to take fewer medications.52  Finally, 
although most of the trials reported improvements in medication appropriateness,48 there has been no study to 
evaluate the effects of deprescribing on health outcomes. 
 
Preliminary Data 
Our interdisciplinary research team has performed innovative, critical preliminary work that supports the rationale 
and feasibility of the DROP trial. This work includes (1) a determination of the prevalence of multiple geriatric 
syndromes in Veteran hospitalized older patients discharged to SNF; (2) identification of the potential link 
between polypharmacy and specific medications with contributing side effects to geriatric syndromes; and (3) a 
pilot-tested patient-centered deprescribing intervention (DROP). 
 
We examined geriatric syndrome and polypharmacy prevalence in a predominately male (96%), White (86%) 
Veteran sample (average age 74±10) discharged to SNF (N=134). Overall, 75% endorsed symptoms for two or 
more syndromes and 43% endorsed symptoms for three or more syndromes, with an average of 2.6 syndromes per 
Veteran. Polypharmacy was almost universal among both Veterans. Specifically, 99% of Veterans were 
prescribed > 5 medications and 80% were prescribed > 10, with a mean of 14.2 (± 5.3) per person at hospital 
discharge to SNF. Discharge medication lists included an average of 2.5 medications per patient that met criteria 
for being potentially inappropriate (PIMs), with 1.0 newly prescribed PIM during their hospital stay.  

      
We implemented a structured patient-centered intervention protocol (DROP) to reduce the total number of 
medications prior to hospital discharge among a sample of non-Veterans. Our deprescribing protocol was based 
on a conceptual framework that considers patient and disease factors, goals of care, treatment targets and the 
duration of treatment required for benefit.29 This framework also considers the clinical context of the patient’s 
care and providers’ willingness to deprescribe (provider barriers and facilitators). Finally, patient preferences 
were viewed as a key component that informs final deprescribing actions by identifying medications the 
patient is willing to deprescribe (e.g., including facilitators such as poor compliance, side effects or cost burden) 
and potential barriers (e.g., concern about symptoms worsening). The results of two recent qualitative studies 
revealed that most Veterans with polypharmacy expressed a desire to take fewer medications52 and the importance 
of involving the patient in the decision process related to medication changes to improve adherence.59 In addition, 
a survey of VA providers showed that assistance with follow-up, which a SNF care setting provides, and 
increased patient involvement in prescribing decisions were rated as two of the most preferred interventions to 
improve provider ability to discontinue medications.60,61 
 
The DROP intervention was implemented for 20 hospitalized patients referred to SNF and a control group of 20 
patients, who received routine hospital care. The intervention and control groups had a comparable number of 
total medications upon hospital enrollment. Overall, the research team identified an average of 12.75 (± 6.08) 
medications/patient for potential deprescribing based on initial chart review. The patient preference interview 
(intervention patients only) resulted in an average of 10.2 (± 4.5) changes (e.g., dose adjustments) to the initial 
recommendations based on chart review only. The large number of changes in recommendations demonstrates the 
importance of involving the patient in the decision process. Recommendations were communicated to the 
inpatient team and outpatient provider(s) for the intervention group only. The DROP pilot resulted in an average 
of 12.6 total deprescribed medications in the intervention group (P<.001), which included 6.1 pre-hospital 
medications (Table 3. Total deprescribed). The control group had an average of 6.5 total (4 pre-hospital) 
deprescribed medications as part of routine hospital care. 
      
The results of the DROP intervention demonstrate our ability to reduce the total number of medications, PIMs, 
and medications associated with geriatric syndromes through a patient-centered deprescribing protocol 
implemented during the hospital stay. Because our protocol included dose reductions, we were able to reduce the 
DBI from enrollment to hospital discharge. The intervention also demonstrates the importance of involving the 
patient in the decision-making process along with the inpatient team and outpatient providers. Our patient 
preference interview is a unique component of our intervention and one that is absent from most prior studies. 
 
Innovation: 
This trial is advancing science in multiple ways: 
1) One of the first controlled intervention trials designed to improve post discharge outcomes for the 
high-risk population of older Veterans transitioning from hospital to SNF to home.  Healthcare costs 
are increasing for this patient population, and they are at high risk for medication-associated 
complications and newly acquired geriatric syndromes.   
2) Although the number of medications is strongly associated with increases in geriatric syndromes,45 it 
is unknown whether reducing medications will improve geriatric syndromes. This trial will generate 
data to evaluate the impact of medication reduction on Veteran health outcomes. 
3) To date, there have been no controlled intervention trials focused on reducing the number of 
medications prescribed for hospitalized patients discharged to SNF, and the proposed intervention is 
one of the first to explicitly incorporate Veteran preferences into deprescribing efforts, which is 
consistent with Veteran-centered care initiatives. Moreover, our preliminary data show that 
incorporating patient preferences in the intervention protocol significantly changes these clinical 
decisions. 
4) The proposed trial will evaluate both clinical effectiveness and implementation to inform the potential 
for DROP to be adopted into VA clinical practice.10  

STUDY DESIGN 
 
The study is a 3-year, randomized controlled clinical intervention trial at a singular VA medical center. 
 
Primary Outcomes are change in total number (and/or dose) of medications including potentially inappropriate 
medications, number of medications associated with geriatric syndromes, and medications that contribute to 
anticholinergic and sedative drug burden. 
 
Secondary Outcome is the impact of deprescribing on geriatric syndromes, medication adherence, and self-rated 
health status.  
 
Implementation Science Outcomes are to identify patient and provider level barriers and facilitators as well as 
system-level factors required for sustainability. 
 
Eligible Veteran population is aged 50 years or older, experiencing polypharmacy (based on pre-hospital 
medications), and hospitalized at Nashville VA Medical Center with a recommendation for skilled nursing facility 
care. Exclusion criteria include limited life expectancy (less than 6 months or hospice admission), non-English 
speaking, no telephone, admitted from long-term care facility, incarcerated, no valid surrogate (if unable to 
consent), or enrolled in another drug trial. 
 
The timeline for the study is 3.5 years with enrollment beginning October 2019 with enrollment closing in 
November 2022. Final follow-up ends in March 2023. 
 
The DROP intervention is a deprescribing protocol that considers patient and disease factors, life expectancy, 
goals of care, and appropriate treatment targets. Medication-specific factors such as drug-drug interactions, drug-
disease interactions, and drug-specific safety profiles are also incorporated. Finally, Veteran preferences are key 
to final deprescribing actions by identifying the medications Veterans are willing to deprescribe. The inpatient 
(hospital) treatment team makes the final decision on deprescribing and incorporates the changes in the hospital 
discharge orders. In this intervention, deprescribing is defined as either stopping a medication or reducing the 
dose/frequency of a medication. 
 
PARTICIPANT RECRUITMENT AND ENROLLMENT 
Eligibility Screening and Recruitment 
The Nashville VA Institutional Review Board permits a record review to screen patients for research studies. 
Screening is conducted every weekday by the project coordinator or research assistant. The screening process 
starts with a structured query of the VISTA reporting system. The Physical Therapy Consult Report allows the 
study team to identify Veterans recommended for SNF care after hospital discharge. All Veterans on this report 
are added to the screening panel in the electronic medical record then reviewed for the following inclusion and 
exclusion criteria: 
 
Inclusion Criteria: (1) Confirm that the Veteran is aged 50 years or older. (2) Next review the Essential 
Medication List Review to confirm the Veteran has 5 or more home medications excluding topical agents.  
(3) Review the inpatient social work admission note to verify that the Veteran speaks English, has a working 
telephone, and was admitted from the community (i.e., non-LTC location). 
 
Exclusion Criteria: (1) The EMR is reviewed for indication of life expectancy less than 6 months by searching for 
palliative care consults with hospice recommendations, referrals to hospice agency, and diagnoses of Stage IV 

cancer. (2) Lastly, the research flags are reviewed to determine whether the Veteran’s current trial enrollment(s) 
include a pharmaceutical trial. 
 
For Veterans who have multiple hospitalizations during the trial period, they are re-screened at each new 
admission to determine eligibility for participation. 
 
Enrollment Procedures 
All Veterans meeting eligibility requirements are approached for consent. While any member of the research team 
can obtain informed consent, we preferred to have a study clinician, either Nurse Practitioner (NP) or Pharmacist 
(PharmD), provide an overview of the study and intervention in lay terminology. The Veterans and/or their 
surrogates were given time to review the study brochure and informed consent document then study personnel 
answered any questions. Prior to signing the consent documents, all Veterans were asked to complete a four 
question ‘evaluation to sign consent’ (approved by the IRB) to ensure they were capable of providing consent.  
 
In the event that the Veteran was not capable of providing consent due to cognitive impairment, underlying 
comorbid conditions, or use of psychoactive medications, the study team sought the Veteran’s legally authorized 
representative. In the case that a Veteran’s inability to consent is temporary, the Veteran will be asked to provide 
verbal assent once they are deemed competent to consent. Participants will have full disclosure of who provided 
consent on their behalf and retain the right to re-consent or withdraw. 
The process to obtain consent can occur in-person or via telephone. Study team’s first preference is to meet with 
the Veteran and/or their surrogate in person.  
1. However, in the event that study personnel cannot enter the Veteran’s hospital room (due to COVID-19 
precautions), the IRB approved a verbal consent process via the telephone in the Veteran’s room. At the 
point the Veteran is no longer isolated, study staff will enter the room to provide the Veteran with a 
hardcopy of the study informed consent documentation and to have the Veteran sign a release of 
information form. 
2. If the Veteran does not pass the evaluation to sign consent and their surrogate is not at the hospital, the 
IRB approved a verbal surrogate consent documentation. After verbal consent is given, study personnel 
mail a copy of the consent form to the surrogate for their records.  
 
All enrolled Veterans will have a research flag placed in their medical record to identify them as a study 
participant. The research alert includes a brief description of the study and contact information for key study 
personnel. After enrolling, the Veteran will be added to an enrollment panel in the electronic medical record. 
 
Following enrollment, Veterans are randomized to either intervention or control groups using the REDCap 
randomization feature which automatically assigns allocations based on a schedule (computer generated using 
Mersenne-Twister), which is uploaded by the team statistician. Veterans are randomized using permuted blocks of 
two or four where the size of each block is selected uniformly at random. This randomization ensures balance 
between the groups after every second or fourth randomization.  
 
STUDY PROCEDURES 
Data collection includes Veteran descriptive data along with geriatric syndromes, medications, health status, 
safety, and implementation science as noted in the table below. Upon enrollment, the Veteran will complete 
interviewer-administered questionnaires (marked with an asterisk below) with interviews conducted by trained 
study personnel. In the event the Veteran is unable to complete assessments (e.g., delirious, cognitively impaired), 
their designated surrogate will be asked to complete the assessments for which surrogate responses have been 
validated. Assessments that can be completed by surrogates are the ICIQ (urinary incontinence), DETERMINE, 
falls, pressure ulcers, medication history, and demographics. The remainder of the data will be abstracted from 
each patient’s medical record; however, total number and type of medications will be determined based on a 

combination of patient interview, medical record and pharmacy refill history to ensure an accurate, complete 
medication list.  
 
The data shown in the below table for the “SNF” column is abstracted from SNF medical records; thus, research 
personnel will not interview the participant again during their SNF stay. However, participants will be contacted 
via telephone by research personnel at 7 and 90 days after they leave the SNF. If the Veteran is willing to also 
complete our implementation evaluation interview to assess barriers and enablers of deprescribing during their 
routine 7-day follow-up call, we will conduct this additional interview at the current 7-day follow-up timepoint in 
conjunction with other 7-day assessments.  However, in consideration of Veteran response burden, we will 
provide the Veteran with the option to schedule the implementation evaluation interview component anytime 
during the initial 14-days following SNF discharge, based on the preference and convenience of the Veteran, so 
that they may choose to complete this interview separately. Both the intervention and control group will be 
monitored using that same data collection schedule and measures.  
 
Schedule of Assessments 
Measures and Data Collection Timeline 
Baseline 
Hospital 
SNF 
Discharge 
Post SNF Discharge 
7-Days    90-  Days 
Descriptives 
 
 
Telephone Interviews 
Demographics and Length of Stay 
X 
X 
 
 
Elixhauser Comorbidity Index 
X 
 
 
 
Patient Attitudes Toward Deprescribing 
(PATD)* 
X 
 
 
X 
Primary Outcome – Medications 
 
 
 
 
Total number and type of Routine and PRN 
Medications, including PIMs 
X 
X 
X 
X 
Pharmacy Calls to Verify Refill History 
X 
 
 
X 
Drug Burden Index (DBI) 
X 
X 
 
X 
Medication Adherence (ARMS)* 
X 
 
X 
X 
Secondary Outcome – Geriatric Syndromes 
 
 
 
 
Cognitive Impairment (BIMS)* 
X 
 
X 
X 
Delirium (BCAM)* 
X 
 
N/A 
N/A 
Depression (PHQ-9)* 
X 
 
X 
X 
Urinary Incontinence (ICIQ-UI SF)* 
X 
 
X 
X 
Unintentional Weight Loss (DETERMINE)* 
X 
 
X 
X 
Pain (Brief Pain Inventory, BPI-short form)* 
X 
 
X 
X 
Falls 
X 
 
X 
X 
Pressure Ulcers 
X 
 
X 
X 
Secondary Outcome – Health Status 
 
 
 
 
Functional Health Status (VES-13)* 
X 
 
X 
X 
Secondary Outcomes – Safety 
 
 
 
 
Unplanned Healthcare Utilization  
(hospitalizations, emergency room visits) 
 
X 
X 
X 
Adverse Drug / Withdrawal Events 
X 
X 
X 
X 
Status: Long-Term Care, Hospice, Death 
 
X 
X 
X 
Implementation Evaluation 
 
 
 
 

Veteran & Provider Barriers and Facilitators 
X 
 
X 
X 
System-Level Factors related to Sustainability 
 
X 
X 
X 
Staff Time for Intervention Implementation 
X 
X 
X 
X 
Stakeholder Input 
X 
 
 
 
 
Description of Assessments 
Demographic and Administrative Data: The sociodemographic data is obtained primarily obtained from medical 
record abstraction then verified with the Veteran (or their surrogate). Using a standardized abstraction form, study 
personnel collects and records age, gender, race, ethnicity, home address, telephone number, insurance status, 
outpatient providers, and pharmacies. We also abstract key information related to this hospitalization including 
site prior to hospitalization, admission date, admission diagnoses, hospital service/team, and discharge date and 
disposition. Data is verified with the Veteran, and participants are also asked their highest level of education and 
complete the Brief Health Literacy Screen. 
 
GerontoNet Adverse Drug Event risk assessment calculated the Veteran’s risk for experiencing an adverse drug 
event. The assessment contains items related to certain comorbid conditions or diagnoses, which are assessed via 
the Veteran’s problem list. The other component is previous adverse drug reactions, which are assessed in the 
baseline demographic interview. 
 
Walter Index is a prognostic tool to predict mortality within one year of hospital discharge. A higher score 
indicates a greater likelihood of mortality. The components of this tool are comorbid conditions and lab values 
which are abstracted from the Veteran’s problem list and hospital intake assessment. The component assessing 
assistance with activities of daily living is completed by both medical records review (physical therapy notes) and 
during the baseline demographic interview. 
 
Patients’ Attitudes Toward Deprescribing (PATD) is a 15-item survey of which the first 10 items are part of a 5-
point Likert scale ranging from ‘strongly agree’ to ‘strongly disagree.’ Examples include: “I feel that I am taking 
a large number of medicines” and “I believe that all my medications are necessary.” The remaining five questions 
are related to patient’s perception of their total number of medications, history and comfort level with stopping a 
medication. If the patient is unable to answer, the questionnaire can be administered to the surrogate. 
 
Primary Outcomes – Medications 
Total number of medications: Data collection begins with the Veteran’s Essential Medication Review List 
(EMLR). After this list is abstracted from the medical record, a study NP or PharmD pulled the Controlled 
Substance Monitoring Database report, called non-VA pharmacies for recently filled prescriptions, reviewed non-
VA medical records (i.e., outside hospital or SNF records), and interviewed the Veteran or their surrogate. We 
included all medications, either prescription or over-the-counter (OTC) that were administered by the following 
routes: oral, intravenous, intramuscular, sublingual, or ophthalmologic. Veterans (or their surrogate) were given 
specific prompts if they reported no OTC usage, for example, asking them if they take anything for constipation 
or allergies. If a patient was admitted from an institutional setting (e.g., outside hospital, SNF, ALF), we request a 
copy of the medication administration record from the previous 30 days. Medications are considered 
current/active if the Veteran took it within 30 days of hospitalization. The hospital discharge and SNF discharge 
medication lists, serve as the outcome data for those respective time points. During the follow-up calls, the study 
NP or PharmD systematically asked the Veteran for the status of each medication on the enrollment list and 
discharge lists to determine if and how they are taking it. Afterwards the study clinician prompted the Veteran for 
any new medications they may be taking. 
 

Potentially Inappropriate Medications (PIMs): We used previously published and validated lists including the 
Beers criteria, the STOPP criteria, and the RASP list, which have a large degree of overlap. The total number of 
PIMs is the sum of medications that are found on these lists.  
 
Drug Burden Index (DBI): This score is calculated separately for anticholinergic and sedative medications, which 
have been linked to functional impairment, falls, and delirium. The DBI is the sum of each individual 
anticholinergic/sedative medication’s prescribed daily dose divided by the sum of the minimum effective dose 
(per the FDA minimum recommended dose) and the patient’s daily dose. The DBI is calculated for all 
medications including OTCs. We will calculate the DBI at each timepoint, and this will capture dose reductions 
even when the total number of medications is not reduced. 
 
Secondary Outcomes – Geriatric Syndromes, Medication Adherence, and Functional Status 
Delirium: is assessed via the Brief Confusion Method (bCAM), a screening tool validated for use with 
hospitalized older adults. If the participant screens positive for delirium, no other participant interviews are 
conducted. Members of the research team will re-assess delirium daily during the remainder of the 
hospitalization; if/when the Veteran screens negative, the remaining assessments will be administered to the 
Veteran. If delirium persists throughout the hospitalization, the Veteran’s surrogate is approached for syndrome 
assessments. The bCAM is not repeated at any other time point as it cannot be completed via telephone. 
 
Cognitive Impairment: is assessed by the Brief Interview for Mental Status (BIMS), which has a total score range 
from 0 to 15 (0-7: severe impairment; 8-12 moderate impairment; 13-15 cognitively intact). 
 
Depression: The Patient Health Questionnaire-9 (PHQ-9) is a validated screen to assess for depressive symptoms 
and their severity. Each item is scored from 0 (“not at all”) to 3 (“nearly every day”) to produce a cumulative 
score between 0 (no depressive symptoms) and 27 (severe depressive symptoms). If a Veteran reports severe 
depression or thoughts of self-harm, the study team elicits more information on their immediate safety then 
contacts the primary treatment team to close the loop for follow-up. The study team also offers to connect the 
Veteran with the VA’s emergency helpline.  
 
Urinary Incontinence: The International Consultation on Incontinence Questionnaire – Urinary Incontinence Short 
Form (ICIQ-UI SF) has four components and measures symptoms, frequency, and impact of urinary incontinence 
on quality of life. This tool has well established reliability and validity including sensitivity to treatment.  
 
Unintentional Weight Loss and Poor Appetite: Nutritional concerns are assessed through the Determine Your 
Nutritional Health checklist, which is a 10-item tool utilized by the state government to determine nutritional risk 
in older adults receiving meal assistance. The checklist has 10-items which yields a nutritional risk score of 0-2 
(low), 3-5 (moderate), and ≥ 6 (high). One item asks if they experienced a 10-pound weight change; if the Veteran 
indicates they had experienced a weight change, the study team will ask a structured question to clarify if the 
weight change was a gain or a loss.  
 
Pain: is assessed with the Brief Pain Inventory (BPI) short form, which has three primary components: location, 
pain severity, and pain interference with daily activities. The pain severity score is comprised of four questions 
(e.g., worst, best, average, current) in which the Veteran rates their pain on a 0-10 scale in the last 24 hours. 
 
Falls: The Veteran (or their surrogate) is asked if they have fallen in the last month or since the previous timepoint 
during follow-up phase. If the response is ‘yes,’ then the patient is asked how many times they have fallen, and if 
any of the falls led to an emergency room visit or hospitalization. 
 
Pressure Ulcers: At enrollment, the medical record is reviewed (via flowsheets and free text search) for the 
presence of pressure ulcers, including the staging (Stages 0-4). During the follow-up timepoints, the Veteran 
and/or their surrogate are interviewed directly about the presence of a pressure ulcer. 

 
Medication Adherence: The Adherence to Refills and Medications Scale (ARMS) is 12 items on a Likert scale 
with the options ranging from “none of the time” to “all of the time.” Example questions include “How often do 
you forget to take your medicines?” and “How often do you put off refilling your medicines because they cost too 
much money?”. The assessment’s score range is 12 to 48 points with lower scores indicating better medication 
adherence.  
 
Functional Health Status: The Vulnerable Elders Survey (VES-13) is a measure of health status that assesses a 
patient’s cognitive, physical and self-care activities, and self-rated health status. Scores range from 1 to 10, 
wherein lower scores indicate better health. 
 
Safety Outcomes 
Unplanned Healthcare Utilization: The study team will monitor Veterans’ healthcare utilization, both at the VA 
and outside the VA system, after study enrollment. During the consent process, Veterans sign a release of 
information form that allows the team to request records from non-VA entities. We will track all emergency room 
visits, hospitalizations, and deaths, and these events will be adjudicated by a blinded clinician (see Safety 
Assessments section). 
 
Adverse Drug Withdrawal Events (ADWEs): any unplanned healthcare utilization is reviewed by a blinded 
physician co-investigator to determine if the event was medication related, and more specifically if it was related 
to medication withdrawal. The standardized adjudication form includes validated scales such as the Naranjo. 
 
Implementation Science  
Veteran Barriers & Enablers: Veteran level barriers and enablers to deprescribing are assessed for every Veteran 
randomized to the intervention group. For every medication recommended to the Veteran for deprescribing, the 
study NP or PharmD records the agreement to deprescribing and field notes of the Veteran’s reasoning for 
agreement/disagreement. The field notes are later coded into pre-set categories of barriers/facilitators created 
through a systematic review by the creators of the PATD. This will allow the study team to compare the barriers 
and enablers of Veterans with non-Veteran populations from other deprescribing trials. 
 
To gain additional insight into Veteran preferences for deprescribing, Veterans both treatment arms will be asked 
to complete a semi-structured interview at the 7-day follow-up call. This interview broadly discusses changes to 
medication regimens including the Veteran’s perception of how medication changes are currently made and if 
they have ever initiated a medication change. Then the interview gauges the Veteran’s comfort with having 
medication conversations with their provider, and finally ends with how they would prefer medication and 
deprescribing conversations take place (e.g., what type of provider, inpatient v. ambulatory setting). 
 
Provider Barriers & Enablers: Similar to the Veteran level barriers and enablers, provider level barriers and 
enablers are documented at the medication level during the deprescribing conversation. These field notes are 
coded using pre-set categories: awareness, inertia, self-efficacy, and feasibility. Study team members probe the 
inpatient provider for a rationale, but in the event that a provider offers a one-word agreement (e.g., sure, yes, 
okay) to deprescribe, we have added ‘tacit’ as an enabler category. 
 
System Level Factors: The study team engages both inpatient pharmacists and physicians as part of the 
deprescribing protocol. The adoption of a deprescribing intervention into clinical practice would likely be the 
responsibility of inpatient pharmacists; therefore, we chose to conduct semi-structured interviews with 
pharmacists who interacted with the study team. The pharmacists were explicitly asked about the feasibility of 
incorporating the intervention into their workflow and workload, how it would change their work processes, and 
what organizational support (or factors) would be necessary to routinely implement a deprescribing intervention. 
 

Staff Time to Implement Intervention: To understand the resources necessary to implement the intervention (and 
thus provide feedback to the organization), we time certain components of the intervention to calculate staff time. 
Specifically, we document the time required for calling outside pharmacies for refill information, reviewing the 
medication list and assigning every medication and indication and deprescribing recommendation, and conducting 
a deprescribing conversation with the Veteran and/or their surrogate. 
 
STUDY INTERVENTION 
The deprescribing protocol is based on a conceptual framework that considers patient and disease factors, goals of 
care, treatment targets and the duration of treatment required for benefit (Figure 2). We also incorporated 
medication-specific factors for minimizing inappropriate medication use (drug-drug and drug-disease 
interactions). Additionally, this framework considers the clinical context of the patient’s care and providers’ 
willingness to deprescribe. Lastly, patient preferences are a key component that informs final deprescribing 
actions by identifying medications the patient is willing to deprescribe (e.g., including facilitators such as poor 
compliance, side effects or cost burden) and potential barriers (e.g., concern about symptoms worsening).  
 
Conceptual Model 
Figure 2. Deprescribing Framework 
 
 
Pre-Review (Target Medications for Deprescribing) 
Following baseline assessments and medical record review, a study Pharmacist or Nurse Practitioner will review 
the total enrollment medication list. Using medical record data, the following information will be ascertained for 
each medication: (1) Medication Indication: If an indication (i.e. diagnosis or symptom) cannot be identified, “no 
indication indicated” will be specified; and, (2) Deprescribing rationale: Rationales for deprescribing (i.e., 
stopping or reducing dose) will be assessed for each medication as summarized below in Table 2. For each 
medication recommended for deprescribing, the deprescribing action will be specified as: (1) Stop prior to 
hospital discharge without need for monitoring; (2) Stop prior to hospital discharge with symptoms/physiologic 
monitoring; (3) Stop at specified time point following hospital discharge; (4) Reduce over time with monitoring 

until medication is stopped; (5) Reduce to lower dose without need for monitoring; (6) Reduce to lower dose with 
symptoms/physiologic monitoring.  
 
All medications, both prescription and OTC including vitamins and herbal supplements, are reviewed for 
potential deprescribing. Select medication classes will not be under consideration for active deprescribing, which 
include the following: 
• 
Anti-rejection medications for organ/ bone-marrow transplantation 
• 
Chemotherapeutic medications for the treatment of known solid organ or hematologic malignancy.  
The above medications may be deprescribed during the study period; however, it would solely be under the 
direction and recommendation of the primary treatment team or primary prescriber of the medication. 
 
Table 2. Deprescribing Rationale 
A. No indication for medication / Indication not clear  
B. Wrong dose or directions for medication 
C. Inappropriate for current indication due to: 
 1. Indication has resolved 
 2. Patient is below treatment threshold 
 3. Treating guidelines have changed, medication  
      no longer indicated 
 4. Wrong Indication for medication 
D. Medication is ineffective as evidenced by no 
change in symptom or condition 
E. Duplicate medication for same indication 
F. High risk medication based on: 
 1. Potential drug-drug interaction 
 2. Potential drug-disease interaction (e.g. associated 
with geriatric syndrome) 
 3. On Explicit list of PIMs (i.e., Beer’s list47, STOPP 
list48, 49, and/or RASP list50) 
G. Medications are inconsistent with goals of care 
H. Risk > benefit given patients limited life 
expectancy 
I. Evidence of poor adherence or high risk of poor 
adherence (directions impractical, high cost) 
J. Medication currently indicated, however is time-
limited and expect indication to resolve 
 
Incorporating Veteran Preferences 
Following medication targeting, intervention Veteran (and/or their surrogate) will receive a structured interview 
by the study pharmacist or nurse to elicit their preferences regarding medications identified for deprescribing. The 
following will be assessed for each targeted medication: adherence, side effects, perceived benefit (or harm), cost, 
and willingness to stop or reduce the medication. We also will document patient barriers (e.g., concern about 
increased pain) and facilitators (e.g., high dose frequency, cost) that influence their willingness to deprescribe. If 
the Veteran raises a concern about a medication which the study team did not target for deprescribing, the 
PharmD or NP should still address these concerns and note them in communications with the treatment team. As 
noted in the Description of Assessments, field notes were categorized into specific barriers and enablers.  
 
Inpatient Provider Communication 
 After completing the deprescribing interview with the Veteran, the study NP or PharmD will reach out the 
Veteran’s inpatient treatment team including both the pharmacist and the resident physician. The study clinician 
will present the team with the deprescribing recommendations that the Veteran agreed to along with the rationale 
for deprescribing. Similar to the Veteran deprescribing interview, the study NP or PharmD will record field notes 
and team agreement to deprescribing, which will be coded into barriers and enablers (see Description of 
Assessments). 
 
Final Deprescribing Actions 
A crucial component to successful intervention is the Veteran leaving the hospital with an accurate medication list 
that reflects all the agreed upon deprescribing actions. The study NP or PharmD will remain in communication 
with the treatment team to ensure that final agreed upon recommendations are included on Veteran’s final 
discharge list. Ultimately any medication changes are at the discretion of the inpatient treatment team. 

SNF Handover 
Within 24-hours of hospital discharge the study team will contact the SNF admissions nurse to review the 
Transfer Medication List in conjunction with the list of deprescribed medications and the need for medication-
specific monitoring, if applicable. In addition, recommended dose titrations may be highlighted during this SNF 
handover.   
 
Post-Intervention Follow-Up 
The intervention ends at hospital discharge. Originally, if the Veteran discharged to any location other than SNF, 
they were discontinued from study. Due to retention concerns, the IRB approved the retention of Veterans who 
discharged home (beginning in March 2021). 
 
Skilled Nursing Facility (SNF) 
The study team will contact the SNF weekly to monitor the Veteran’s expected discharge date and monitor for 
any unplanned healthcare utilization. At the point of SNF discharge, the study team will request the Veteran’s 
discharge medication list. 
 
7- and 90-Day Follow-Up 
The 7-Day follow-up call occurs 7 days after SNF discharge (±3 days), and the 90-Day call occurs 90 days after 
SNF discharge (±10 days). The study NP or PharmD asks the Veteran to have their medication bottles, pill 
organizer, and list nearby during the call. If a surrogate assists with medication management, we also ask that 
person to be available. The Veteran lists of the medications they are currently taking with the dose and frequency 
information. Afterwards, the study clinician will inquire about medications from enrollment or discharge lists that 
the Veteran did not address in order to confirm their usage or discontinuation. After the medication history is 
obtained, the study team administers the geriatric syndrome and medication adherence assessments. 
 
SAFETY MONITORING AND ASSESSMENTS 
We have established a system to report and track adverse events (AEs) including adverse drug withdrawal events 
(ADWEs), serious adverse events (SAEs), and Suspected Unexpected Serious Adverse Reaction (SUSARs). In 
this study, an AE is defined as any unplanned healthcare utilization or unexpected death (i.e., patient not receiving 
hospice services at time of death). These AEs are considered SAEs if they include any untoward medical outcome 
that results in the following: inpatient hospitalization or prolongation of existing hospitalization, life threatening 
condition with immediate risk of loss of life (including escalation of hospital care to Intensive Care Unit), or 
unexpected death. A SUSAR is an SAE that is suspected to be secondary to the drug withdrawal and is 
unexpected. Study personnel will monitor the safety of subjects and follow them until the event resolves or is 
explained.  
 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
Notification of Unplanned Healthcare Utilizations and Deaths 
Unplanned healthcare utilization (intensive care unit transfers, emergency department visits and/or 
hospitalizations) and deaths are monitored throughout all study phases for each Veteran. The study coordinator 
and research assistant share a study patient panel in the electronic health record. Any time a participant is 
admitted to the Nashville VA Medical Center, they are alerted. To identify if a Veteran experience an unplanned 
healthcare utilization at an outside hospital (OSH), the Veterans are asked at each follow-up time point if they 
have been to an emergency room or had an inpatient stay, and if so, at what facility. Additionally, the research 
assistant or study clinician reviews VISTA for any uploaded OSH records at the time of the follow-up calls. The 
research assistant is responsible for requesting medical records from OSHs (and SNFs) relevant to the utilization.  
 
 

Review of Unplanned Healthcare Utilizations and Deaths 
Any unplanned healthcare utilization or unexpected death (e.g., patient not receiving hospice care) is reviewed to 
determine if it was an adverse event that was serious, related to the study, and unexpected (SUSAR). Once all 
necessary records have been obtained by the research assistant, the case is assigned to a physician co-investigator 
(adjudicator) blinded to group assignment. Through a structured review protocol of all relevant medical records 
from both within and outside of VA, the adjudicator uses an established methodology to determine the presence 
of serious medication errors. Clinician-adjudicators will decide whether the unplanned healthcare utilization is 
related to medication withdrawal (i.e., ADWE) using the 10-question Drug Withdrawal Probability Scale,96 a 
scale based on the Naranjo algorithm,97 which is a validated scoring system to assess causality of adverse drug 
events. ADWE will be coded as definite (>8), probable (5-8), possible (1-4), and doubtful (<1).  For all ADWEs, 
clinician-adjudicators will then determine whether it was avoidable by any change in management.  
 
After review by the clinician-adjudicator, the case is sent to the Principal Investigator to review to determine if the 
event was unexpected and/or study related. Should the event be determined as SUSAR (serious, unexpected, and 
study related) it will be reported as such to the DSMB and IRB as outlined below. 
 
Adverse Event Reporting Procedures 
The Principal Investigators (PIs) are responsible for reporting to the respective governing bodies in accordance 
with their prescribed timelines and regulations. 
 
Institutional Review Board 
PIs will notify the IRB of any Serious, Unexpected, Study Related Adverse Event within 7 days of PI notification 
of the event. All deaths regardless of study relatedness will be reported to the IRB within 7 days of PI notification. 
At the time of the IRB annual continuing review, the IRB will receive (1) a listing of all adverse events, and (2) 
copies of the reports generated from DSMB meetings. If the DSMB meeting report identifies a new risk to or a 
change in the risk benefit ratio, the IRB will be notified within 5 days of PIs receipt of the report.  
 
Data Safety Monitoring Board (DSMB) 
The Health Services Research and Development Service (HSR&D) Data and Safety Monitoring Board convenes 
annually in March. The PI will submit a report to the VA Program Officer and DSMB coordinator by January 31st 
each year. This report will include case listings for all deaths, serious adverse events, and non-serious adverse 
events regardless of unexpectedness or study relatedness. At the conclusion of the closed session meeting, the 
DSMB will note any concerns about Veteran safety and issue an approval for study continuation. In the event that 
the DSMB has additional concerns, issues a conditional approval, or requests a temporary study stoppage, the PIs 
will be given 30 days to respond to the DSMBs concerns. 
 
STATISTICAL CONSIDERATIONS 
Sample Size and Randomization 
Existing data indicate that approximately 600 to 700 hospitalized Veterans are referred to SNF annually. Thus, we 
conservatively estimate that 40% (or, 240 per year) will provide consent, complete baseline assessments and 
discharge to SNF to yield a total consented sample of 540 across all study months. During the SNF stay, we 
anticipate ~5% will die, which will leave 513 (or ~256 per group) discharged from SNF. Based on preliminary 
data, ~15% of patients die within 90 days of SNF discharge. Thus, ~85% (or 393 total) will be alive at 90 days. In 
addition, we estimate we will be unable to reach ~10%, which will leave ~354 total participants (~177/group) for 
90-day follow-up. The population and sample size were adjusted mid-study due to the significant enrollment and 
retention challenges caused by the COVID-19 pandemic.  

It was determined that a sample of 260 Veterans was sufficient to provide power greater than 93% for both the 
primary and secondary outcomes. Finally, the study enrollment was continued for an additional 10 months beyond 
the original project timeline. 
 
Participants will be randomized in a 1:1 ratio using permuted blocks of two or four, where the size for each 
block is selected uniformly at random. This type of randomization ensures balance across the intervention and 
control groups after every second or fourth randomization (depending on the size of the current block). This 
randomization scheme will be generated by computer using the Mersenne-Twister pseudo random number. 
 
Interim Analysis and Stopping Rules 
Interim analyses will be conducted to evaluate safety endpoints but will not be conducted to evaluate conditional 
power (futility) or to assess efficacy.   
 
Safety will be evaluated by examining group differences in death and serious adverse events semi-annually in 
conjunction with scheduled DSMB meetings to evaluate the safety of the study intervention, and the associated 
risk-to-potential benefit ratio. The Principal Investigators will address study efficacy only at the end-of-study, and 
thus will not consider terminating the trial early on the basis of conditional power (futility) or evidence of 
efficacy. This is because firm evidence will be required to change current clinical practice, and because trials that 
have stopped early for efficacy often report implausibly large effect sizes (and therefore should be considered 
with skepticism).41 At the conclusion of each DSMB meeting, the Board should take into account the statistical 
evidence as well as practical and clinical considerations to make one of the following recommendations based on 
safety: 
a. Suspend enrollment due to safety concerns secondary to study intervention including: 
1. A difference in all-cause mortality between patients randomized to the deprescribing intervention 
versus usual care such that the DSMB deems the difference to be study-related and excessive. 
2. A difference in drug related SAEs between patients randomized to the deprescribing intervention 
versus usual care such that the DSMB deems the difference to be study-related and excessive. 
b. Continue Enrollment 
 
Outcomes 
Hypotheses 1a -1b: Among participants assigned to the intervention group, we will summarize both the number 
of deprescribing recommendations and the number of actual medication changes at hospital and SNF discharge 
and 90-days following SNF discharge. The effect of the intervention on the total number of medications, PIMs, 
and medications associated with geriatric syndromes at hospital discharge, SNF discharge, and 90-days following 
SNF discharge will be assessed using mixed effects Poisson regression, allowing for overdispersion (more or less 
variability than is expected under the Poisson regression model), and adjusting for measurement time point (as a 
categorical covariate) and the total number of medications at  enrollment and the interaction of intervention and 
time point. The heterogeneity in outcome measures across participants will be modeled using a random intercept 
term, indexed by subject. Heterogeneity among VA providers and SNFs in the effectiveness of intervention will 
be modeled using a random intervention effect, indexed by VA provider and SNF.  The overall intervention effect 
will be evaluated using a Wald-type multiple degree-of-freedom test against the null hypothesis of no effect at any 
time point.  The intervention effect at each time point will be summarized using a Wald-type 95% confidence 
interval. Model fit will be assessed by examining the associated Pearson residuals and other graphical methods. 
Alternative regression techniques may be used in the case of poor fit, for example, negative-binomial regression.  
A secondary analysis to explore the possibility of intervention effect modification by hospital length of stay (e.g., 
longer stay may result in more deprescribing) will be implemented by considering the interaction of hospital 
length of stay with intervention.   
 
Hypothesis 1c: The effect of intervention on the anticholinergic and sedative drug burden index scores at hospital 
discharge, SNF discharge, and 90-days following SNF discharge will be assessed using linear mixed effects 

regression, adjusting for measurement time point, its interaction with intervention and using random effects, 
testing and summary methods as described for Hypotheses 1a, 1b and 1d. Model fit will be assessed using 
residual diagnostics and graphical methods. Due to the constrained nature of the DBI values, a ‘beta’ regression 
method may be required, which is suitable for scores that often occur at a boundary. 
 
Hypothesis 2a: Medication adherence will be measured using the ARMS based on an ordinal scale. Functional 
health status will be measured using the VES-13 total score, also an ordinal outcome. Patient attitudes toward 
deprescribing (PATD) also will be measured on an ordinal scale. The effects of intervention on these outcomes 
will be assessed at 7 (except PATD) and 90-days following SNF discharge using mixed-effects logistic regression 
or proportional odds logistic regression similar to analyses for Hypothesis 2b. 
 
Hypothesis 2b: The prevalence and severity of geriatric syndromes will be analyzed at baseline, 7 and 90 days 
following SNF discharge. The effects of intervention on the prevalence of each type of geriatric syndrome will be 
assessed using mixed-effects logistic regression, adjusting for measurement time point (categorical) and its 
interaction with intervention. The severity of each geriatric syndrome is measured on an ordinal scale. Thus, 
severity will be analyzed using mixed-effects proportional odds logistic regression, also adjusting for 
measurement time point and its interaction with intervention. For either method random effects, testing, summary 
and diagnostic methods will be used as described for Hypotheses 1a, 1b and 1d. 
 
Hypotheses 3a-c: Descriptive analyses will be performed to examine implementation outcomes: anticipated 
barriers and facilitators, medication changes per patient following hospitalization, and staff time required for each 
intervention component. Unanticipated barriers and facilitators and stakeholder input responses will be analyzed 
using qualitative methods. A research assistant will generate clean versions of the data collection notes. We will 
code notes using NVivo11® software based on a two-pronged approach that relies on: a) a priori factors, and b) 
emergent themes or “grounded theory”, an inductive approach in which the categories used for the analysis are 
derived from the data. The a priori factors include the categories of anticipated barriers and facilitators as well as 
constructs from CFIR. Analyses will then compare all cases to identify the range among and differences between 
respondents. Themes will be noted, counted, and documented by illustrative quotations from the notes. Data 
collection will continue until saturation of themes are reached, likely requiring 20-25 respondents. Ten percent of 
the notes will be double coded (first by PI then by the study coordinator) to calculate a reliability statistic.]     
 
Data Analyses 
Missing Data 
We have extensive preliminary data describing attrition due to mortality, which should not differ between 
intervention and control groups. However, we cannot exclude the possibility that missing data will be associated 
with intervention. We will examine the incidence of missing data by group. If imbalances are found, we will 
implement a series of sensitivity analyses using multiple imputations to assess the degree of bias that might be 
induced by missing data. 
 
Randomization, Intent-to-Treat, & Safety Outcomes 
Participants will be assigned to the usual care control or intervention group in randomly permuted blocks of size 
two or four, where block sizes are selected uniformly at random. This type of randomization ensures balance 
across groups after every second or fourth randomization (depending on block size). The effectiveness of 
randomization will be assessed by summarizing the balance of baseline demographic and clinical factors across 
groups. The sample mean, standard deviation, and five-number summary will be used to summarize continuous 
variables. The count and proportion will be used to summarize categorical variables. All randomized Veterans 
discharged from the hospital to SNF rather than to home or hospice will be included in analyses. We will 
implement both intent-to-treat and per-protocol analyses. 
 
 

Repeated Measures 
Barring study withdrawal or death (or hospice transfer), each participant will be assessed at multiple time points. 
Participants may be clustered by VA provider and/or SNF discharge location. Thus, outcome measurements may 
exhibit heterogeneity across participants and clusters. Our statistical plan takes full advantage of this information 
by using a mixed-effects framework for each analysis. In the event that a mixed-effects technique cannot be 
implemented, an alternative method will be used, and the standard errors of effect estimates will be adjusted using 
the robust Huber-White ‘sandwich’ method. 
 
DATA MANAGEMENT AND QUALITY ASSURANCE 
Data Collection Forms & Data Entry 
The study team chose to utilize hard copy case report forms to allow for quality assurance reviews of entered data. 
The standardized interview and abstraction forms were approved by the IRB. Data recorded on the case report 
forms are entered into a VA REDCap database. Assessment and interview forms are entered within the same 
week of data collection, and if possible, the same day.   
 
Data Storage 
Paper data collection forms are stored in locked filing cabinets in the academic partner’s offices. Upon study 
completion, each Veterans files are moved to the local VA research offices where they are stored in a locked 
filing cabinet. Electronic data is stored in the VA REDCap and on a shared project folder only accessible to study 
team members. With permission of the IRB, de-identified data is allowed to be temporarily stored on the secure 
server of the academic partner. All electronic files are username and password protected. Data in the REDCap 
databases and secure server will be stored indefinitely to all for subsequent data analyses. 
 
Quality Assurance 
No quality assurance training or metrics are required beyond standard IRB Human Subjects training. To ensure 
data integrity, the project coordinator will conduct weekly data reviews to check for completion and accuracy. 
 
PARTICIPANT RIGHTS AND CONFIDENTIALITY 
The DROP trial’s intervention is considered human subjects research and is subject to standard review by the 
local institutional review board (IRB). All protocols, consent forms, and other research materials were submitted 
and approved prior to the recruitment of any Veterans. As noted above, the study is subject to an annual safety 
review by the IRB. All study personnel complete annual human subjects and good clinical practice training. 
Below is a summary of key human subjects information submitted to the IRB. 
 
Protection Against Risks 
The deprescribing intervention protocol is a carefully developed, multi-stage process that includes the 
independent review of multiple clinicians, each of whom can stop any recommended deprescribing action. This 
includes the research team pharmacist or nurse practitioner, primary hospital team, and the Veteran or their 
surrogate. Each medication recommended for deprescribing will be considered for its potential for physiologic 
withdrawal, pharmacokinetic/pharmacodynamic effects, and medical condition exacerbation. Strategies to protect 
against risks are as follows: 
• 
Any medication believed to have increased potential for physiologic withdrawal will undergo a prescribed 
drug taper, where the identified drug will not be reduced by more than 25% to 50% during any 1-week 
interval when a patient is receiving greater than the minimum therapeutic dose. 

• 
Deprescribing pharmacists / NPs will alert the primary medical team and make recommendations to the 
post-acute care for surveillance of symptoms, signs (e.g., vital signs), labs (e.g., electrolytes, INR), or 
follow-up tests (e.g., EKG).   
• 
A strength of this trial is that we will be able to monitor for exacerbations of medical conditions in a post-
acute care setting (mean length of stay = 26.9 days), where monitoring of vital signs and symptoms are 
done daily by licensed nurses. In addition, during the “SNF handover” process, all discontinued 
medications will be clearly delineated along with any expected signs or symptoms that may be expected 
to return.  
• 
Medications can be restarted or increased at any time should adverse pharmacokinetic/ 
pharmacodynamics effects or a physiologic drug withdrawal effect be detected. 
 
Veteran Confidentiality 
Research subjects’ identities will be kept confidential at all times. Subject identifiers will never be revealed in 
publication, presentation, or other scientific purpose. All data obtained with subject identifiers will be maintained 
in locked file cabinets and locked offices on the VA Medical Center (GRECC offices) campus or the academic 
partner. All study subjects will be assigned a unique study identification number for use in computer database and 
analytic work. Linkage of patient study IDs to patient identifiers will be maintained by the PIs and Project 
Coordinator with username/password protected access.  
 
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