Anticoagulation With Enhanced Gastrointestinal Safety (AEGIS): A Pragmatic Randomized Trial to Evaluate Clinician Outreach to Reduce Upper Gastrointestinal Bleeding Risk in Patients Taking Warfarin and Antiplatelet Therapy
Phase: NA
Conditions: Upper Gastrointestinal Bleeding, Peptic Ulcer Hemorrhage, Anticoagulant-induced Bleeding
Sponsor: University of Michigan

Anticoagulation with Enhanced Gastrointestinal 
Safety (AEGIS): A pragmatic randomized trial to 
evaluate clinician outreach to reduce upper 
gastrointestinal bleeding risk in patients taking 
warfarin and antiplatelet therapy 
Protocol Number: 1.0 
National Clinical Trial (NCT) Identified Number:   TBD  
Principal Investigator: Jacob E. Kurlander, MD, MS 
Sponsor: NIDDK 
Grant Title: Using Intervention Mapping and the Multiphase Optimization 
Strategy to Develop Multilevel Interventions to Prevent Upper GI Bleeding 
Grant Number: K23DK 118179 
Funded by: National Institute of Diabetes and Digestive and Kidney 
Diseases 
Version Number:  v.1.4 
13 December 2022  
  
 
 

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AMENDMENTS 
5 
STATEMENT OF COMPLIANCE 
7 
1        PROTOCOL SUMMARY 
8 
1.1      Synopsis 
8 
1.2      Schema 
10 
1.3      Schedule of Activities 
11 
Schedule of Activities 
12 
2         
INTRODUCTION 
12 
2.1      Study Rationale & Background 
13 
2.2      Objectives 
14 
3   RISK/BENEFIT ASSESSMENT 
14 
3.1   
Known Potential Risks to Patients 
14 
3.2      Known Potential Risks to Clinicians 
15 
3.3      Assessment of Potential Risks and Benefits 
15 
4        OBJECTIVES AND ENDPOINTS 
15 
5        STUDY DESIGN 
17 
5.1      Overall Design 
17 
5.2  Scientific Rationale for Study Design 
18 
5.3      Justification for Intervention 
18 
5.4   
End-of-Study Definition 
18 
6        STUDY POPULATION 
19 
6.1      Sample size 
19 
6.2   
Inclusion Criteria 
19 
6.3   
Exclusion Criteria 
19 
6.4      Patient and Clinician Selection 
20 
6.5   
Screen Failures 
20 
6.6      Strategies for Recruitment and Retention 
20 
7        STUDY IMPLEMENTATION STRATEGIES 
20 
7.1      Quality Improvement Strategy Descriptions 
20 
7.2   
Fidelity 
21 
7.2.1        Anticoagulation Nurse Training 
21 
7.2.2        Quality Improvement Strategy Delivery 
21 
7.2.3        Quality Improvement Strategy Receipt & Enactment 
21 

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7.3   
Measures to Minimize Bias: Randomization and Blinding 
22 
7.4   
Concomitant Therapy 
22 
7.5      Rescue Therapy 
22 
8        END-OF-INTERVENTION/END-OF-STUDY 
22 
8.1      Discontinuation of Intervention 
22 
8.2   
Participant Discontinuation/Withdrawal from the Study 
23 
8.3 
Lost to Follow-Up 
23 
9  STUDY ASSESSMENTS AND PROCEDURES 
23 
9.1      Eligibility Assessment 
23 
9.2      Assessment of the Primary Endpoint 
23 
9.3      Assessment of the Secondary and Exploratory Endpoints 
24 
11  STATISTICAL CONSIDERATIONS 
24 
11.1 Sample Size Determination 
24 
11.2 General Statistical Approach 
25 
11.3 Descriptives 
25 
11.4 Hypotheses 
25 
11.5 Analysis of the Primary Endpoint(s) 
25 
11.6 Analysis of the Secondary Endpoint(s) 
26 
11.7 Exploratory Analyses 
26 
11.8 Other Analyses 
26 
11.9 Safety Analyses 
26 
11.10   Planned Interim Analyses 
26 
11.11            Subgroup Analyses 
26 
12 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
27 
12.1 Regulatory, Ethical, and Study Oversight Considerations 
27 
12.1.1 Informed Consent Process 
27 
12.1.1.1 Quality improvement strategy delivery 
27 
12.1.1.2 Patient phone survey 
27 
12.1.1.7 Chart Review for Randomized Participants 
28 
12.2 Confidentiality and Privacy 
28 
12.2.1    Future Use of Stored Specimens and Data 
28 
12.2.2  Data sharing 
28 
12.3 Safety Oversight 
28 

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12.4 Key Roles and Study Governance 
28 
12.5 Clinical Monitoring 
29 
12.6 Data Handling and Record Keeping 
29 
12.7 Data Collection and Management Responsibilities 
29 
12.8 Study Records Retention 
29 
12.9  Protocol Deviations 
29 
13   DATA SAFETY MONITORING PLAN 
30 
13.1    Study Leadership Roster 
31 
13.2    Protocol Amendment Procedures and Approvals 
33 
13.3    Clinical Trial Registry and Publication Policy 
33 
14  APPENDICES 
33 
14.1 Appendix 1. Criteria for determining appropriateness of antiplatelet therapy. 
33 
15  ABBREVIATIONS AND SPECIAL TERMS 
37 
16  REFERENCES 
38 
 
 
 
 

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AMENDMENTS 
Date 
Version 
Section(s) 
Changes 
8/4/2022 
V.1.1 
1.1 
1.2 
1.3 
2.2 
4 
7.3 
8.1 
8.2 
8.3 
9.1 
9.2 
9.3 
11.5 
 
Updated trial timeline to reflect that CNNF follow-up 
will be delivered to non-responders 2 weeks rather 
than 4 weeks after delivery of the initial CNNF 
notification, and patient calls will thus be moved up 
from week 9-10 to week 7-8 to ensure patient recall 
of medication use will not be impacted due to too 
much time passing between delivery of the CNNF 
strategy and the phone assessment.  The 
amendment also clarifies that CNNF will be delivered 
to up to 4 patients each week per anticoagulation 
nurse. While the total number of participants will not 
change, this may result in the randomized trial 
lasting for more than the originally stated 25 weeks. 
10/27/2022 
V.1.2 
1.1 
1.2 
1.3 
2.2 
4 
5.4 
7.2 
7.3 
8.1 
8.2 
8.3 
9.2 
9.3 
11.5 
 
Updated trial timeline to reflect extension of timing 
for chart review and patient phone assessments 
from week 7-8 to week 7-9.  
11/30/2022 
V.1.3 
1.1 
1.2 
1.3 
2.2 
4 
5.4 
7.2 
7.3 
8.1 
8.2 
8.3 
Updated trial timeline to reflect extension of timing 
for chart review and patient phone assessments 
from week 7-9 to week 7-10. 

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9.2 
9.3 
11.5 
 
12/13/2022 
V.1.4 
7.3 
Updated protocol to reflect that while we will attempt 
to have blinded research staff conduct all patient 
phone calls, unblinded staff will assist with calls if 
necessary to complete all assessments within the 
specified time window of week 7-10 of study 
participation.  
 
  
 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with research best practices, applicable United States 
Code of Federal Regulation, and the terms and conditions of the sponsor. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without 
documented approval from the Institutional Review Board (IRB), except where necessary to 
eliminate an immediate hazard(s) to the trial participants. All research personnel involved in the 
conduct of this study have completed Human Subjects Protection and research best practices 
training. 
 
  
 
 

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1        PROTOCOL SUMMARY 
1.1      Synopsis   
  
Title: 
Anticoagulation with Enhanced Gastrointestinal Safety (AEGIS): 
A pragmatic randomized trial to evaluate clinician outreach to 
reduce upper gastrointestinal bleeding risk in patients taking 
warfarin and antiplatelet therapy 
Grant Number: 
K23 DK118179 
Background 
Patients who use an anticoagulant together with an antiplatelet 
drug (anticoagulant-antiplatelet therapy or AAT) are at increased 
risk for serious bleeding, which most commonly occurs in the 
gastrointestinal tract. For patients on AAT, there are two 
evidence-based medication optimization strategies to reduce 
upper gastrointestinal (GI) bleeding risk. Many of these patients 
may safely discontinue the antiplatelet drug. For patients who 
must continue the antiplatelet drug, proton pump inhibitors (PPIs) 
effectively reduce upper GI bleeding risk. Both strategies are 
underused. The aim of this trial is to evaluate the effectiveness of 
a novel clinician-facing quality improvement implementation 
strategy to optimize the use of antiplatelet therapy and PPI 
gastroprotection for patients who use warfarin and are followed 
by the Michigan Medicine anticoagulation monitoring service, as 
part of a quality improvement initiative.  
Study Population: 
Clinicians will be eligible for receipt of the implementation 
strategy if they care for patients who are enrolled with the 
anticoagulation monitoring service. Patients will be eligible for 
inclusion if they are prescribed warfarin and an antiplatelet drug 
without a PPI and are enrolled in the Michigan Medicine 
anticoagulation monitoring service. See section 6.1 for additional 
inclusion and exclusion criteria. We anticipate including 220 
patients and 110 clinicians.   

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Study Description: 
The study is designed as a pragmatic cluster randomized quality 
improvement trial. For each patient, a target clinician will be 
identified, defined as either a cardiologist at Michigan Medicine, 
if the patient has seen one in the past year, or else the patient’s 
primary care provider if within Michigan Medicine, or else the 
clinician of record on file with the anticoagulation service. For 
each patient, assignment to receipt of the quality improvement 
strategy vs. usual care will be done at the cluster level according 
to the identity of the target clinician. Each clinician (cluster) will 
be randomized 1:1 to receive either clinician notification with 
nurse facilitation (CNNF), consisting of a notification message 
sent in the electronic health record, or to a usual care arm. Each 
clinician cluster will be limited to 4 or fewer patients. Following 
delivery of the quality improvement (QI) strategy to clinicians in 
the CNNF arm, the study team will conduct phone surveys with 
all patients whose clinicians received usual care or CNNF and 
perform chart review in the medical record to evaluate the effect 
of CNNF on reducing upper GI bleeding risk through 
discontinuation of all antiplatelet drugs or initiation of PPI co-
therapy.   
  
  
Primary Objective: To determine the extent to which clinician 
notification with nurse facilitation (CNNF) versus usual care is 
associated with differences in the proportion of patients who 
have medication optimization (defined as either discontinuation 
of all antiplatelet drugs or initiation and adherence to a PPI) at 
week 7-10. 
 
Secondary Objectives: To determine the extent to which CNNF 
(vs usual care) is associated with differences in the proportion of 
patients who are recommended to have medication optimization 
based on chart review after 6 weeks. 
Endpoints*: 
Primary Endpoint: The proportion of patients who self-report 
either discontinuing all antiplatelet therapy (defined as none in 
the past 7 days) or initiation and adherence to a proton pump 
inhibitor (defined as use for at least 5 of the prior 7 days) at week 
7-10.  
 
Secondary Endpoints:  
• 
The proportion of patients with a documented 
recommendation in the electronic health record to either 
discontinue all antiplatelet therapy or initiate a PPI 
Phase or Stage: 
Randomized quality improvement project with a wait-list control 
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Description of 
Sites/Facilities Enrolling 
Participants: 
Participants will be included from a single site (the Michigan 
Medicine anticoagulation monitoring service in Ann Arbor, 
Michigan, USA). 
Description of Study 
Intervention/Experimental 
Manipulation: 
1.       Clinician Notification with Nurse Facilitation: A protocol-
driven QI strategy in which an anticoagulation clinic nurse sends 
a templated message to the patient’s target clinician that 
identifies the patient as high risk for upper GI bleeding and 
summarizes options for medication optimization. In addition, 
once clinicians decide on a medication optimization plan, the 
nurse will facilitate execution of the plan and communicate 
recommendations to the patient. 
2.       Usual Care: No additional education or clinical assistance 
outside of routine anticoagulation monitoring service care will be 
included.  
 
Assessments 
The only live patient assessment will be a phone survey at week 
7-10. Endpoints will also be assessed by chart review. 
Human subject’s 
protection: 
A waiver of informed consent will be sought for delivery of the 
clinician notifications, as well as for the patient phone survey, 
since they constitute minimal risk, the waiver will not adversely 
affect the rights or welfare of participants, and the research could 
not practically be carried out otherwise. 
Study Duration: 
 ~25 weeks  
Participant Duration: 
 10 weeks  
1.2      Schema 

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 1.3      Schedule of Activities  
It is anticipated that 110 clinicians will be included in the study, and 220 patients who are cared 
for by those clinicians. QI strategies will be delivered to clinicians of eligible patients by 

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anticoagulation clinic nursing staff. Up to 50-56 patients will enter the study each week for 5 
weeks (or longer if fewer patients enter each week).  
For informational purposes, whether the evaluation vs. the anticoagulation clinic staff performs 
the activity is indicated in bold. Failure of the anticoagulation clinic staff to follow the clinical 
protocols for delivery of the clinician- level QI strategies will not be considered study deviations. 
Schedule of Activities  
Activity  
Screening and 
randomization 
Week 1 
Week 2-5 
Week 7-
10 
Week 11-
25 
 
Eligibility determination of 
clinicians and patients 
(research team) 
X 
 
 
 
 
Cluster randomization of 
patients to CNNF vs. usual 
care (research team) 
X 
 
 
 
 
Clinician delivery of CNNF 
for patients randomized to 
receive it (anticoagulation 
clinic staff) 
 
X 
X 
 
 
Additional outreach, 
communication, or 
facilitation steps for 
patients and clinicians as 
per anticoagulation clinic 
protocol for CNNF 
recipients 
(anticoagulation clinic 
staff) 
 
X 
X 
 
 
Patient phone survey, with 
waiver of informed consent 
(research team)  
 
 
 
X 
 
Chart review to ascertain 
exploratory outcomes 
(research team)  
X 
X 
 
X 
X 
 
2         INTRODUCTION       

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2.1      Study Rationale & Background 
 
Increasing numbers of patients in the United States are prescribed oral anticoagulants to treat 
or prevent a range of thromboembolic conditions 1. The main risk with anticoagulants is major 
bleeding, most commonly from the gastrointestinal tract 2,3. Many patients prescribed 
anticoagulants are co-prescribed an antiplatelet drug (aspirin or a thienopyridine), and these 
patients are at particularly high risk for major bleeding. In an observational study of patients 
prescribed warfarin, use of an antiplatelet drug increased the risk of major bleeding (5.7% vs. 
3.3%), emergency department visits for bleeding (13.3% vs. 9.8%), and hospitalizations for 
bleeding (8.1% vs. 4.1%), but did not reduce the rate of thrombosis 4. 
Medication optimization can substantially reduce bleeding risk for patients prescribed 
anticoagulant-antiplatelet therapy (AAT). One evidence-based practice is to discontinue 
antiplatelet therapy in patients for whom it is inappropriate. Based on recent clinical trial data, 
the indications for AAT are increasingly narrow, and most patients prescribed anticoagulants 
should only use antiplatelet drugs for a limited time after acute coronary syndrome, coronary 
stenting, or other vascular procedures 5. A second evidence-based practice is the use of a 
proton pump inhibitor (PPI gastroprotection) for patients in whom AAT is truly indicated, a 
strategy recommended by professional guidelines 5,6. A meta-analysis showed PPIs reduce the 
risk of UGIB by up to 79% in patients using aspirin or non-steroidal anti-inflammatory drugs 7. 
Both of these evidence-based practices are underused 8. In an observational study of six 
anticoagulation clinics, 45% of patients prescribed warfarin were co-prescribed an antiplatelet 
drug. Of these, 44% had no identifiable indication for antiplatelet therapy, and 36% were 
appropriately prescribed AAT but without a PPI 8. 
There are multiple barriers to use of these evidence-based practices. Clinicians may lack 
knowledge of appropriate use of medication optimization strategies, have inadequate time or 
prioritization, or lack “ownership,” since many patients are co-managed by a PCP and a 
subspecialist (typically a cardiologist) 9. In many cases, a clinician may be prepared to assess 
use of one of the evidence-based practices but not the other, which may lead to suboptimal 
care. Clinicians may also have concerns about provoking a cardiovascular event when 
deprescribing antiplatelet drugs, and about possible PPI adverse effects when initiating a PPI 10. 
There is a critical need for implementation strategies to improve medication optimization for 
upper GI bleeding risk reduction in patients prescribed AAT. Importantly, to ensure the most 
appropriate care, any implementation strategy should simultaneously address both evidence-
based practices, determining first the appropriateness of antiplatelet therapy, then of PPI 
gastroprotection. Previous one- or two- component clinician-facing interventions aimed at 
improving use of PPI gastroprotection (including decision support tools, electronic alerts, audit 
and feedback, and clinician education) have had limited success 11–13. Several European studies 
that have tested multi-component interventions involving professional education, incentive 
payments, clinician feedback, and pharmacist support have effectively reduced the proportion of 
high-risk patients without gastroprotection (odds ratios 0.55-0.72) 14–16. However, such 

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multicomponent strategies are resource intensive and challenging to implement in the 
fragmented US healthcare system.  
As part of a quality improvement program through the Michigan Medicine anticoagulation 
service, a novel clinician-facing strategy has been identified to improve the safety of patients 
using AAT: clinician notification by electronic health record (EHR) message including a multi-
faceted nurse facilitated process. The anticoagulation clinic has recently completed a pilot 
feasibility study that confirmed that delivery of the implementation strategy was feasible, that the 
strategy was acceptable to clinicians and patients, and that completing the necessary steps for 
the project did not impair the anticoagulation clinic nurses ability to perform other duties. In the 
pilot study, feedback was elicited from patient, clinician, and nursing staff participants through 
qualitative semi-structured phone questionnaires. The data from these interviews were used to 
optimize the implementation strategy and methodology described in this protocol. This protocol 
describes a randomized evaluation of a quality improvement initiative to determine the 
effectiveness of this novel clinician-facing approach to improve medication optimization.  
2.2      Objectives   
Primary Objective: To determine the extent to which clinician notification with nurse 
facilitation (CNNF) versus usual care is associated with differences in the proportion of 
patients who have medication optimization (defined as either discontinuation of all 
antiplatelet drugs or initiation and adherence to a PPI based on self-report) at week 7-10. 
 
Secondary Objectives: To determine the extent to which CNNF (vs usual care) is 
associated with differences in the proportion of patients who are recommended to have 
medication optimization based on chart review after 6 weeks. 
3   RISK/BENEFIT ASSESSMENT  
3.1   Known Potential Risks to Patients  
No novel therapeutic medications or devices are being tested in this study and participants are 
not required to discontinue an antiplatelet agent, initiate a PPI, or make any other medication 
changes as part of study participation. The risks and benefits discussed here relate to the 
implementation strategy and assessments of the implementation strategy, but not any possible 
medication changes undertaken by their clinicians, which are done as part of usual clinical care. 
  
1. Inconvenience. Participants may feel inconvenienced by the attempts to reach them, or 
the time it takes to engage in study phone surveys.  
2. Breach of Data Confidentiality. It is possible that the identity of the participant or 
protected health information (PHI) could be unintentionally revealed to persons outside 
of the research team. As this study does not deal with sensitive or stigmatized behavior 

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(i.e., illicit drug use), a potential data breach is anticipated to cause minimal harm to the 
participant if it were to occur.  
3.2      Known Potential Risks to Clinicians  
1. Potential Psychological Discomfort due to Subject Content. The clinician messages 
will deal with the topic of clinical care practices, including opportunities for clinical care 
improvement. This could cause clinicians to be upset or concerned. All efforts will be 
made to discuss these topics in a considerate manner. 
2. Inconvenience. Clinician participants may feel inconvenienced by the attempts to reach 
them or the time it takes to engage with communications from anticoagulation clinic staff. 
3. Breach of Data Confidentiality. It is possible that the identity of the participant could be 
unintentionally revealed to persons outside of the research team. However, no PHI will 
be sought from clinicians. As this study does not deal with sensitive or stigmatized 
behavior (i.e., illicit drug use), a potential data breach is anticipated to cause minimal 
harm to the participant if it were to occur. 
3.3      Assessment of Potential Risks and Benefits 
The risks to patients and clinicians are all minimal and justified by the value of the potential 
benefits and knowledge gained. Risks of confidentiality breach will be mitigated by separation of 
personal identifiers (enrollment forms) from data source documents. All data source documents 
and any personally identifying information for trial participants will be stored on a secure drive or 
in a locked file cabinet and will be accessible only to the study team. 
4        OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
 
Primary 
  
To determine the extent to which 
clinician notification with nurse 
facilitation (CNNF) versus usual 
care is associated with 
differences in the proportion of 
patients who have medication 
optimization (defined as either 
discontinuation of all antiplatelet 
drugs or initiation and adherence 
to a PPI based on self-report) at 
week 7-10. 
The proportion of patients who self-report either 
discontinuing all antiplatelet therapy (defined as none in 
the past 7 days) or initiating and adhering to a proton 
pump inhibitor (defined as use for at least 5 of the prior 7 
days) at week 7-10.  
Secondary 

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To determine the extent to which 
CNNF (vs usual care) is 
associated with differences in the 
proportion of patients who are 
recommended to have 
medication optimization based on 
chart review after 6 weeks. 
The proportion of patients with a documented 
recommendation in the electronic health record to either 
discontinue all antiplatelet therapy or initiate a PPI 
 
Exploratory  
  
To determine how often the 
anticoagulation clinic nurse 
communicated the 
recommendation to either 
discontinue all antiplatelet 
therapy or start a PPI for patients 
who were randomized to receive 
CNNF.  
 
The proportion of patients for whom an anticoagulation 
clinic RN documented communicating a recommendation 
to the patient to either discontinue all antiplatelet therapy 
or start a PPI based on chart review. 
To determine how often the 
anticoagulation clinic nurse 
pended an order for a PPI for 
patients randomized to CNNF 
and recommended by their 
clinician to initiate PPI. 
 
The proportion of patients for whom an anticoagulation 
clinic RN pended an order for a PPI among patients 
randomized to CNNF and recommended by their clinician 
to initiate PPI. 
To explore why patients 
recommended to either 
discontinue an antiplatelet drug 
or initiate a PPI may choose not 
to make the medication change. 
  
The reasons why patients who received a 
recommendation to make a medication change chose not 
to adhere to the recommendation according to patient 
self-report at week 7-10 (qualitative). 
 
To explore the accuracy of the 
electronic health record’s 
medication list for PPIs and 
antiplatelet drugs at baseline. 
The proportion of patients who, retrospectively, report that 
they had been using antiplatelet therapy at baseline 
during the patient phone survey at week 7-10. 
  
The proportion of randomized patients who, 
retrospectively, report that they had been using PPI at 
baseline during the patient phone survey at week 7-10. 
To explore the accuracy of the 
electronic health record’s 
medication list for PPIs and 
antiplatelet drugs at week 7-10. 
The accuracy of the EHR medication list at week 7-10 for 
antiplatelet drugs compared to self-report.  
  
The accuracy of the EHR medication list at week 7-10 for 
proton pump inhibitors compared to self-report.  
 
To explore the appropriateness 
of antiplatelet therapy used by 
patients at the time of study 
entry. 
The clinical appropriateness of baseline antiplatelet 
therapy as determined by a physician reviewing the 
medical record. Antiplatelet appropriateness will be 
categorized as probably guideline concordant, probably 
not guideline concordant, or uncertain in reference to 

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practice recommendations (Appendix 1). Baseline 
antiplatelet therapy will be ascertained by self-report at 
week 7-10. 
 
To explore the extent to which 
CNNF (vs. usual care) is 
associated with the 
appropriateness of antiplatelet 
therapy at week 7-10. 
The clinical appropriateness of antiplatelet therapy at 
week 7-10 (relative to appropriateness assessment at the 
time of study entry, as determined by a physician 
reviewing the medical record). Antiplatelet 
appropriateness will be categorized as probably guideline 
concordant, probably not guideline concordant, or 
uncertain in reference to practice recommendations 
(Appendix 1). Antiplatelet therapy at week 7-10 will be 
determined by patient self-report.  
 
We will also evaluate this endpoint for the subset of 
patients who were recommended to make a medication 
change. 
To explore fidelity to the CNNF 
vs. usual care  
Fidelity to CNNF will be determined by performing a chart 
review on patients whose clinicians received the CNNF 
strategy, to confirm that it was delivered as intended. 
 
We will also perform chart review for patients randomized 
to usual care to ensure that they did not receive CNNF. 
To explore patient and clinician 
factor associated with successful 
medication optimization. 
Regression analysis will be used to identify patient and 
clinician factors associated with successful medication 
optimization.  
To determine the extent to which 
CNNF (vs usual care) is 
associated with differences in the 
proportion of patients who exhibit 
PPI adherence, based on self-
report, at week 7-10 among 
patients recommended to start a 
PPI. 
Among patients recommended by a clinician to initiate a 
PPI (based on chart review at week 7-10), the proportion 
of days out of the prior 7 when a PPI was taken based on 
self-report 
 
 
5        STUDY DESIGN 
5.1      Overall Design 
 
This is a pragmatic, single center randomized quality improvement trial to evaluate a clinician-
facing implementation strategy to increase the use of evidence-based practices (EBPs) to 
reduce bleeding in patients who are using anticoagulant-antiplatelet therapy (AAT) and who are 
managed by the Michigan Medicine anticoagulation monitoring service. A clinician-level strategy 
will be evaluated and compared to usual care: clinician notification with nurse facilitation (CNNF) 
consists of an EHR message that identifies the patient as high-risk for upper GI bleeding and 

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suggests either discontinuing the antiplatelet agent or initiating a PPI and in which a nurse 
undertakes multiple steps to overcome barriers to medication optimization. Clinicians will be 
cluster randomized, such that up to 4 patients cared for by each clinician will receive the same 
clinician-level notification.  
5.2  Scientific Rationale for Study Design 
The current study is a quality improvement trial that will evaluate the effectiveness of a novel 
quality improvement strategy to reduce the risk of upper GI bleeding in patients using AAT.  
Clinician notification is commonly used by the anticoagulation service as part of routine clinic 
practice to improve the safety of patients using warfarin. For example, the anticoagulation clinic 
previously undertook a quality improvement project that consisted of notifications to clinicians 
about the potential benefits of discontinuing aspirin in certain patients. However, even though 
these clinician-facing strategies are considered standard practices, it remains important for the 
clinic to understand the extent to which such strategies are effective, and whether they justify 
the significant resource investment of the anticoagulation clinic staff. This study will help to 
answer that question in the context of medication optimization to reduce upper GI bleeding. 
The anticoagulation clinic eventually plans to use CNNF with all eligible patients. However, 
because deployment of CNNF requires additional effort by the nursing staff, only a limited 
number of patients (n=28) can be delivered CNNF each week. Therefore, we will use a “wait-
listed design,” in which each week patients will be randomized to either have their clinicians 
receive CNNF or be included in wait-list control group. The patients in the wait list control group 
will serve as comparators to the patients who received CNNF, allowing for valid causal 
inference about the effect of CNNF compared to usual care. This design is often used to 
evaluate the effectiveness of interventions that are planned for a wider rollout because they are 
considered fair by patients in the setting of limited capacity to rollout the intervention all at once. 
At the completion of the study, the patients who were randomized to the wait-list control group 
will receive the quality improvement strategy. 
5.3      Justification for Intervention 
Upper GI bleeding is a serious risk to patients who use AAT. However, both medication 
optimization EBPs to reduce upper GI bleeding risk are underused.  
This trial will rigorously evaluate a clinician outreach approach that is commonly used by the 
anticoagulation service to improve the safe use of warfarin. 
5.4   End-of-Study Definition 
 
Patients are considered to have completed the study after week 25. 

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Clinicians are considered to have completed the study 10 weeks after trial entry of the last 
patient within the clinicians’ cluster.  
6        STUDY POPULATION 
6.1      Sample size 
The target sample size for the study is 220 patients cared for by 110 target clinicians. See 
sample size determination (below) for a justification of the size. 
6.2   Inclusion Criteria 
For patients: 
● 
 Enrollment with the Michigan Medicine anticoagulation monitoring service 
● Currently prescribed warfarin with anticipated use for ≥90 days on day 1 of trial 
enrollment, according to the MiChart documentation. 
● Currently prescribed an antiplatelet drug (aspirin, clopidogrel, ticagrelor, or prasugrel) 
according to the MiChart medication list 
For clinicians: 
● Cardiologists at Michigan Medicine who in the prior year had a face-to-face or virtual visit 
with a patient who meets eligibility criteria  
● Michigan Medicine primary care providers for patients who meet eligibility criteria 
● Clinicians in any specialty who are designated as the clinician of record with the 
anticoagulation clinic for a patient who meets eligibility criteria 
 
6.3   Exclusion Criteria 
For patients: 
● 
 Age less than 18 
● Currently prescribed a PPI 
● Documented intolerance or allergy to PPI use 
● Left ventricular assist device 
● Heart transplant 
● Participation in a previous pilot study of these QI strategies 
For clinicians: 

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● Cardiologists specializing in electrophysiology or saw the patient for a clinic visit related 
to a TAVI procedure unless they are the clinician of record for a patient followed by the 
anticoagulation service who does not have a Michigan Medicine PCP. 
● Participation in a previous pilot study of these QI strategies 
6.4      Patient and Clinician Selection 
Since this evaluation is part of a quality improvement initiative, we will include 220 patients who 
may benefit from medication optimization. These patients will be identified using a report 
developed in the EHR. The same report will identify the “target clinician” for each eligible 
patient. A patient’s target clinician is defined as, in order of descending priority, either a (non-
electrophysiologist) Michigan Medicine cardiologist (excluding TAVI visits) who has seen the 
patient in the prior year (if one exists), or else a Michigan Medicine PCP for the patient, or else 
the patient’s clinician of record for the anticoagulation monitoring service.  
All target clinicians will be randomized to receive CNNF or usual care. Eligibility will be 
determined based on information in the electronic health record. All participants will be screened 
for eligibility in the week prior to study entry. 
6.5   Screen Failures     
Patients who are ineligible for the study at the time of screening will not be included.  
6.6      Strategies for Recruitment and Retention 
 
This trial will be conducted as a pragmatic quality improvement initiative in partnership with the 
Michigan Medicine anticoagulation monitoring service. There will therefore not be a formal 
recruitment process. No strategies will be used for participant retention.  
7        STUDY IMPLEMENTATION 
STRATEGIES 
 
7.1      Quality Improvement Strategy Descriptions 
The clinician notification process has been formalized as a clinical protocol approved by the 
anticoagulation clinic to address upper GI bleeding risk. As part of routine care, the QI strategy 
will be delivered by the anticoagulation nurses assigned to each of 7 anticoagulation clinic 
teams.  

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Clinician Notification (CNNF): An anticoagulation clinic nurse sends a templated message to 
the patient’s target clinician that identifies the patient as high risk for upper GI bleeding, 
summarizes guidelines on appropriate antiplatelet drug use and PPI gastroprotection, and 
recommends that the clinician consider either discontinuing the patient’s antiplatelet drug or 
initiating a PPI for gastroprotection. The nurse will also offer to pend the order for a PPI if the 
clinician wants to initiate a PPI and will provide education to the patient on any medication 
changes recommended by the clinician. 
Usual care: With usual care, the anticoagulation clinic will not send the clinician notification 
letter or other project-specific materials to the clinician or patient. 
7.2   Fidelity   
7.2.1        Anticoagulation Nurse Training 
Prior to commencing the quality improvement initiative, the anticoagulation clinic staff will attend 
an instructional meeting with a research team member on how and when to administer the QI 
strategy components and how to document delivery of strategies in the EHR. This training is 
anticipated to be 60 minutes long.  
For anticoagulation clinic staff, the implementation strategies and how to perform them are 
additionally described in anticoagulation clinic protocol documents. 
During week 1 of the trial, the research team will audit the charts of all patients randomized to 
CNNF and meet with the anticoagulation nurses to provide feedback if there were any 
discrepancies in delivery of the intervention. A similar meeting will recur in later weeks if 
discrepancies continue. 
Fidelity will be assessed during the week 7-10 chart review for all patients to ensure that they 
received the QI strategy to which they were randomized.  
7.2.2        Quality Improvement Strategy Delivery 
Anticoagulation clinic nurses will have templated written materials to use as part of CNNF. 
Nurses will also have an example script available to use when talking with patients about 
medication changes if the clinician requests that the nurse provide patient education. 
7.2.3        Quality Improvement Strategy Receipt & Enactment 
Chart review will be performed for patients whose clinicians were randomized to the clinician 
notification (CNNF) arm to ensure that the implementation strategy was delivered as intended 
and that the strategies had fidelity. A fidelity checklist will be used. 

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7.3   Measures to Minimize Bias: Randomization and 
Blinding   
Assignment of clinicians to CNNF vs. usual care will be done at the cluster level according to 
the identity of the clinician to be contacted. Clinicians will be stratified by treating small vs. large 
numbers of patients eligible for the trial, and by procedural vs. non-procedural specialist. The 
cluster of patients cared for by each anticoagulation clinic target clinician will be randomized 1:1 
to get either clinician notification with nurse facilitation (CNNF) or usual care. Randomization will 
be carried out by the study statistician. For each included clinician, up to 4 patients will be 
included in their  cluster (see section 11.1 for justification). For clinicians with more than 4 
eligible patients in their cluster, 4 patients will be selected at random. 
Neither patients, clinicians, or anticoagulation staff can practically be blinded. We will attempt to 
blind the research staff who are making patient calls at week 7-10 to the randomization group of 
the patient by not providing them with any information that would allow them to infer the 
randomization group, by not having them enter MiChart for the patients, where such information 
could be obtained, and by excluding any information from the call script that might help identify 
the randomization group. However, if due to staffing or personnel issues, blinded research staff 
are unable to complete all calls within the specified time frame, unblinded research staff will 
assist with completing patient calls.  
7.4   Concomitant Therapy  
Patients in this study will continue to receive all other usual care through the anticoagulation 
clinic. They will not be prevented from seeking or being exposed to any other medications or 
information from other sources during the study period or from seeking care from other 
clinicians.  
7.5      Rescue Therapy 
N/A 
8        END-OF-INTERVENTION/END-OF-
STUDY     
8.1      Discontinuation of Intervention 
The QI strategies will not be delivered to patients who discontinue warfarin therapy or are 
closed to the anticoagulation monitoring service between the time of randomization and the 

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anticipated date of QI strategy delivery. Patients who discontinue warfarin therapy or are closed 
to the anticoagulation monitoring service after QI strategy delivery but before week 7-10 will not 
be assessed by phone at week 7-10, though chart review will still be completed for these 
patients. The QI strategies will additionally not be delivered to patients whose target clinician on 
the report changes between the time of randomization and the anticipated date of QI strategy 
delivery.  However, patients whose target clinician changes after QI strategy delivery but before 
week 7-10 will still be assessed at week 7-10.  
8.2   Participant Discontinuation/Withdrawal from the 
Study 
Patients who wish not to participate in the phone survey at week 7-10 will have the phone 
survey discontinued.  
8.3 Lost to Follow-Up   
For patients unable to be reached for the phone survey at week 7-10, chart review will still be 
performed.  
9  STUDY ASSESSMENTS AND 
PROCEDURES  
9.1      Eligibility Assessment 
All eligible patients will be identified using a MiChart workbench report prior to the start of the 
study. Eligibility will be assessed based on information in the EHR. Each week, it is anticipated 
that 42 patients will be randomized to receive either CNNF or usual care, and that 21 will have 
CNNF directed at their target clinicians. Each anticoagulation nurses will deliver CNNF to up to 
4 patients each week but may deliver CNNF to fewer some weeks depending on staffing. At the 
start of each week, eligibility will be re-assessed for patients anticipated to receive the QI 
strategy in the coming week. 
Similarly, clinician eligibility will be determined at the start of the trial and at the beginning of 
each week to ensure that only actively practicing Michigan Medicine clinicians are included. 
9.2      Assessment of the Primary Endpoint 
The primary endpoint, defined as the proportion of patients for whom medication optimization 
was achieved (defined as either discontinuation of all antiplatelet therapy or initiation and 

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adherence to a proton pump inhibitor) will be determined by patient reported medication use at 
week 7-10. Up to three attempts will be made to contact patients by phone over the course of 4 
weeks to assess the primary endpoint. The phone call is anticipated to take not more than 5 
minutes. With calls 1 and 3, a brief message will be left stating the research assistant’s name 
and affiliation with the anticoagulation clinic and asking the patient to call back at their earliest 
convenience. A script has been developed to guide the phone survey. If the patient self-reports 
any use or non-use of medications that contradicts the information in their MiChart medication 
list, the research assistant will send a message to the patient’s anticoagulation clinic nurse so 
that the nurse can reconcile the chart. No remuneration will be offered with this patient 
assessment. We request a waiver of informed consent for this patient phone survey. 
There will be no assessments that require physical exams, radiology, biological specimens or 
laboratory evaluations. 
9.3      Assessment of the Secondary and Exploratory 
Endpoints 
The secondary and exploratory endpoints outlined in section 4 of this protocol document will be 
determined based on chart review, as well as patient self-reported data from the week 7-10 
phone survey.  
10  ADVERSE EVENTS  
Since this trial constitutes a quality improvement trial intended to improve the use of evidence-
based practices to reduce bleeding in patients using AAT, and since all decisions regarding 
changes in drug treatment will be made by patients’ own clinicians as part of usual care, the 
study will not proactively monitor for adverse events. No experimental drug is being 
investigated. However, any adverse events that are identified will be logged in an adverse event 
database. 
11  STATISTICAL CONSIDERATIONS       
11.1 Sample Size Determination 
The study is powered to have 90% power to identify a difference between usual care and CNNF 
with a two-sided 5% type I error. We estimate that the rate of medication optimization will be 5% 
with usual care and 35% with CNNF. In the pilot study, we observed substantial variation at the 
clinician-level in whether clinicians responded to the notification messages at all. In our sample 
size estimates, we therefore assumed a high-level of correlation in the outcome for patients 
within clinician clusters (ICC=0.95). While our clinician population includes providers with 1-32 
patients, if a clinician is selected to participate who has more than 4 patients (27/156), we will 

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randomly select 4 of their patients to participate in order to avoid overwhelming some clinicians 
with a large number of notifications in a short period of time. Therefore, capping the 27 
providers who have more than 4 participants, there is a coefficient of variation=0.62 (calculated 
using preliminary data) of the number of patients per provider and an average of 2 participants 
per clinician. For 90% power to detect the 30% difference between interventions, we require 44 
clinicians/arm and 176 total patient participants. We will assume a 20% dropout or ineligibility 
rate, so we plan to increase the N (176/0.8). This results in a final N of 220, equating to 110 
participants and 55 clinicians per arm. 
 
11.2 General Statistical Approach   
For the primary and secondary endpoints, an intention-to-treat analysis approach will be used.  
11.3 Descriptives 
We will calculate descriptive statistics (means, standard deviations, range and proportions) for 
all patient variables for the sample in total, by main effect (CNNF vs usual care) with and without 
controlling for clinician. 
11.4 Hypotheses 
For the primary endpoint, we hypothesize that the CNNF compared to usual care will be 
associated with a higher probability of medication optimization. 
11.5 Analysis of the Primary Endpoint(s) 
We will use generalized linear mixed effects modeling (logit link) to estimate the odds of 
medication optimization at week 7-10. This model will include fixed effects for CNNF (vs. usual 
care), target provider specialty and size, and a random effect for clinician to account for the 
clustering of patients. We will report the odds ratios with corresponding confidence intervals for 
the main effect. The main effect will be tested at a two-sided 5% significance level. Sensitivity 
analyses will adjust for patient age, gender, comorbidities, antiplatelet drug at study entry, and 
clustering at the nurse level. 
For patients who were unable to be contacted by phone for the week 7-10 phone call (lost to 
follow up), or who declined to participate, we will perform exploratory analyses to determine 
whether they differed (with respect to demographic characteristics, medical history, or target 
clinician specialty) from patients who were able to be reached. We will use multiple imputation 
to account for any missing data for the patients lost to follow up considering all demographic, 
medical history and target clinician specialty variables considering the data missing at random 
and combine results across imputation via Rubin’s rules. Best and worst case sensitivity 

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analyses will assess the robustness of the findings and provide the range of uncertainty of 
conclusions made.  For patients who call back the research team after week 10, the survey will 
still be completed, but their outcome will be considered missing and imputed in primary analysis 
with a sensitivity analysis using the week 10 outcome. 
Patients who reported at the week 7-10 phone call that they were either not using antiplatelet 
therapy at the start of the trial or were using a PPI will be included in the primary ITT analysis. 
We expect those who were not initially eligible to be balanced across the groups, thus the 
comparison of CNNF vs usual care will remain valid; however, for more accurate estimates, we 
will also conduct a per-protocol analysis where we exclude these individuals.   
11.6 Analysis of the Secondary Endpoint(s) 
The approach for analyzing the secondary endpoints will be similar to the approach for the 
primary endpoint, using mixed effects modelling with a random effect for clinician. 
11.7 Exploratory Analyses 
Exploratory analyses will mainly consist of descriptive analyses using cross-tabulations, means, 
standard deviations and proportions, as well as regressions using a similar approach as for the 
primary outcome.  
11.8 Other Analyses 
N/A 
11.9 Safety Analyses 
N/A 
11.10   Planned Interim Analyses 
None planned. 
11.11            Subgroup Analyses 
N/A 

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12 SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS   
12.1 Regulatory, Ethical, and Study Oversight 
Considerations 
12.1.1 Informed Consent Process 
12.1.1.1 Quality improvement strategy delivery  
The type of quality improvement strategy (clinician notification) described in this document is 
routinely used by the anticoagulation clinic as part of clinical care to improve the safety of 
patients using warfarin. The quality improvement strategy used in this pilot trial was developed 
specifically for use as part of a quality improvement effort to promote the use of evidence-based 
practices and reduce bleeding risk among the anticoagulation clinic’s patient population.  
We request a waiver of informed consent for delivery of the clinician notifications. This is 
justified on the grounds that the study presents only minimal risk to participants (and is likely to 
be beneficial), the waiver does not adversely affect the rights and welfare of participants, and 
the research could not practically be carried out without the waiver. The study could not 
practicably be carried out if patients and clinicians are consented because the goals of this 
pragmatic quality improvement trial are to evaluate the effectiveness of these strategies when 
used as part of routine care for improving patient safety in the setting of upper GI bleeding risk 
reduction. The ethicality of this approach is further bolstered by the wait-listed control design, 
which will ensure that all participants will eventually receive the quality improvement strategies. 
12.1.1.2 Patient phone survey   
We request a waiver of informed consent for the conduct of the patient phone survey. The 
patient phone survey will consist of a one-time phone questionnaire anticipated to take 5 
minutes (based on the duration of these calls in the pilot study). The survey will solely include 
questions that will allow the anticoagulation clinic to ensure that information in MiChart related to 
medications that influence bleeding risk are accurately documented in the patient's EHR both at 
baseline and at the time of the call and assess whether the patient made any medication 
changes during the study period. Accurate patient medication information in MiChart is 
necessary to correctly identify patients at high-risk for adverse events associated with warfarin 
use and knowledge of whether medication changes were made because of the study QI 
strategies or routine standard care is essential in assessing the impact of the strategy being 
tested and observing how often medication optimization occurs without CNNF, and as such 
these phone surveys are in-line with quality improvement efforts.  

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12.1.1.7 Chart Review for Randomized Participants  
A waiver of informed consent will be sought for the chart review component of this study as it 
poses minimal risk to participants, does not adversely affect the risks and benefits of 
participation for the participant, and the study could not practically be completed without a 
waiver.  
12.2 Confidentiality and Privacy      
12.2.1    Future Use of Stored Specimens and Data 
The data from this study may be used for future studies by the investigator team.  
12.2.2  Data sharing 
This study will be conducted in accordance with the National Institutes of Health (NIH) Public 
Access Policy, which ensures that the public has access to the published results of NIH funded 
research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from 
NIH funds to the digital archive PubMed Central upon acceptance for publication. This study will 
also comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission 
rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this 
trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish 
results in peer-reviewed journals. Data from this study may be requested 3 years after the 
completion of the primary endpoint by contacting Dr. Kurlander. 
12.3 Safety Oversight 
This study will not have a Data and Safety Monitoring Board or Safety Monitoring committee 
since it constitutes quality improvement. 
12.4 Key Roles and Study Governance 
Principal Investigator 
Jacob E. Kurlander, MD, MS 
Assistant Professor 
Michigan Medicine 
1500 E. Medical Center Drive, SPC 5362 
Ann Arbor, MI 48109 
(734) 660-4883 

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jkurland@umich.edu 
12.5 Clinical Monitoring 
N/A 
12.6 Data Handling and Record Keeping 
The source materials will include documentation of information collected during phone surveys 
and the results of chart review. Each study subject will be given a unique numeric identifier upon 
study entry. All individuals who wish to access the information system will need to pass through 
two levels of username and password authentication. All data will be stored on secured, 
password-protected UM computers. To access these data, approval must be obtained from the 
PI. These data will be kept only if specific use requires and then will be destroyed when all 
necessary linkages between data collection instruments have been accomplished. 
Any paper records associated with this study will be stored at 2800 Plymouth Road, Ann Arbor 
MI in a locked cabinet.  
12.7 Data Collection and Management Responsibilities 
Data collection will be the responsibility of the research staff at the site under supervision of the 
PI. The PI will be responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. 
All source documents will be completed in a neat, legible manner or collected in digital form to 
ensure accurate interpretation of the data. 
12.8 Study Records Retention 
As this trial will involve collection of health-related data through interaction with participants, all 
study documents will be retained for at least 7 years after the trial is completed in accordance 
with the University of Michigan’s Human Research Protections Program (HRPP) Operations 
Manual Part 6.II.B.  
12.9  Protocol Deviations   
Deviations from the clinic protocol by anticoagulation clinic staff members when sending or 
delivering the implementation strategies as part of the quality improvement project will not 
constitute protocol deviations and will not be reported. This protocol defines a protocol deviation 

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as any noncompliance with the clinical trial protocol, related only to the research components. 
The noncompliance may be either on the part of the investigator, or research staff. As a result of 
deviations, corrective actions will be developed by the site and implemented promptly. Any 
study design modifications that affect the risks and benefits of study participation will be 
submitted to the IRB at Michigan Medicine as study amendments and documented in the 
amendment section of this document. 
All major protocol deviations or protocol amendments which affect the risks and benefits of 
participation will be reported to the IRB per the IRBMED reporting guidelines. It will be the 
responsibility of the site investigator to use continuous vigilance to identify and report major 
deviations or recurring minor deviations within 1 week of identification of the protocol deviation 
or deviation trend, or within 1 week of the scheduled protocol-required activity. Any protocol 
changes will be submitted to the IRB as a study amendment and will require IRB approval prior 
to implementation of the protocol change. The site investigator will be responsible for knowing 
and adhering to the reviewing IRB requirements. 
13   DATA SAFETY MONITORING PLAN 
As this trial constitutes a low-risk study with a small number of participants, participant safety 
will be monitored by the study PI and there will be no data safety monitoring board or 
independent safety monitor for this project. Any unanticipated adverse events associated with 
the implementation strategies tested in this study will be identified by the study team and PI 
through participant self-report during any of the study phone surveys. Adverse events related to 
any medication changes made by the patient’s clinician will not be tracked or reported and the 
patient would be expected to discuss any such side effects with the clinician who initiated the 
medication change. The justification for not monitoring for adverse events related to a 
medication change is that participants in this study are not required to make a medication 
change as part of their participation and all medication changes will be made by the patient’s 
clinician as part of usual care. Any unanticipated problems or adverse events self-reported by 
participants will be reported to the PI immediately and communicated to the IRB according to 
the policies described in the Human Research Protection Program Operations Manual.  No 
individual stopping rules will apply to any participants as all patient-facing quality improvement 
strategies will be delivered one-time only.  However, any participants who request to no longer 
be contacted by the study team for study assessments will not be contacted again and will be 
considered to have withdrawn from the study. 

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13.1    Study Leadership Roster 
A study leadership roster is included herein. All CVs and licenses for investigators and staff members included on the roster will be 
filed in the essential document binder for this study. 
Name 
Study Team Role 
Contact Information  
Responsibilities  
Jacob E. Kurlander 
Principal Investigator 
(PI) 
734-647-9252, 
jkurland@umich.edu  
● Identification and enrollment of participants  
● Collection of study data through chart review, and 
patient surveys  
● Development and maintenance of study materials and 
protocols  
● Maintenance of regulatory and study related documents  
Geoffrey D. Barnes 
Co-Principal 
Investigator (Co-PI) 
734-763-0047,  
gbarnes@umich.edu  
● Identification and enrollment of participants  
● Collection of study data through chart review, and 
patient surveys  
● Development and maintenance of study materials and 
protocols  
● Maintenance of regulatory and study related documents  
Danielle Helminski 
Study Coordinator  
734-615-3952,  
dhelmins@umich.edu  
● Identification and enrollment of participants  
● Collection of study data through chart review, and 
patient surveys  
● Development and maintenance of study materials and 
protocols  
● Maintenance of regulatory and study related documents  
Kelley Kidwell 
Statistician  
734-764-6724, 
kidwell@umich.edu  
● Develop randomization procedure  
● Assign participants to groups  
● Maintain the master randomization list  
● Notify PIs and study coordinator when participants have 
been randomized  
● Perform statistical analyses  
 

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Michael Lanham  
Co-Investigator  
934-936-1644, 
mlanham@umich.edu 
● Develop randomization procedure  
● Assign participants to groups  
● Maintain the master randomization list  
● Notify PIs and study coordinator when participants have 
been randomized  
● Develop EMR tools to assist with identifying participants 
and sending quality improvement strategy components  
Sameer D. Saini 
Faculty Mentor 
734-936-4785, 
sdsaini@umich.edu  
● Provides expert advice on research conduct and study 
design  
● Monitor study progress to ensure completion of project  
Caroline Richardson 
Faculty Mentor 
734-998-7120, 
caroli@umich.edu  
● Provides expert advice on research conduct and study 
design  
● Monitor study progress to ensure completion of project  
Sarah L. Krein 
Faculty Mentor 
734-845-3621, 
skrein@umich.edu  
● Provides expert advice on research conduct and study 
design  
● Monitor study progress to ensure completion of project  
Raymond De Vries  
Faculty Mentor  
734-936-1644, 
rdevries@umich.edu  
● Provides expert advice on research conduct and study 
design  
● Monitor study progress to ensure completion of project  

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13.2    Protocol Amendment Procedures and Approvals  
Protocol amendments require approval by both the PI and the Co-PI, Jacob E. Kurlander and 
Geoffrey D. Barnes, prior to submitting the amendment to the IRB.  Written IRB approval of 
protocol amendments is required prior to implementation.  Any amendment to the protocol will 
be adhered to by all study staff and will apply to all subjects. 
13.3    Clinical Trial Registry and Publication Policy 
Prior to subject enrollment, this clinical trial will be registered with clinicaltrials.gov by a 
University of Michigan’s Michigan Institute for Clinical and Health Research (MICHR) 
representative. After the trial has been registered, the Co-PIs and study coordinator will be 
responsible for providing study updates and posting study results within 1 year of the primary 
completion date for the study on clinicaltrials.gov. Results from this trial will additionally be 
presented at cardiology or gastroenterology conferences and manuscripts of findings will be 
submitted for publication in relevant journals. As this study is being funded by the NIDDK 
through Dr. Kurlander’s K23 award, all journal articles that arise from this study will be submitted 
to PubMed Central in accordance with NIH Public Access Policy. 
14  APPENDICES 
 
14.1 Appendix 1. Criteria for determining appropriateness 
of antiplatelet therapy.  
Recommended duration of antiplatelet therapy for patients using anticoagulation, by indication.  
Clinicians should use their judgment in applying these recommendations to patients depending on the 
specific clinical scenario. 
Indication for 
antiplatelet drug 
Recommended 
management of 
antiplatelet drug 
Notes 
Ref.  
Primary prevention of coronary artery disease 
Primary prevention 
Stop antiplatelet 
drug 
  
1 
Treatment of coronary artery disease with atrial fibrillation (AF) 
PCI ≤ 6 
months ago 
Continue 
antiplatelet drug 
-Clopidogrel preferred 
-Consider switch to aspirin 81mg 
1 

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PCI for 
stable 
CAD 
PCI >12 
months ago 
Antiplatelet therapy 
is typically stopped, 
but may still be 
appropriate in 
select patients at 
high risk for stent 
thrombosis 
  
CABG for 
stable 
CAD 
CABG ≤12 
months ago 
Continue aspirin 
81mg 
  
CABG >12 
months ago 
Stop aspirin 
  
Acute 
Coronary 
Syndrome 
(ACS) +/- 
PCI 
ACS +/- PCI 
≤12 months 
ago 
Continue 
antiplatelet drug 
Clopidogrel preferred 
ACS +/- PCI 
>12 months 
ago 
Antiplatelet therapy 
is typically stopped, 
but may still be 
appropriate in 
select patients at 
high risk for stent 
thrombosis 
  
Treatment of coronary artery disease with venous thromboembolism (VTE) 
PCI for 
stable 
CAD 
PCI <6 
months ago 
Continue 
antiplatelet drug 
-Clopidogrel preferred 
-Consider stopping anticoagulant 
at 3 months if reversibly 
provoking risk factors 
1 
PCI >6 
months ago 
Continue 
antiplatelet drug 
-Consider switch to aspirin 81mg 
-Consider stopping anticoagulant 
if reversibly provoking risk factors 
PCI >12 
months ago 
Antiplatelet therapy 
is typically stopped, 
but may still be 
appropriate in 
select patients at 
high risk for stent 
thrombosis 
-Consider stopping anticoagulant 
if reversibly provoking risk factors 
CABG for 
stable 
CAD 
CABG ≤12 
months ago 
Continue aspirin 
81mg 
  
CABG >12 
months ago 
Stop aspirin 
  
 
 
Acute 
coronary 
syndrome 
ACS +/- PCI 
<3 months 
ago 
Continue 
antiplatelet drug 
Clopidogrel preferred 

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(ACS) +/- 
PCI 
ACS +/- PCI 
3-12 months 
ago 
Continue 
antiplatelet drug 
-Consider switch to aspirin 81mg 
-Consider stopping anticoagulant 
if reversibly provoking risk factors 
ACS +/- PCI 
>12 months 
ago 
Antiplatelet therapy 
is typically stopped, 
but may still be 
appropriate in 
select patients at 
high risk for stent 
thrombosis  
-Consider stopping anticoagulant 
if reversibly provoking risk factors 
Cerebrovascular disease 
History of TIA or CVA 
Stop antiplatelet 
drug 
  
1 
History of CEA 
Continue 
antiplatelet drug 
 
Carotid stent ≤ 3 months 
ago 
Continue 
antiplatelet drug 
Clopidogrel preferred 
Carotid stent > 3 months 
ago 
Stop antiplatelet 
drug 
  
Peripheral arterial disease 
Without prior intervention 
Stop antiplatelet 
drug 
 
 
Endovascular intervention  Continue 
antiplatelet drug 
Clopidogrel preferred for the first 
1-3 months 
Institutional 
practice 
Surgical repair / bypass 
Continue 
antiplatelet drug 
Vascular graft 
Continue 
antiplatelet drug 
 
Valve replacement 
Mechanical Heart Valve, 
excluding On-X valves 
Stop antiplatelet 
drug unless 
another indication 
is present 
  
2  
Mechanical On-X Aortic 
Heart Valve 
Continue aspirin 
81mg 
 
Bioprosthetic Heart Valve    
≤ 3 months ago 
Continue aspirin 
81mg only if high 
  

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thromboembolic 
risk 
Bioprosthetic Heart Valve    
> 3 months ago 
Stop aspirin 
  
TAVR ≤ 3 months 
Continue 
antiplatelet drug 
only if high 
thromboembolic 
risk 
  
3 
Venous Intervention (including IVC and Iliofemoral venoplasty/stenting) 
Venous procedure ≤2 
months prior 
Continue dual 
antiplatelet therapy 
  
  
Venous procedure >2 
months prior 
-Stop P2Y12 
inhibitor 
-Continue aspirin 
81mg indefinitely 
  
  
Anti-phospholipid Syndrome  
Anti-phospholipid 
syndrome 
Antiplatelet therapy 
should be 
individualized and 
may be appropriate 
 
4 
Polycythemia vera, essential thrombocythemia, and other myeloproliferative neoplasms 
Polycythemia vera, 
essential 
thrombocythemia, and 
other myeloproliferative 
neoplasms 
Antiplatelet therapy 
should be 
individualized and 
may be appropriate 
 
Institutional 
practice 
PCI=Percutaneous coronary intervention. 
 
 

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References 
1.  
Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC Expert Consensus Decision Pathway for 
Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or Venous 
Thromboembolism Undergoing Percutaneous Coronary Intervention or With Atherosclerotic 
Cardiovascular Disease: A Report of the American College of Cardiology Solution Set Oversight 
Committee. Journal of the American College of Cardiology. 2021;77(5):629-658. 
doi:10.1016/j.jacc.2020.09.011 
2.  
Writing Committee Members, Otto CM, Nishimura RA, et al. 2020 ACC/AHA Guideline for the 
Management of Patients With Valvular Heart Disease: A Report of the American College of 
Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll 
Cardiol. 2021;77(4):e25-e197. doi:10.1016/j.jacc.2020.11.018 
3.  
Saito Y, Nazif T, Baumbach A, et al. Adjunctive Antithrombotic Therapy for Patients With Aortic 
Stenosis Undergoing Transcatheter Aortic Valve Replacement. JAMA Cardiol. 2020;5(1):92-101. 
doi:10.1001/jamacardio.2019.4367 
4.  
Madison JA, Duarte-García A, Zuo Y, Knight JS. Treatment of thrombotic antiphospholipid 
syndrome in adults and children. Curr Opin Rheumatol. 2020;32(3):215-227. 
doi:10.1097/BOR.0000000000000702 
 
15  ABBREVIATIONS AND SPECIAL 
TERMS 
Abbreviation 
Term 
AAT 
Anticoagulant-antiplatelet therapy 
CFR 
Code of Federal Regulations 
EHR 
Electronic Health Record 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council on Harmonisation 
IRB 
Institutional Review Board 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 

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NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
NIH 
National Institute of Health 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PCP 
Primary Care Provider 
PI 
Principal Investigator 
PPI 
Proton Pump Inhibitor 
PUD 
Peptic Ulcer Disease 
UGIB 
Upper Gastrointestinal Bleeding 
UM 
University of Michigan 
US 
United States 
  
16  REFERENCES 
1.  
Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National Trends in Ambulatory Oral 
Anticoagulant Use. Am J Med. 2015;128(12):1300-1305.e2. 
doi:10.1016/j.amjmed.2015.05.044 
2.  
Lamberts M, Staerk L, Olesen JB, et al. Major Bleeding Complications and Persistence 
With Oral Anticoagulation in Non‐Valvular Atrial Fibrillation: Contemporary Findings in 
Real‐Life Danish Patients. J Am Heart Assoc. 2017;6(2):e004517. 
doi:10.1161/JAHA.116.004517 
3.  
Hippisley-Cox J, Coupland C. Predicting risk of upper gastrointestinal bleed and 
intracranial bleed with anticoagulants: cohort study to derive and validate the QBleed 
scores. BMJ. 2014;349:g4606. doi:10.1136/bmj.g4606 
4.  
Schaefer JK, Li Y, Gu X, et al. Association of Adding Aspirin to Warfarin Therapy Without 
an Apparent Indication With Bleeding and Other Adverse Events. JAMA Intern Med. 
2019;179(4):533-541. doi:10.1001/jamainternmed.2018.7816 
5.  
Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC Expert Consensus Decision 
Pathway for Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or 
Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or With 
Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology 
Solution Set Oversight Committee. J Am Coll Cardiol. 2021;77(5):629-658. 
doi:10.1016/j.jacc.2020.09.011 
6.  
Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus 
document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a 

AEGIS Trial Protocol  
 
v.1.4 
 
39 
 
report of the American College of Cardiology Foundation Task Force on Clinical Expert 
Consensus Documents. J Am Coll Cardiol. 2008;52(18):1502-1517. 
doi:10.1016/j.jacc.2008.08.002 
7.  
Scally B, Emberson JR, Spata E, et al. Effects of gastroprotectant drugs for the prevention 
and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised 
trials. Lancet Gastroenterol Hepatol. 2018;3(4):231-241. doi:10.1016/S2468-
1253(18)30037-2 
8.  
Kurlander JE, Gu X, Scheiman JM, et al. Missed opportunities to prevent upper GI 
hemorrhage: The experience of the Michigan Anticoagulation Quality Improvement 
Initiative. Vasc Med. 2019;24(2):153-155. doi:10.1177/1358863X18815971 
9.  
Anderson K, Stowasser D, Freeman C, Scott I. Prescriber barriers and enablers to 
minimising potentially inappropriate medications in adults: a systematic review and 
thematic synthesis. BMJ Open. 2014;4(12):e006544. doi:10.1136/bmjopen-2014-006544 
10.  Kurlander JE, Helminski D, Kokaly AN, et al. Barriers to Guideline-Based Use of Proton 
Pump Inhibitors to Prevent Upper Gastrointestinal Bleeding. Ann Fam Med. 2022;20(1):5-
11. doi:10.1370/afm.2734 
11.  Gill JM, Mainous AG 3rd, Koopman RJ, et al. Impact of EHR-based clinical decision 
support on adherence to guidelines for patients on NSAIDs: a randomized controlled trial. 
Ann Fam Med. 2011;9(1):22-30. doi:10.1370/afm.1172 
12.  Laine L, Connors L, Griffin MR, Curtis SP, Kaur A, Cannon CP. Prescription rates of 
protective co-therapy for NSAID users at high GI risk and results of attempts to improve 
adherence to guidelines. Aliment Pharmacol Ther. 2009;30(7):767-774. 
doi:10.1111/j.1365-2036.2009.04090.x 
13.  Lanas A, Esplugues JV, Zapardiel J, Sobreviela E. Education-based approach to 
addressing non-evidence-based practice in preventing NSAID-associated gastrointestinal 
complications. World J Gastroenterol WJG. 2009;15(47):5953-5959. 
doi:10.3748/wjg.15.5953 
14.  Avery AJ, Rodgers S, Cantrill JA, et al. A pharmacist-led information technology 
intervention for medication errors (PINCER): a multicentre, cluster randomised, controlled 
trial and cost-effectiveness analysis. Lancet Lond Engl. 2012;379(9823):1310-1319. 
doi:10.1016/S0140-6736(11)61817-5 
15.  Dreischulte T, Donnan P, Grant A, Hapca A, McCowan C, Guthrie B. Safer Prescribing--A 
Trial of Education, Informatics, and Financial Incentives. N Engl J Med. 
2016;374(11):1053-1064. doi:10.1056/NEJMsa1508955 
16.  Guthrie B, Kavanagh K, Robertson C, et al. Data feedback and behavioural change 
intervention to improve primary care prescribing safety (EFIPPS): multicentre, three arm, 
cluster randomised controlled trial. BMJ. 2016;354:i4079. doi:10.1136/bmj.i4079 
17.  Wallis KA, Elley CR, Moyes SA, Lee A, Hikaka JF, Kerse NM. Safer Prescribing and Care 
for the Elderly (SPACE): a cluster randomised controlled trial in general practice. BJGP 

AEGIS Trial Protocol  
 
v.1.4 
 
40 
 
Open. Published online December 14, 2021:BJGPO.2021.0129. 
doi:10.3399/BJGPO.2021.0129