Anticoagulation With Enhanced Gastrointestinal Safety (AEGIS): A Pilot Trial to Evaluate Clinician- and Patient-facing Strategies to Reduce Upper Gastrointestinal Bleeding Risk in Patients on Combination Antithrombotic Therapy
Phase: NA
Conditions: Upper Gastrointestinal Bleeding
Sponsor: University of Michigan

Anticoagulation with Enhanced Gastrointestinal 
Safety (AEGIS): A pilot quality improvement trial 
to evaluate clinician- and patient-facing 
strategies to reduce upper gastrointestinal 
bleeding risk in patients on combination 
antithrombotic therapy 
Protocol Number: 1.0 
National Clinical Trial (NCT) Identified Number:   NCT05085405   
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.1.5 
31 March 2022  
  
 
 

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AMENDMENTS 
6 
STATEMENT OF COMPLIANCE 
8 
1        PROTOCOL SUMMARY 
9 
1.1      Synopsis 
9 
1.2      Schema 
12 
1.3      Schedule of Activities 
13 
Schedule of Patient-Targeted Activities 
14 
Schedule of Clinician-Targeted Activities 
15 
Schedule of Anticoagulation Clinic Staff-Targeted Activities 
16 
2         
INTRODUCTION 
16 
2.1      Study Rationale & Background 
18 
2.2      Objectives 
19 
3   RISK/BENEFIT ASSESSMENT 
19 
3.1   
Known Potential Risks to Randomized Patients 
20 
3.2 Known Potential Risks to All Anticoagulation Clinic Patients who Undergo Chart 
Review 
22 
3.3      Known Potential Risks to Clinicians and Staff 
22 
3.4   
Known Potential Benefits to Randomized Patients 
22 
3.5   Known Potential Benefits to All Anticoagulation Clinic Patients who Undergo 
Chart Review 
23 
3.6   Known Potential Benefits to Clinicians and Staff 
23 
3.7      Assessment of Potential Risks and Benefits 
23 
4        OBJECTIVES AND ENDPOINTS 
24 
5        STUDY DESIGN 
31 
5.1      Overall Design 
31 
5.2  Scientific Rationale for Study Design 
32 
5.3      Justification for Intervention 
33 
5.4   
End-of-Study Definition 
33 
6        STUDY POPULATION 
33 
6.1      Sample size 
33 
6.2   
Inclusion Criteria 
34 
6.3   
Exclusion Criteria 
35 
6.4      Patient and Clinician Selection 
35 
6.5   
Screen Failures 
36 

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6.6      Strategies for Recruitment and Retention 
36 
7        STUDY INTERVENTION(S) 
37 
7.1      Study Intervention(s) Administration 
37 
7.1.1        Study Intervention Description 
37 
7.1.2        Administration and/or Dosing 
38 
7.2   
Fidelity 
38 
7.2.1        Anticoagulation Nurse Training 
38 
7.2.2        Intervention Delivery 
38 
7.2.3        Intervention Receipt & Enactment 
38 
7.3   
Measures to Minimize Bias: Randomization and Blinding 
39 
7.4   
Concomitant Therapy 
39 
7.5      Rescue Therapy 
39 
8        END-OF-INTERVENTION/END-OF-STUDY 
39 
8.1      Discontinuation of Intervention 
39 
8.2   
Participant Discontinuation/Withdrawal from the Study 
40 
8.3 
Lost to Follow-Up 
40 
9  STUDY ASSESSMENTS AND PROCEDURES 
40 
9.1      Eligibility Assessment 
40 
9.2 Qualitative Assessments with Participants 
41 
9.2.1 Clinicians: 
41 
9.2.2 Patients: 
42 
9.2.3 Anticoagulation clinic staff: 
43 
9.3      Assessment of the Primary Endpoint 
44 
9.4      Assessment of the Secondary Endpoint 
44 
9.5   
All Other Study Assessments 
44 
9.5.1 Chart Review for Randomized Patients 
45 
9.5.2 Chart Review for All Anticoagulation Clinic Patients who Meet Eligibility Criteria 
at Baseline 
45 
10  ADVERSE EVENTS 
46 
11  STATISTICAL CONSIDERATIONS 
46 
11.1 Sample Size Determination 
46 
11.2 General Statistical Approach 
46 
11.3 Descriptives 
47 

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11.4 Hypotheses 
47 
11.5 Analysis of the Primary Endpoint(s) 
47 
11.6 Analysis of the Secondary Endpoint(s) 
47 
11.7 Exploratory Analyses 
48 
11.8 Other Analyses 
48 
11.9 Safety Analyses 
48 
11.10   Planned Interim Analyses 
48 
11.11            Subgroup Analyses 
48 
12 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
49 
12.1 Regulatory, Ethical, and Study Oversight Considerations 
49 
12.1.1 Informed Consent Process 
49 
12.1.1.1 Intervention delivery 
49 
12.1.1.2 Patient assessment #1 
49 
12.1.1.3 Patient Assessment #2 and Patient Assessment #3 
50 
12.1.1.4 Clinician Qualitative Semi-Structured Interviews 
51 
12.1.1.5 Anticoagulation Clinic Staff Qualitative Semi-Structured Interviews 
51 
12.1.1.6 Chart Review for Randomized Participants 
51 
12.1.1.7 Chart Review for All Anticoagulation Clinic Patients who Meet Eligibility Criteria 
at Baseline (other than having a participating clinician) 
51 
12.1.2 Consent Procedures and Documentation 
51 
12.2 Confidentiality and Privacy 
52 
12.2.1    Future Use of Stored Specimens and Data 
52 
12.2.2  Data sharing 
53 
12.3 Safety Oversight 
53 
12.4 Key Roles and Study Governance 
53 
12.5 Clinical Monitoring 
53 
12.7 Data Handling and Record Keeping 
53 
12.8 Data Collection and Management Responsibilities 
54 
12.9 Study Records Retention 
54 
12.10  Protocol Deviations 
54 
13 DATA SAFETY MONITORING PLAN 
55 
14  ADMINISTRATIVE 
Error! Bookmark not defined. 
14.1    Study Leadership Roster 
56 

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14.2    Protocol Amendment Procedures and Approvals 
58 
14.3    Clinical Trial Registry and Publication Policy 
58 
15  APPENDICES 
58 
15.1 Appendix 1. Criteria for determining appropriateness of antiplatelet therapy. 
58 
16  ABBREVIATIONS AND SPECIAL TERMS 
61 
17  REFERENCES 
62 
 
 
 
 

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AMENDMENTS 
Date 
Version 
Section(s) 
Changes 
 9/22/2021 
V.1.1 
1.1 
7.1.1 
7.2.2 
9.1  
Protocol was amended to remove all mentions of the 
anticoagulation clinic LPN and RN and revise 
language to show that anticoagulation clinic nursing 
staff (RN or LPN) will deliver the quality improvement 
strategies for this study. The language about the role 
of the LPN and the RN are being removed following 
feedback from the clinic staff about LPN staffing 
shortages (e.g., maternity leave, part-time staff) and 
concerns about the feasibility of the LPN having the 
time and bandwidth to deliver the strategies in the 
desired timeframe. However, as it is possible that 
either LPNs or RNs may deliver these strategies 
while covering for other staff members, the language 
in the protocol was revised to be inclusive of all 
anticoagulation clinic nursing staff.  
10/13/2021 
V.1.2  
1.1 
1.3 
6.1 
6.4 
9.1 
9.2.1 
 
Protocol was amended to reflect an increase in 
clinician and patient participant enrollment numbers. 
The number of clinician participants was increased 
from 10 to 12 in order to allow for a balanced 
number of cardiologists and non-cardiologists to be 
included in each clinician-facing intervention arm. As 
all eligible patients cared for by a clinician participant 
will be included in this pilot trial, the number of 
patient participants increased as a result of the 
increase in clinicians. All informed consent 
documents for clinician and patient participants have 
been revised to reflect this increase in enrollment.  
11/04/2021 
V1.3 
1.1 
1.2 
1.3 
2.1 
4 
5.1 
5.2 
7.1.1 
7.3 
Protocol was amended to reflect a semantic name 
change for the more resource-intensive clinician-
facing implementation strategy. The “clinician 
notification and information relay” implementation 
strategy was renamed to “clinician notification and 
nurse facilitation” following feedback from topic 
experts in the implementation science field.  
1/26/2022 
V.1.4 
1.1 
1.4  
2.2 
Protocol was amended to reflect the addition of 
participant group 2, a convenience sample of 8 
primary care clinicians and their eligible patients, and 

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2.3 
3.1 
3.2 
4 
5.4 
6.1 
6.2 
6.3 
6.4 
6.6 
7.2 
8.1 
8.2 
8.3 
9 
11 
12.1 
 
the outcomes being assessed for group 2 
participants. This group was added to the study to 
elicit feedback from this specialty group about the 
feasibility and appropriateness of the implementation 
strategies after only 1 primary care clinician was 
included in group 1 and did not respond to invitations 
to participate in the qualitative research interview. 
Protocol was additionally amended to change the 
timing of assessment #3 for group 1 patient 
participants from week 9-12 to week 15-17.  
3/31/2022 
V.1.5 
1.1 
2.3 
4.2 
9.4.2 
9.7 
11.2.1 
11.4.2 
11.5.2 
Protocol was amended to clarify that all endpoints 
associated with group 2 participants are exploratory 
endpoints, and no primary or secondary endpoints 
will be evaluated or uploaded to clinicaltrials.gov for 
this participant group.  
 
  
 
 

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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 pilot quality improvement trial to evaluate clinician- and patient-
facing strategies to reduce upper gastrointestinal bleeding risk in 
patients on combination antithrombotic therapy 
Grant Number: 
K23 DK118179 
Background 
Patients who use an anticoagulant together with an antiplatelet 
drug (combination antithrombotic therapy, or CAT) are at 
increased risk for serious bleeding, which most commonly occurs 
in the gastrointestinal tract. For patients on CAT, 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 of these 
strategies are underused. The aim of this trial is to evaluate the 
feasibility of conducting a future large-scale randomized quality 
improvement trial of quality improvement (QI) implementation 
strategies to increase medication optimization for patients on 
CAT at high risk for upper GI bleeding. 
Study Population: 
Group 1: Quality improvement strategy components will be 
directed at both patients and clinicians. 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. Clinicians will be eligible for 
inclusion if they are the clinician of record for a patient meeting 
inclusion criterion (i.e., the clinician who receives routine 
communications from the anticoagulation service), or if they are 
a cardiologist who has had a visit with the patient in the prior 
year. We anticipate including 12 clinicians and 51 patients. All 
participating anticoagulation clinic staff, who will deliver the QI 
strategies, will also be included to assess their perceptions of 
program feasibility and acceptability.  
Group 2: Quality improvement strategy components will be 
directed at both patients and clinicians. Patients will be eligible 
for inclusion if they are prescribed warfarin and an antiplatelet 
drug without a PPI, are enrolled in the Michigan Medicine 
anticoagulation monitoring service, and have a physician in 
Group 2 as their clinician of record for the anticoagulation clinic. 
See section 6.1 for additional inclusion and exclusion criteria. 

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Clinicians will be eligible for inclusion if they are the clinician of 
record for a patient meeting inclusion criterion (i.e., the clinician 
who receives routine communications from the anticoagulation 
service), and are a primary care specialist. We anticipate 
including 8 primary care clinicians and 8-16 of their patients.  
Study Description: 
The study is designed as a pilot 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 clinician 
of record on file with the anticoagulation service. For each 
patient, assignment to one of two clinician-level QI strategies 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 (consisting of a notification 
message sent in the electronic health record) or clinician 
notification + nurse facilitation (consisting of a similar notification, 
but which additionally includes provision of clinically relevant 
information identified on chart review, along with other steps to 
facilitate appropriate care). Separately, patients will be 
individually randomized to receive an activation guide that 
provides patient education and encouragement to discuss 
medication optimization with their clinicians, or to usual care. 
Following delivery of the QI strategies, patients, clinicians, and 
anticoagulation staff will be invited to participate in semi-
structured interviews about their experiences with and 
perceptions of the QI strategies.  
  
  
Group 1: Primary Objective: To explore the feasibility of patient 
participation in a one-time assessment of medication use 
following delivery of the QI strategies. 
Group 1: Secondary Objectives: To explore the feasibility of 
delivering QI strategy components to clinicians and patients as 
intended. 
Group 2: Primary Exploratory Objective: To explore the 
feasibility and appropriateness of the QI strategies from the 
perspective of primary care clinicians to inform a future clinic-
wide trial.   
Endpoints*: 
Group 1: Primary Endpoint: The proportion of randomized 
patients who complete a brief phone assessment (patient 
assessment #1) at week 5. 
Group 1: Secondary Endpoints:  The proportion of patients 
and clinicians who received the QI strategies to which they were 
randomized. 
Group 1: Exploratory Endpoints: Multiple additional 
quantitative endpoints will be evaluated, as documented in the 
section 4 of the protocol. 

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Group 2: There is no quantitative endpoint. The primary 
exploratory objective is to conduct a qualitative evaluation of 
primary care providers’ perceptions of the intervention strategies. 
Group 2 Exploratory endpoints: Multiple exploratory endpoints 
will be evaluated, as documented in section 4. 
Phase or Stage: 
This project is a pilot feasibility quality improvement trial. 
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: 
Quality improvement implementation strategies to be 
delivered: 
Two clinician-facing QI strategies will be evaluated, both of which 
are intended to assist the clinician in making an appropriate 
decision to optimize patients’ medications: 
1.       Clinician Notification: 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, summarizes options for 
medication optimization, and asks that the clinician manage any 
medication changes. 
2.       Clinician Notification +Nurse Facilitation: A protocol-
driven QI strategy in which an anticoagulation clinic nurse sends 
a templated message to the patient’s target clinician, similar to 
clinician notification, but which also includes clinical information 
about the patient identified by the nurse during chart review, 
along with a concise evidence summary relevant to the patient. 
In addition, once clinicians decide on a medication optimization 
plan, the nurse will facilitate execution of the plan and 
communicate recommendations to the patient. 
Two patient-facing strategies s will be evaluated: 
1.       Patient Activation Guide: A guide to educate patients 
about their risk for bleeding and activate them to talk with their 
clinician about medication changes to reduce their bleeding risk. 
2.       Usual care: No additional education or activation strategies 
outside of usual care will be included. 
Assessments 
Group 1: Semi-structured interviews will be conducted with 
patients, clinicians, and anticoagulation staff to evaluate 
perceptions of the QI strategies, as described in the body of the 

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protocol. Data will also be extracted from the medical record at 
multiple timepoints. 
Group 2: Semi-structured interviews will be conducted with 
primary care clinicians to evaluate perceptions of the QI 
strategies, as described in the body of the protocol. Data will also 
be extracted from the medical record for included patients.  
Human subject’s 
protection: 
A waiver of informed consent will be sought for delivery of the QI 
strategies, as well as for patient assessment #1, 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: 
Group 1: 28 weeks 
Group 2: 12 weeks  
Participant Duration: 
Group 1: 12 weeks 
Group 2: 12 weeks  
1.2      Schema 

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 1.3      Schedule of Activities – Group 1  
It is anticipated that 12 clinicians will be included in the study, and up to 51 patients who are 
cared for by those clinicians. Eight to ten patients will enter the study cohort each week for 6 
weeks. 
For informational purposes, whether the research team performs the activity, or 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 patient and clinician level QI 
strategies will not be considered study deviations. 

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Schedule of Patient-Targeted Activities  
Activity  
Screening and 
randomization 
Week 1 Week 
2-4 
Week 
5-8 
Week 
9-12 
Week 
15-17 
Week 
13-28 
Eligibility determination by 
chart review (research 
team) 
X 
 
 
 
 
 
 
Randomization of patient to 
QI strategy (research 
team) 
X 
 
 
 
 
 
 
Delivery of education and 
activation guide for patients 
randomized to receive it 
(anticoagulation staff) 
 
X 
 
 
 
 
 
Possible outreach to the 
patient by their clinical care 
team and/or anticoagulation 
clinic staff as per usual 
clinical care (no research 
team activity) 
 
X 
X 
X 
 
 
 
Administration of patient 
assessment #1 by phone, 
with waiver of informed 
consent (research team)  
 
 
 
X 
 
 
 
Verbal informed consent 
followed by patient 
assessment #2 (research 
team) 
 
 
 
X 
 
 
 
Administration of patient 
assessment #3 by phone, 
with verbal informed 
consent (research team) 
 
 
 
 
 
X 
 
Chart review to ascertain 
exploratory outcomes 
(research team)  
X 
X 
X 
X 
X 
X 
X 

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Activity  
Screening and 
randomization 
Week 1 Week 
2-4 
Week 
5-8 
Week 
9-12 
Week 
15-17 
Week 
13-28 
Chart review to determine 
appropriateness of initial 
and subsequent use of 
antiplatelet therapy 
(research team) 
 
 
 
 
 
 
X 
 
Schedule of Clinician-Targeted Activities   
Activity  
Screening, 
selection, and 
randomization 
Week 1-5 
Week 6-10 
  
Eligibility determination (research team) 
X 
  
  
Randomized selection of 12 clinicians to be 
included (research team) 
X 
  
  
Randomization of selected clinicians to either 
clinician notification arm or clinician notification + 
nurse facilitation arm (research team) 
X 
  
  
Delivery of clinician-facing QI strategies, 
synchronized with patient-level strategies 
(anticoagulation clinic staff) 
  
X 
  
Additional outreach, communication, or facilitation 
steps as per anticoagulation clinic protocol for 
clinician notification and clinician notification + 
information relay strategies (anticoagulation 
clinic staff) 
  
X 
 
Verbal informed consent and semi-structured 
interviews with clinicians (research team). This 
may occur as soon as week 5 if the clinician has 
already responded to messages for all of their 
patients involved in the trial. 
  
X 
X 

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 Schedule of Anticoagulation Clinic Staff-Targeted Activities  
Activity  
Week 1-5 
Week 6-8  
Week 9-16 
Anticoagulation clinic staff receive weekly list of up 
to 10 patients starting trial each week, and the 
name of the target clinicians (research team) 
X 
 
 
Anticoagulation staff initiate clinician and patient 
facing QI strategies synchronously 
(anticoagulation clinic staff) 
X 
 
 
Additional outreach, communication, or facilitation 
steps as per anticoagulation clinic protocol for 
clinician notification and clinician notification + 
nurse facilitation strategies (anticoagulation clinic 
staff) 
X 
X 
 
Verbal informed consent and semi-structured 
interviews with anticoagulation staff (research 
team) 
 
 
X 
1.4      Schedule of Activities – Group 2  
A convenience sample of 8 primary care clinicians will be selected. Additionally, all eligible 
patients for whom the primary care clinician is the responsible provider on record for the 
anticoagulation clinic will be included in group 2. We anticipate that each included primary care 
clinician will have 1-2 eligible patient included in group 2, for a total of 8-16 patient participants.  
For informational purposes, whether the research team performs the activity, or 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 patient and clinician level QI 
strategies will not be considered study deviations. 
Schedule of Patient-Targeted Activities  
Activity  
Screening and 
randomization 
Week 1 Week 
2-4 
Week 
5-8 
Week 
9-12 
Eligibility determination by 
chart review (research 
team) 
X 
 
 
 
 

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Activity  
Screening and 
randomization 
Week 1 Week 
2-4 
Week 
5-8 
Week 
9-12 
Randomization of patient to 
QI strategy (research 
team) 
X 
 
 
 
 
Delivery of education and 
activation guide for patients 
randomized to receive it 
(anticoagulation staff) 
 
X 
 
 
 
Possible outreach to the 
patient by their clinical care 
team and/or anticoagulation 
clinic staff as per usual 
clinical care (no research 
team activity) 
 
X 
X 
X 
 
Chart review to ascertain 
exploratory outcomes 
(research team)  
 
 
X 
X 
X 
 
Schedule of Clinician-Targeted Activities   
Activity  
Screening, 
selection, and 
randomization 
Week 1 
Week 2-6 
  
Eligibility determination (research team) 
X 
  
  
Selection of 8 primary care clinicians (research 
team) 
X 
  
  
Randomization of selected clinicians to either 
clinician notification arm or clinician notification + 
nurse facilitation arm (research team) 
X 
  
  
Delivery of clinician-facing QI strategies, 
synchronized with patient-level strategies 
(anticoagulation clinic staff) 
  
X 
  

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Additional outreach, communication, or facilitation 
steps as per anticoagulation clinic protocol for 
clinician notification and clinician notification + 
information relay strategies (anticoagulation 
clinic staff) 
  
 
X 
Verbal informed consent and semi-structured 
interviews with clinicians (research team). This 
may occur as soon as week 3 if the clinician has 
already responded to messages for all of their 
patients involved in the trial. 
  
 
X 
2         INTRODUCTION       
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 
combination antithrombotic therapy (CAT). 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 CAT 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 CAT 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 CAT 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 

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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 
[Kurlander AFM, in press]. 
There is a critical need for implementation strategies to improve medication optimization for 
upper GI bleeding risk reduction in patients prescribed CAT. 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 10–13. 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) 15–17. However, such 
multicomponent strategies are resource intensive and challenging to implement in the 
fragmented US healthcare system. There have been limited efforts to activate patients to 
enhance the quality of their care in this clinical domain 14. 
As part of a quality improvement program through the Michigan Medicine anticoagulation 
service, three potential implementation strategies have been identified to improve the safety of 
patients using CAT, including clinician notification by electronic health record (EHR) message, a 
multi-faceted nurse facilitated process involving clinician notification + nurse facilitation, and 
activation of patients to discuss medication optimization with their clinicians using a newly 
developed guide. The anticoagulation clinic intends to undertake a clinic-wide randomized 
quality improvement trial in the near future to evaluate the effectiveness of these strategies. This 
protocol describes plans for a pilot randomized evaluation of the quality improvement project, 
focused on feasibility, which will provide essential information for planning the future quality 
improvement trial. 
2.2      Objectives  - Group 1  
Primary Objective: To explore the feasibility of patient participation in a one-time 
assessment of medication use following delivery of the quality improvement 
implementation strategies.  
Secondary Objectives: To explore the feasibility of delivering QI strategy components 
as intended. 
2.3     Objectives  - Group 2  

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Primary Exploratory Objective: To explore primary care providers’ perceptions of the 
QI strategies.   
3   RISK/BENEFIT ASSESSMENT  
3.1   Known Potential Risks to Randomized Patients in 
Group 1 
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 strategies and assessments of the implementation strategies, but not any 
possible medication changes undertaken by their clinicians, which are done as part of usual 
clinical care. 
  
1. Potential Psychological Discomfort due to Subject Content. The patient activation 
guide and patient assessments will deal with the topic of their potential for bleeding. This 
could cause them to be upset or concerned. All efforts will be made to discuss these 
topics in a careful and thoughtful manner. 
2. Inconvenience. Participants may feel inconvenienced by the attempts to reach them 
and send them educational materials, or the time it takes to engage in study 
assessments. 
3. 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 
(i.e., illicit drug use), a potential data breach is anticipated to cause minimal harm to the 
participant if it were to occur.  
4. Potential questions about the quality of their clinical care. It is possible that patient 
participants may have questions about their clinical care. During creation of the patient 
activation guide, steps were taken to mitigate this risk by including language throughout 
that this project is being conducted in response to evidence from newer research studies 
and they are being contacted as part of a new patient safety initiative.  
5. Patient-initiated changes in medications without clinician consultation. Patients 
who receive the patient-facing activation guide may make a change in their medications 
without first consulting one of their clinicians for input. Because antiplatelet drugs like 
aspirin and some PPIs are available over-the-counter, it is possible that a patient may 
choose to discontinue aspirin therapy or initiate a PPI on their own in response to the 
information included in the activation guide. To discourage patients from making 
medication changes on their own, language has been included throughout all patient-

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facing materials to regularly remind the patient to speak with their clinician before 
making any medication changes and that their clinician will have to carefully consider 
which change would be most beneficial.  
3.2   Known Potential Risks to Randomized Patients in 
Group 2 
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 strategies and assessments of the implementation strategies, but not any 
possible medication changes undertaken by their clinicians, which are done as part of usual 
clinical care. 
  
1. Potential Psychological Discomfort due to Subject Content. The patient activation 
guide will deal with the topic of their potential for bleeding. This could cause them to be 
upset or concerned. All efforts will be made to discuss these topics in a careful and 
thoughtful manner. 
2. Inconvenience. Participants may feel inconvenienced by the attempts to send them 
educational materials. 
3. 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 
(i.e., illicit drug use), a potential data breach is anticipated to cause minimal harm to the 
participant if it were to occur.  
4. Potential questions about the quality of their clinical care. It is possible that patient 
participants may have questions about their clinical care. During creation of the patient 
activation guide, steps were taken to mitigate this risk by including language throughout 
that this project is being conducted in response to evidence from newer research studies 
and they are being contacted as part of a new patient safety initiative.  
5. Patient-initiated changes in medications without clinician consultation. Patients 
who receive the patient-facing activation guide may make a change in their medications 
without first consulting one of their clinicians for input. Because antiplatelet drugs like 
aspirin and some PPIs are available over-the-counter, it is possible that a patient may 
choose to discontinue aspirin therapy or initiate a PPI on their own in response to the 
information included in the activation guide. To discourage patients from making 
medication changes on their own, language has been included throughout all patient-
facing materials to regularly remind the patient to speak with their clinician before 
making any medication changes and that their clinician will have to carefully consider 
which change would be most beneficial.  
 

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3.3 Known Potential Risks to All Anticoagulation Clinic 
Patients who Undergo Chart Review  
Chart review of all anticoagulation clinic patients who are documented in the electronic health 
record as using CAT without PPI gastroprotection at study initiation will be completed to provide 
information about the number of patients who may require medication optimization in the future 
clinic-wide trial and about the use of the evidence-based medication optimization strategies in 
usual practice to assess feasibility of completing the future clinic-wide trial. Anticipated risks to 
patients who are not randomized to receive a QI strategy and solely undergo chart review are 
minimal.  
1. 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 
(i.e., illicit drug use), a potential data breach is anticipated to cause minimal harm to the 
participant if it were to occur.  
3.4      Known Potential Risks to Clinicians and Staff (Group 
1 and Group 2) 
1. Potential Psychological Discomfort due to Subject Content. The clinician messages 
and assessment 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 careful and thoughtful 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 
or in the clinician assessment. 
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. 
3.5  Known Potential Benefits to Randomized Patients 
(Group 1) 
Potential benefits associated with study participation include: 
1. Increased knowledge and understanding of personal risk for GI bleeding, which will 
be discussed in the patient activation guide and during research interviews. 
2. Increased sense of self-efficacy to discuss risk status and medication optimization 
with their clinicians. 
3. Reduced risk of upper GI bleeding events if patients have medication optimization as 
a result of participation. 

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4. Self-Satisfaction – participants may derive a sense of personal satisfaction and 
purpose from contributing new knowledge to help advance science and medicine. 
3.6   Known Potential Benefits to Randomized Patients 
(Group 2) 
Potential benefits associated with study participation include: 
1. Increased knowledge and understanding of personal risk for GI bleeding, which will 
be discussed in the patient activation guide. 
2. Increased sense of self-efficacy to discuss risk status and medication optimization 
with their clinicians. 
3. Reduced risk of upper GI bleeding events if patients have medication optimization as 
a result of participation. 
 
 
3.7   Known Potential Benefits to All Anticoagulation 
Clinic Patients who Undergo Chart Review  
Potential benefits for all patients who receive care from the anticoagulation clinic service who 
are not randomized to receive one of the QI strategies but are identified as being at high-risk for 
upper GI bleeding through a workbench report in MiChart at baseline and undergo chart review 
include:  
1. Increased knowledge and understanding of the prevalence of CAT use without PPI 
gastroprotection among patients cared for by the anticoagulation clinic will help gain 
clinic leadership buy-in to allocate resources to lower bleeding risk and improve patient 
safety through wide-scale implementation of the QI strategies being tested.  
3.8   Known Potential Benefits to Clinicians and Staff 
(Group 1 and Group 2) 
1. Increased knowledge of risk factors for upper gastrointestinal bleeding and of 
evidence-based practices to reduce the risk. 
2. Self-Satisfaction – clinicians and anticoagulation clinic staff may derive a sense of 
satisfaction and purpose from working to prevent bleeding and adverse events related to 
warfarin use in their patient population.  
3.9      Assessment of Potential Risks and Benefits 
The risks to patients, clinicians and staff 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 (consent forms, enrollment forms) from data source documents. All data 

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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 
4.1 Objectives and Endpoints (Group 1)  
OBJECTIVES 
ENDPOINTS 
Primary 
  
To explore the feasibility of 
patient participation in a 
one-time assessment of 
medication use following 
delivery of the QI 
strategies. 
Proportion of patient participants who are able to be contacted 
by phone and are willing to participate in and fully complete 
patient assessment #1, related mainly to medication use (week 
5 interview). 
Secondary 
  
To explore the feasibility of 
delivering QI strategy 
components as intended. 
Proportion of participants who received all implementation 
components to which they were randomized in the appropriate 
time frame. 
Exploratory 
  
To explore additional 
aspects of the feasibility of 
recruitment. 
Proportion of randomized patients able to be reached by phone 
after three attempts for patient assessment #1 at week 5. 
  
Average number of phone call attempts to reach each patient 
for patient assessment #1 at week 5. 
  
The number of anticoagulation clinic patients who meet 
eligibility criteria for the AEGIS trial on the first day of the pilot 
study according to the EHR workbench report.  
To explore changes in the 
proportion of eligible 
patients during the study 
duration.  
The proportion of all patients in the anticoagulation clinic who 
meet eligibility criteria for the study, regardless of whether they 
are included, who discontinued warfarin or were otherwise 
closed to the anticoagulation service during the study period.  
 
The proportion of patients who were randomized who 
discontinued warfarin or were closed to the anticoagulation 
clinic service during the participants’ study duration. 

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OBJECTIVES 
ENDPOINTS 
To explore the accuracy of 
the electronic health 
record’s medication list for 
ascertaining inclusion 
criteria 
The proportion of randomized patients who, retrospectively, 
report that they had been using antiplatelet therapy at baseline 
during patient assessment #1 at week 5. 
  
The proportion of randomized patients who, retrospectively, 
report that they had been using PPI at baseline during patient 
assessment #1 at week 5. 
 
The proportion of randomized patients who met inclusion criteria 
based on retrospective medication use in patient assessment 
#1 at week 5. 
To explore the accuracy of 
the electronic health 
record’s medication list for 
ascertaining medication 
changes 
The accuracy, positive predictive value, and negative predictive 
value of the electronic health record for use of antiplatelet 
therapy, and for use of PPIs at the time of assessment #3.  
 
The accuracy, positive predictive value, and negative predictive 
value of the electronic health record for “medication 
optimization” at the time of assessment #3. A patient will be 
considered to have had medication optimization if they are 
either no longer using combination antithrombotic therapy or are 
using a PPI. 
To explore the feasibility of 
complete collection of study 
data 
The proportion of patients with complete data entry in RedCAP 
database at study completion  
 
Average duration of interviews on medication use/adherence 
during patient assessment #3 at week 15-17. 
To explore the feasibility of 
delivering the clinician-level 
QI strategies 
Proportion of patients whose clinician was sent the clinician-
level strategy by the anticoagulation clinic staff in the prescribed 
time period per the clinic protocol. We will also separately 
calculate this endpoint for the two levels of the clinician QI 
strategy. 
To explore the feasibility of 
delivering the patient 
activation tool 
The proportion of patients randomized to receive the activation 
guide who were sent the guide in the prescribed period of time, 
as determined by chart review.  
  
The proportion of patients randomized to receive the guide who 
recalled receiving the guide during patient assessment #1 at 
week 5. 
 
The proportion of patients randomized to receive the guide who 
recalled reviewing the guide in patient assessment #1 at week 
5. 

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OBJECTIVES 
ENDPOINTS 
To explore the feasibility of 
prompting patient-clinician 
communication about 
medication optimization 
The number of days after delivery of the clinician-facing QI 
strategy at which the patient and the target clinician (or their 
healthcare team) had communication (either by phone, in 
person visit, or portal message) about medication optimization, 
based on chart review. This will be calculated overall and 
separately for each QI strategy.  
 
The proportion of patients who had a communication about 
medication optimization with their clinicians based on patient 
recall at week 5 (patient assessment #1) and at week 9-12 
(patient assessment #3). This will be calculated overall and 
separately for each QI strategy.  
 
For patients who had a communication with their clinician about 
medication optimization, the proportion in whom initial contact 
was made by the clinician vs. by the patient, according to chart 
review. This will be calculated overall and separately for each of 
the QI strategies. This will be assessed based on week 5 call. 
 
For patients who had a communication with their clinician about 
medication optimization, the proportion in whom initial contact 
was made by the clinician vs. by the patient, according to 
patient recall. This will be calculated overall separately for each 
QI strategy.  
 
For patients who contacted a clinician about medication 
optimization, the specialty of the clinician and whether the 
clinician who was sent the clinician notification was the target 
clinician. This will be determined separately based on chart 
review and patient recall. 
 
For patients who had communication with their clinician 
documented in the electronic health record, whether this 
occurred by phone, portal, or in-person/telehealth visit based on 
chart review.  
To explore process 
measures associated with 
clinician notification 
For clinicians randomized to clinician notification: 
  
Number of days taken for clinicians to send a response 
message to anticoagulation staff after first receiving the clinician 
QI strategy. 
 
Proportion of clinicians who documented their plan-of-care for 
the patient in the response message to the anticoagulation staff. 
 
The number of clinicians who appropriately documented 
changes in antiplatelet drugs or PPI in the EHR medication list. 

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OBJECTIVES 
ENDPOINTS 
To explore process 
outcomes associated with 
the clinician notification + 
nurse facilitation 
implementation strategy 
For patients randomized to clinician notification + nurse 
facilitation: 
 
Number of days taken for clinicians to send a response 
message to anticoagulation staff after first receiving the clinician 
notification. 
 
Proportion of clinicians who documented their plan-of-care for 
the patient in the response message to the anticoagulation staff.  
 
Proportion of patients randomized to clinician notification + 
nurse facilitation for whom the anticoagulation nurse provided 
patient education. 
 
Proportion of patients randomized to clinician notification + 
nurse facilitation for whom the anticoagulation nurse pended the 
PPI order. 
To explore aspects of 
effectiveness of the 
implementation strategies. 
For anticoagulation clinic patients who meet inclusion criteria 
but are not randomized to a QI strategy in the pilot trial, whether 
or not they initiate PPI or discontinue antiplatelet therapy over 
the study period, as determined using electronic health record 
data, which will provide data on use of the evidence-based 
practices in usual care.  
  
For randomized patients, initiation of either a PPI or 
discontinuation of all antiplatelet therapy at week 5 (patient 
assessment #1), and at week 15-17 (patient assessment #3), as 
determined by patient interview. 
  
For randomized patients, the level of adherence to the 
recommended medication change (either PPI initiation or 
antiplatelet discontinuation) at week 15-17 measured using the 
Wilson questionnaire, as determined by patient assessment #3. 
  
Documentation of a recommendation by one of the patient’s 
Michigan Medicine clinicians to discontinue antiplatelet therapy 
or initiate a PPI as indicated by a clinical documentation or by a 
change in the EHR medication list, ascertained by EHR review. 
To explore the 
appropriateness of 
antiplatelet therapy used by 
patients at the time of study 
randomization. 
The clinical appropriateness of antiplatelet therapy at the time of 
study initiation, classified as either (probably guideline 
concordant, probably not guideline concordant, or uncertain), 
based on detailed chart review and in reference to practice 
recommendations (Appendix 1). 

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OBJECTIVES 
ENDPOINTS 
To explore the 
appropriateness of 
medication changes in 
antiplatelet therapy during 
the trial. 
For patients who either stopped antiplatelet therapy or initiated 
a PPI during the trial, to explore the appropriateness of 
antiplatelet management according to patient-reported use in 
patient assessment #3 at week 15-17. The clinical 
appropriateness of antiplatelet management will be determined 
according to pre-specified criteria (probably guideline 
concordant, probably not concordant, uncertain). See appendix 
1 for criteria. 
Additional objectives to be explored in qualitative interviews with patients, clinicians, and 
anticoagulation clinic staff: 
● Acceptability of the implementation strategy components 
● Perceptions of the implementation strategies 
● Barriers to successful implementation 
Please see associated interview guides. The interview guides used to complete patient, 
clinician, and anticoagulation clinic staff assessments will be iteratively revised throughout the 
pilot study, allowing initial findings from assessments to inform subsequent assessments and 
ensuring capture of all relevant information necessary for effective planning of the future clinic-
wide quality improvement trial.  
4.2 Objectives and Endpoints (Group 2) 
OBJECTIVES 
ENDPOINTS 
Primary Exploratory  
  
To explore perceptions of the 
QI strategies from the 
perspective of primary care 
clinicians. 
 
No quantitative endpoint. Clinician perceptions will be 
assessed qualitatively. 
Secondary Exploratory 
  
To explore aspects of 
effectiveness of the 
implementation strategies. 
For randomized patients, initiation of either a PPI or 
discontinuation of all antiplatelet therapy based on chart 
review at week 3. 
 
To explore the feasibility of 
delivering the patient 
activation tool 
The proportion of patients randomized to receive the 
activation guide who were sent the guide in the prescribed 
period of time, as determined by chart review.  
 

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OBJECTIVES 
ENDPOINTS 
To explore the feasibility of 
delivering the clinician-level 
QI strategies 
Proportion of patients whose clinician was sent the clinician-
level strategy by the anticoagulation clinic staff in the 
prescribed time period per the clinic protocol. We will also 
separately calculate this endpoint for the two levels of the 
clinician QI strategy. 
To explore process outcomes 
associated with the clinician 
notification + nurse facilitation 
implementation strategy 
For patients randomized to clinician notification + nurse 
facilitation: 
 
Number of days taken for clinicians to send a response 
message to anticoagulation staff after first receiving the 
clinician notification. 
 
Proportion of clinicians who documented their plan-of-care for 
the patient in the response message to the anticoagulation 
staff.  
 
Proportion of patients randomized to clinician notification + 
nurse facilitation for whom the anticoagulation nurse provided 
patient education. 
 
Proportion of patients randomized to clinician notification + 
nurse facilitation for whom the anticoagulation nurse pended 
the PPI order. 
To explore the feasibility of 
prompting patient-clinician 
communication about 
medication optimization 
The number of days after delivery of the clinician-facing QI 
strategy at which the patient and the target clinician (or their 
healthcare team) had communication (either by phone, in 
person visit, or portal message) about medication 
optimization, based on chart review. This will be calculated 
overall and separately for each QI strategy.  
 
For patients who had a communication with their clinician 
about medication optimization, the proportion in whom initial 
contact was made by the clinician vs. by the patient, 
according to chart review. This will be calculated overall and 
separately for each of the QI strategies. 
 
For patients who contacted a clinician about medication 
optimization, the specialty of the clinician and whether the 
clinician who was sent the clinician notification was the target 
clinician. This will be determined separately based on chart 
review. 
 
For patients who had communication with their clinician 
documented in the electronic health record, whether this 
occurred by phone, portal, or in-person/telehealth visit based 
on chart review. 

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OBJECTIVES 
ENDPOINTS 
 
To explore process measures 
associated with clinician 
notification 
For clinicians randomized to clinician notification: 
  
Number of days taken for clinicians to send a response 
message to anticoagulation staff after first receiving the 
clinician QI strategy. 
 
Proportion of clinicians who documented their plan-of-care for 
the patient in the response message to the anticoagulation 
staff. 
 
The number of clinicians who appropriately documented 
changes in antiplatelet drugs or PPI in the EHR medication 
list. 
 
 
To explore process outcomes 
associated with the clinician 
notification + nurse facilitation 
implementation strategy 
For patients randomized to clinician notification + nurse 
facilitation: 
 
Number of days taken for clinicians to send a response 
message to anticoagulation staff after first receiving the 
clinician notification. 
 
Proportion of clinicians who documented their plan-of-care for 
the patient in the response message to the anticoagulation 
staff.  
 
Proportion of patients randomized to clinician notification + 
nurse facilitation for whom the anticoagulation nurse provided 
patient education. 
 
Proportion of patients randomized to clinician notification + 
nurse facilitation for whom the anticoagulation nurse pended 
the PPI order. 
To explore aspects of 
effectiveness of the 
implementation strategies. 
For randomized patients, initiation of either a PPI or 
discontinuation of all antiplatelet therapy at week 3 as 
determined by chart review. 
 
Documentation of a recommendation by one of the patient’s 
Michigan Medicine clinicians to discontinue antiplatelet 
therapy or initiate a PPI as indicated by a clinical 
documentation or by a change in the EHR medication list, 
ascertained by EHR review. 
 

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OBJECTIVES 
ENDPOINTS 
To explore the 
appropriateness of 
antiplatelet therapy used by 
patients at the time of study 
randomization. 
The clinical appropriateness of antiplatelet therapy at the time 
of study initiation, classified as either (probably guideline 
concordant, probably not guideline concordant, or uncertain), 
based on detailed chart review and in reference to practice 
recommendations (Appendix 1). 
To explore the 
appropriateness of 
medication changes in 
antiplatelet therapy during the 
trial. 
For patients who either stopped antiplatelet therapy or 
initiated a PPI during the trial, to explore the appropriateness 
of antiplatelet management according to chart review at week 
3. The clinical appropriateness of antiplatelet management 
will be determined according to pre-specified criteria 
(probably guideline concordant, probably not concordant, 
uncertain). See appendix 1 for criteria. 
Additional objectives to be explored in qualitative interviews with clinicians:  
● Acceptability of the implementation strategy components 
● Barriers to successful implementation 
Please see associated interview guide. The interview guide used to complete clinician 
assessments will be iteratively revised throughout the pilot study, allowing initial findings from 
assessments to inform subsequent assessments and ensuring capture of all relevant 
information necessary for effective planning of the future clinic-wide quality improvement trial.  
 
5        STUDY DESIGN 
5.1      Overall Design 
 
This is a pragmatic, single center, feasibility pilot of a cluster randomized quality improvement 
trial with embedded individual randomization to evaluate implementation strategies to increase 
the use of evidence-based practices (EBPs) to reduce bleeding in patients who are using 
combination antithrombotic therapy and who are managed by the Michigan Medicine 
anticoagulation monitoring service. Two clinician-level strategies will be evaluated: (1) a clinician 
notification that identifies the patient as high-risk for upper GI bleeding and suggests 
discontinuing the antiplatelet agent or initiating a PPI; and (2) a clinician notification + nurse 
facilitation strategy in which a nurse undertakes multiple steps in an effort to overcome barriers 
to medication optimization. In addition, two patient-level strategies will be evaluated: (1) a 
patient activation tool; and (2) usual care. Clinicians will be cluster randomized, such that all the 
patients cared for by a single clinician will receive the same clinician-level notification. 

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Simultaneously, patients will be individually randomized to one of the two patient-level 
strategies. 
Since this is a pilot study to assess feasibility of delivering all QI implementation strategies and 
acceptability of the strategies, the study design may be modified during the study period if 
problems are identified. Any study design modifications will be submitted to the IRB at Michigan 
Medicine as study amendments and documented in the amendment section on page 6 of this 
document.  
 5.2  Scientific Rationale for Study Design 
The current study is a pilot quality improvement trial that will inform the design of a larger quality 
improvement trial with a similar design that will take place in the Michigan Medicine 
anticoagulation service in the near future. The justification for conducting the pilot study is to 
ensure that all study components can be feasibly executed. Indeed, it is recommended that pilot 
studies be undertaken prior to larger scale evaluations. 
There are several additional justifications for the study design. Both clinician notification, as well 
as mailed patient education and activation tools, are 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. The anticoagulation clinic has also produced and distributed materials for 
patients on self-management of nosebleeds. However, even though these clinician- and patient-
facing strategies are considered standard practices, it remains important for the clinic to 
understand whether such strategies are effective, and whether they justify the significant 
resource investment of the anticoagulation clinic staff. The study design will help to answer that 
question in the context of medication optimization to reduce upper GI bleeding. 
The study design selected, which can be classified as a factorial study design, is well suited to 
the objectives of this quality improvement trial because it will allow the simultaneous 
investigation of two important questions: (1) How a relatively simple notification message to 
clinicians (“clinician notification”) compares to a simple notification paired with additional steps 
by the anticoagulation nurse to facilitate medication optimization (“clinician notification with 
nurse facilitation”). Prior studies have shown that clinician alerts often have weak and 
inconsistent effects, justifying a more comprehensive clinician-level quality improvement 
strategy. However, the more comprehensive QI strategy is also more labor intensive for 
anticoagulation clinic staff, and so it is therefore important to know how effective it is. (2) How 
effective is a patient-level education and activation tool? While these tools are often used by the 
anticoagulation service, it is important to confirm their effectiveness and gain a better 
understanding of how patients use and perceive such tools.  
Patients will be cluster randomized within clinicians for the clinician-level QI strategy because if 
the same clinician received clinician notification for some of their patients and clinician 

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notification + nurse facilitation for others, this would likely cause some confusion about what 
services the clinician could expect to receive from the anticoagulation service for any individual 
patient. The justification for the individual level randomization for the patient level randomization 
is that it is the best design to make causal inference about the effect of the patient education 
and activation tool. 
Ultimately, this future large-scale cluster randomized trial will identify which combination of QI 
implementation strategies is most effective in reducing UGIB risk, and that strategy will be used 
in the future as a part of usual care by the anticoagulation service. 
5.3      Justification for Intervention 
Upper GI bleeding is a serious risk to patients who use combination antithrombotic therapy. 
However, both of the available evidence-based medication optimization strategies to reduce 
upper GI bleeding risk are underused.  
This trial will rigorously evaluate strategies that are used by the anticoagulation service to 
address safety issues that arise surrounding the safe use of warfarin. 
5.4   End-of-Study Definition 
 
5.4.1 Group 1  
Patient and anticoagulation clinic staff are considered to have completed the study after week 
28. 
Clinicians are considered to have completed the study 10 weeks after trial entry of the last of the 
patients within the clinicians’ cluster once they have completed the clinician interview (or decline 
to do so). 
5.4.2 Group 2  
Patient and clinician participants are considered to have completed the study after week 12.  
6        STUDY POPULATION 
6.1      Sample size 

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6.1.1 Group 1 
The target sample size for group 1 in the pilot study is 40-51 patients cared for by 12 target 
clinicians. See sample size determination (below) for a justification of the size. 
6.1.2 Group 2  
The target sample size for group 2 is 8-16 patients cared for by 8 target clinicians who 
specialize in primary care.  
 
6.2   Inclusion Criteria 
6.2.1 Group 1  
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: 
● 
 Practicing cardiologists at Michigan Medicine who in the prior year had a face-to-face or 
virtual visit with a patient who meets eligibility criteria for this study 
● 
 Practicing clinicians in any specialty who are designated as the clinician of record with 
the anticoagulation clinic for a patient who meets eligibility criteria 
For anticoagulation clinic staff: 
● Participated in the quality improvement project to deliver implementation strategies  
 
6.2.2 Group 2  
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 

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For clinicians: 
● 
 Practicing primary care or family medicine clinicians at Michigan Medicine who in the 
prior year had a face-to-face or virtual visit with a patient who meets eligibility criteria for 
this study 
6.3   Exclusion Criteria 
6.3.1 Group 1 
For patients: 
● 
 Age less than 18 
● Currently prescribed a PPI 
● Documented intolerance or allergy to PPI use 
● Left ventricular assist device 
● Heart transplant 
For clinicians: 
● Cardiologists specializing in electrophysiology unless they are the clinician of record for 
a patient followed by the anticoagulation service. 
For anticoagulation clinic staff 
● None 
6.3.2 Group 2  
For patients: 
● 
 Age less than 18 
● Currently prescribed a PPI 
● Documented intolerance or allergy to PPI use 
● Left ventricular assist device 
● Heart transplant 
For clinicians: 
● None 
6.4      Patient and Clinician Selection 

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6.4.1 Group 1 
At random, we will choose 12 Michigan Medicine clinicians who either serve as the cardiologist 
for (n=6), or the (non-cardiologist) clinician of record (n=6) for patients in the anticoagulation 
clinic. For each of these clinicians, we will include all of their patients who meet eligibility criteria 
based on chart review. We anticipate the number of included patients will be 40-51. 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. 
6.4.2 Group 2  
We will select a convenience sample of 8 Michigan Medicine clinicians who are the clinician of 
record for patients in the anticoagulation clinic and specialize in primary care from a 
convenience sample. For each of these clinicians, we will include all of their patients who meet 
eligibility criteria based on chart review. 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 
 
6.6.1 Group 1  
This trial will be conducted as a pragmatic quality improvement initiative in partnership with the 
Michigan Medicine anticoagulation clinic service. As knowledge of their participation in this 
study prior to receipt of the QI implementation strategies could result in unintended reactivity, in 
which the participant changes their behavior in response to knowing they are being observed, 
and harm the integrity of the study, patient and clinician participants will not be actively recruited 
for this study prior to delivery of the implementation strategies and no strategies will be used for 
participant retention. However, to complete the assessments for the study to evaluate the 
feasibility and acceptability of the Qi strategies, we will contact patients by phone up to 3 times 
over the period of 2 weeks to administer a brief 5-10 minute phone assessment to assess the 
accuracy of the electronic health record and determine whether the patient received the 
implementation strategies. Patient phone numbers will be obtained from the electronic health 
record and a voicemail will be left for the patient if they are unable to be reached at any of the 3 
contact attempts. The research team will also contact clinician and anticoagulation clinic staff 
participants at their institutional email address to invite them to participate in a one-time, hour 
long qualitative assessment to elicit feedback about their experience with the implementation 
strategies and feasibility of continuing the project. Clinician and staff email addresses will be 
obtained from Michigan Medicine departmental websites or the University directory.  

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6.6.2 Group 2 
This trial will be conducted as a pragmatic quality improvement initiative in partnership with the 
Michigan Medicine anticoagulation clinic service. As knowledge of their participation in this 
study prior to receipt of the QI implementation strategies could result in unintended reactivity, in 
which the participant changes their behavior in response to knowing they are being observed, 
and harm the integrity of the study, patient and clinician participants will not be actively recruited 
for this study prior to delivery of the implementation strategies and no strategies will be used for 
participant retention. The research team will, however, contact clinician participants at their 
institutional email address to invite them to participate in a one-time, hour long qualitative 
assessment to elicit feedback about their experience with the implementation strategies and 
feasibility of continuing the project. Clinician email addresses will be obtained from Michigan 
Medicine departmental websites or the University directory.  
 
7        STUDY QUALITY IMPROVEMENT 
STRATEGIES 
 
7.1      Study Implementation Strategy Administration 
7.1.1        Quality Improvement Strategy Descriptions 
All of the implementation strategies have been documented into clinical protocols approved by 
the anticoagulation clinic to address upper GI bleeding risk. All study QI strategies will be 
delivered by anticoagulation clinic staff as part of routine care. 
Two clinician-facing implementation strategies will be evaluated.  
1. Clinician Notification: An anticoagulation clinic nurse sends a templated message to 
the patient’s target clinician that points out the patient’s 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.  
2. Clinician Notification + Nurse facilitation: An anticoagulation clinic nurse sends a 
templated message to the target clinician, similar to the clinician notification strategy. 
However, the message also includes clinical details about the patient’s indication for 
antiplatelet therapy, ascertained by the nurse during chart review, and is intended to 
streamline decision-making by the clinician. In addition, the nurse will pend orders for 
medication changes if given instructions by the clinician and will communicate any 
recommendations to the patient on the clinician’s behalf.  

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In addition, two patient-facing implementation strategies will be evaluated: 
1. Patient Activation: A written guide to educate patients about their risk for bleeding and 
encouraging patients to talk with their clinician about medication changes to reduce their 
bleeding risk. This will be sent to patients through their preferred mode of 
communication (mail or patient portal). All patients will only be sent the guide once. 
2. Usual care: With usual care, the anticoagulation clinic will not send the patient activation 
guide or other project-specific materials to the patient. 
7.1.2        Administration and/or Dosing 
N/A 
7.2   Fidelity   
7.2.1        Anticoagulation Nurse Training 
Prior to the start of the study, the participating 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 electronic health record. 
This training is anticipated to be 90 minutes long.  
For anticoagulation clinic staff, the implementation strategies and how to perform them are 
additionally described in anticoagulation clinic protocol documents. 
7.2.2        Quality Improvement Strategy Delivery 
Anticoagulation clinic nurses will have pre-scripted messages to use as part of clinician-facing 
implementation strategies.  
Nurses will also have an example script available to use when talking with patients about 
medication changes. 
7.2.3        Quality Improvement Strategy Receipt & Enactment 
7.2.3.1 Group 1 
Chart review will be performed for all patients to ensure that they received the implementation 
strategies to which they were randomized. 
For patients randomized to the activation brochure, they will be questioned about receipt of the 
brochure, their understanding of the brochure and its purpose during patient assessment #2 at 
week 5-8.  

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7.3   Measures to Minimize Bias: Randomization and 
Blinding   
Assignment to one of two clinician-level QI strategies will be done at the cluster level according 
to the identity of the clinician to be contacted. The cluster of patients cared for by each 
anticoagulation clinic target clinician will be randomized 1:1 to get either clinician notification 
(CN) or clinician notification + nurse facilitation (CN+NF). Patients will also be individually 
randomized to receive the patient activation guide or to a usual care arm.   
Neither patients nor clinicians can practically be blinded. 
As this is a pragmatic, quality improvement trial, there is no intention to blind anticoagulation 
clinic staff or research team members to group assignment. 
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 
8.1.1 Group 1  
Use of the implementation strategies will be discontinued for patients who discontinue warfarin 
therapy or are closed to the anticoagulation clinic service during the first 5 weeks of study 
participation. Such patients will not be included in the analyses, and will not receive patient 
assessment #1, #2, or #3.  
For patients who discontinue warfarin or are closed to the anticoagulation clinic between week 5 
and the end of the study, they will be contacted for patient assessment #1 and #2 but not #3. 
They will be included in the analysis of the primary and secondary outcomes, as well as the 

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exploratory outcomes, except those related to patient assessment #3 (e.g., medication 
adherence, appropriateness of antiplatelet therapy at week 15-17). 
8.1.2 Group 2  
Use of the implementation strategies will be discontinued for patients who discontinue warfarin 
therapy or are closed to the anticoagulation clinic service during the first 3-5 weeks of study 
participation. Such patients will not be included in any analyses.  
8.2   Participant Discontinuation/Withdrawal from the 
Study 
8.2.1 Group 1 
Patients or clinicians who wish to discontinue any study interview will have the interview 
discontinued.  
8.2.2 Group 2  
Clinicians who wish to discontinue any study interview will have the interview discontinued. No 
patient outreach or assessments will be conducted with group 2 participants.  
8.3 Lost to Follow-Up   
8.3.1 Group 1  
If a patient is unable to be reached for assessment #1, #2, or #3, the data for the variables 
associated with that assessment will be coded as missing. If a patient is unable to be reached 
for assessment #1, no attempt will be made to reach them for assessment #2 or assessment 
#3. Even if patients are unable to be reached for assessment #1, #2, or #3, chart review will still 
be performed for that patient to evaluate the exploratory outcomes. 
8.3.2 Group 2  
Not applicable as no patient assessments will be conducted with group 2 participants. Chart 
review will be performed for patients in group 2 between study initiation and week 6.   
9  STUDY ASSESSMENTS AND 
PROCEDURES  
9.1      Eligibility Assessment 

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9.1.1 Group 1  
Before identifying eligible patients, the 12 participating clinicians will be selected at random. 
Next, the patients who fall into each clinician cluster, and who meet eligibility criteria, will be 
identified. These two tasks will be accomplished using a MiChart workbench report (previously 
developed by the anticoagulation clinic) that contains data on relevant eligibility criteria. All 
eligible patients and clinicians will be identified prior to commencement of the interventions. 
Each week, 8-10 patients from the list of eligible patients will enter into the study, after 
confirming that they still meet eligibility criteria. These patients will be added to a separate 
MiChart report for the participating anticoagulation clinic nurses, identifying the patients and the 
QI implementation strategies to which they have been randomized.  
9.1.2 Group 2  
A convenience sample of 8 primary care clinicians who meet eligibility criteria for group 2 will be 
selected . Next, the patients who fall into each clinician cluster, and who meet eligibility criteria, 
will be identified. These two tasks will be accomplished using a MiChart workbench report 
(previously developed by the anticoagulation clinic) that contains data on relevant eligibility 
criteria. All eligible patients and clinicians will be identified prior to commencement of the 
interventions. 
Each week, up to 12 patients from the list of eligible patients will enter into the study, after 
confirming that they still meet eligibility criteria. These patients will be added to a separate 
MiChart report for the participating anticoagulation clinic nurses, identifying the patients and the 
QI implementation strategies to which they have been randomized.  
 
9.2 Qualitative Assessments with Participants in Group 1  
Qualitative assessments will be conducted with clinicians, patients, and anticoagulation clinic 
staff to elicit feedback on the appropriateness and feasibility of the implementation strategies. 
Semi-structured interview guides have been developed to guide each assessment. These 
interview guides will be iteratively revised throughout the study to allow initial assessments to 
inform later assessments and ensure capture of all relevant information. 
9.2.1 Clinicians: 
One-time semi-structured qualitative interviews will be conducted with up to 12 clinicians who 
received communications from the anticoagulation clinic as part of this project. The interviews 
will be conducted 5-10 weeks after the last patient in the clinician-cluster entered into the study. 
Clinicians will be sent an invite to participate in an hour-long phone or zoom interview at their 
institutional email address by a research assistant. Clinicians will be offered a $100 gift card as 
an incentive for participation. Qualitative interviews with clinicians will focus on clinicians' 

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perceptions of the acceptability of the QI strategies and on feasibility of responding to the 
messages and initiating medication changes for GI bleeding risk reduction. Written informed 
consent will be obtained using SignNow software. 
9.2.2 Patients:  
● Patient Assessment #1 (Week 5): A research assistant will contact all patient 
participants by phone at week 5 to administer patient assessment #1, expected to take 
no more than 10 minutes to complete, with the patient’s permission. This questionnaire 
will ask patients about the medications they used ~30 days prior and the medications 
that they currently use. All patients will be asked whether they have had any changes in 
their medications in the past month, or if they have had a discussion with a healthcare 
provider about any medication changes or their risk of bleeding. Patients who were 
randomized to receive the activation tool will additionally be asked whether they recall 
receiving any educational materials about bleeding risk from the anticoagulation clinic to 
assess the feasibility of delivering patient education and activation materials. 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 MiChart message to the 
patient’s anticoagulation clinic nurse so that the nurse can reconcile the chart. No 
remuneration will be offered with this patient contact. We request a waiver of informed 
consent for patient contact #1. Data on the ability to reach patients for this 
evaluation will be used to assess the pilot trial’s primary outcome. Up to three 
contact attempts over a period of 2 weeks will be made to reach each patient for 
assessment #1. 
○ At the end of this call, patients who self-report having had a discussion with their 
clinician and those who were randomized to receive the patient activation tool will 
be invited to take part in a second 60-minute phone research interview within the 
next 3 weeks(patient assessment #2). All patients who complete assessment #1 
will additionally be invited to participate in another medication review call at week 
15-17 to assess durability of medication changes (patient assessment #3).  
● Patient Assessment #2 (Week 5-8): A research assistant will contact a subset of 
participants (as described above) to participate in an hour-long semi-structured 
qualitative phone or zoom interview for patient assessment #2. The interview will elicit 
patient perceptions about the patient activation tool and about any discussions the 
patient may have had with one of their clinicians about their risk of bleeding and/or ways 
to reduce that risk. Prior to the interview, patient’s will be provided with an informed 
consent document approved by the IRB at the University of Michigan and given the 
chance to ask any questions they may have. Patient’s will then be asked to provide 
verbal consent before the interview may begin. Patient’s will be advised that participation 
is entirely voluntary and choosing not to participate will not affect the care they may 
receive at Michigan Medicine. They will also be instructed that they can decline to 
answer any questions or end the interview at any time shall they wish. As all interviews 
will be conducted over the phone or zoom, and do not deal with sensitive or stigmatized 
subjects, we request a waiver of documentation of written informed consent for patient 

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assessment #2. Patients will receive a $20 gift card as remuneration for participating in 
this assessment. Patient remuneration will be sent through the University of Michigan 
treasurer’s office human subjections incentives payment program gift card payment 
option.    
● Patient Assessment #3 (Week 15-17): A brief 15-20 minute medication phone 
interview that asks patients about their use of antiplatelet drugs and PPIs at the time of 
the call, instructions they received from their clinician on how to use any of these 
medications, and about adherence to any antiplatelet drugs or PPIs the patient self-
reports using. 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 MiChart message to the patient’s anticoagulation clinic nurse so that the nurse 
can reconcile the chart. Prior to the interview, patient’s will be provided with an informed 
consent document approved by the IRB at the University of Michigan and given the 
chance to ask any questions they may have. Patient’s will then be asked to provide 
verbal consent before the interview may begin. Patient’s will be advised that participation 
is entirely voluntary and choosing not to participate will not affect the care they may 
receive at Michigan Medicine. They will also be instructed that they can decline to 
answer any questions or end the interview at any time shall they wish. As all interviews 
will be conducted over the phone, do not deal with sensitive or stigmatized subjects, we 
request a waiver of documentation of written informed consent for patient assessment 
#3. Patients will receive a $10 gift card as remuneration for participating in this 
assessment. Patient remuneration will be sent through the University of Michigan 
treasurer’s office human subjections incentives payment program gift card payment 
option.    
9.2.3 Anticoagulation clinic staff:  
One-time semi-structured qualitative interviews will be conducted with all anticoagulation clinic 
staff members who participated in the pilot project. Anticoagulation clinic staff members will be 
sent an invite to participate in an hour-long phone or zoom interview at their institutional email 
address by a research assistant at the conclusion of the pilot study. Interviews with staff will be 
conducted during normal work hours and anticoagulation clinic staff will not receive additional 
remuneration above their regular pay for participating in the research interview. Qualitative 
interviews with anticoagulation clinic staff will focus on eliciting staff members’ perceptions of 
the acceptability of the implementation strategies and on feasibility of delivering the 
implementation strategies to both patients and clinicians. Written informed consent will be 
obtained using SignNow software.  
9.3 Qualitative Assessments with Participants in Group 2  
Qualitative assessments will be conducted with clinicians to elicit feedback on their perceptions 
of the implementation strategies. A semi-structured interview guide has been developed to 
guide the assessment. The interview guide will be iteratively revised throughout the study to 

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allow initial assessments to inform later assessments and ensure capture of all relevant 
information. 
9.3.1 Clinicians: 
One-time semi-structured qualitative interviews will be conducted with up to 8 primary care 
clinicians who received communications from the anticoagulation clinic as part of this project. 
The interviews will be conducted 3-6 weeks after the last patient in the clinician-cluster entered 
into the study. Clinicians will be sent an invite to participate in an hour-long phone or zoom 
interview at their institutional email address by a research assistant. Clinicians will be offered a 
$100 gift card as an incentive for participation. Qualitative interviews with clinicians will focus on 
clinicians' perceptions of the acceptability of the QI strategies and on feasibility of responding to 
the messages and initiating medication changes for GI bleeding risk reduction. Written informed 
consent will be obtained using SignNow software. 
9.4      Assessment of the Primary Endpoint 
9.4.1 Group 1  
The primary endpoint, defined as the proportion of patients able to be contacted and willing to 
participate in patient assessment #1, will be determined based on up to three contact attempts 
with the patient over the course of 2 weeks. Patients will be counted as meeting the primary 
endpoint if they complete the entirety of assessment #1. A brief message stating the research 
assistant’s name and affiliation with the anticoagulation clinic and asking the patient to call back 
at the earliest convenience will be left for the patient if they do not answer the phone during any 
of the three contact attempts. 
9.4.2 Group 2 
N/A 
9.5      Assessment of the Secondary Endpoint 
9.5.1 Group 1 
The proportion of patients who received all implementation strategies to which they were 
assigned will be determined by EHR chart review in the 6 months following the trial. 
9.5.2 Group 2 
N/A 
9.6   All Other Study Assessments – Group 1 Assessment of all 
exploratory study endpoints will be performed by a research assistant using chart review or 
semi-structured interview assessments conducted by phone or zoom call with patients, 

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clinicians, and anticoagulation clinic staff. There will be no assessments that require physical 
exams, radiology, biological specimens or laboratory evaluations. 
9.6.1 Chart Review for Randomized Patients  
For each patient participating in the trial, review of the electronic health record will be performed 
by a research team member to ascertain documentation of delivery of the quality improvement 
strategy components, documentation of medication changes, documentation of contact between 
clinicians and anticoagulation staff, appropriateness of antiplatelet therapy prior to and after the 
QI strategies, as well as other variables required for evaluation of exploratory outcomes. 
To evaluate the appropriateness of antiplatelet therapy for randomized patients, a study team 
member who has training in internal medicine will conduct a detailed chart review for each 
patient. The team member will determine, first, whether the antiplatelet therapy initially 
prescribed was either probably appropriate, probably inappropriate, or uncertain, and second, 
whether continuation or discontinuation of antiplatelet therapy at the time of chart review was 
either probably appropriate, probably inappropriate, or uncertain.   
9.6.2 Chart Review for All Anticoagulation Clinic Patients who Meet 
Eligibility Criteria at Baseline 
For all patients who are enrolled with the anticoagulation clinic monitoring service at Michigan 
Medicine at the time of study initiation, review of the electronic health record will be performed 
by a research team member to determine (1) the total number of patients who meet eligibility 
criteria for the study, (2) the proportion of patients who met eligibility criteria at study initiation 
who discontinued warfarin therapy or were closed to the service during the study period, and (3) 
the number of patients who were eligible at study initiation and made one of the two medication-
optimization changes during the study period. This data will provide necessary information 
about the number of patients who may require medication optimization in the future full-scale 
trial and also about the use of evidence-based strategies to reduce upper GI bleeding risk in 
usual practice without use of the implementation strategies being tested. This data would be 
obtained using workbench reports developed specifically to identify patients at high-risk for 
upper GI bleeding and through review of the electronic health record for additional data when 
needed. As these assessments are of patients who were not randomized to a QI strategy in this 
pilot trial and this data will be used solely for assessing feasibility of a future larger scale trial, 
we are seeking a waiver of consent and a waiver of HIPAA authorization to obtain this data. 
9.7   All Other Study Assessments – Group 2 
Assessment of the primary exploratory endpoint will be completed by the research team using 
semi-structured interview assessments with primary care clinicians who received one of the 
clinician-level strategies for a patient they care for. Assessment of all secondary exploratory 
study endpoints will be performed by a research assistant using chart review. There will be no 

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assessments that require physical exams, radiology, biological specimens or laboratory 
evaluations. 
9.7.1 Chart Review for Randomized Patients  
For each patient participating in the trial, review of the electronic health record will be performed 
by a research team member to ascertain documentation of delivery of the quality improvement 
strategy components, documentation of medication changes, documentation of contact between 
clinicians and anticoagulation staff, as well as other variables required for evaluation of 
exploratory outcomes. 
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 CAT, 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 
11.1.1 Group 1 
The sample size was determined in consideration of the primary endpoint, which is the rate of 
participant recruitment and participation in assessment #1. With a sample size of 40, we will be 
able to estimate a recruitment rate of 80% to within a 95% confidence interval of +/- 13%, using 
normal approximation to the binomial calculation. 
11.1.2 Group 2  
N/A 
11.2 General Statistical Approach   
11.2.1 Group 1  
For the primary and secondary analyses, all participants who undergo randomization will be 
analyzed. Proportions with confidence intervals will be calculated. 

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11.2.2 Group 2  
For the primary and secondary exploratory analyses, all participants who undergo 
randomization will be analyzed. Proportions with confidence intervals will be calculated. 
11.3 Descriptives 
11.3.1 Group 1 
We will calculate descriptive statistics (means and proportions) for all patient variables. 
11.3.2 Group 2  
We will calculate descriptive statistics (means and proportions) for all patient variables 
obtainable through chart review.  
11.4 Hypotheses 
11.4.1 Group 1  
We hypothesize that the rate of participant recruitment and participation in assessment 1 (the 
primary endpoint) will exceed 66%.  
Similarly, we hypothesize that the rate of delivery of intended quality improvement strategies will 
exceed 66%.  
11.4.2 Group 2  
N/A for qualitative primary exploratory endpoint. 
11.5 Analysis of the Primary Endpoint(s) 
11.5.1 Group 1  
We will calculate the proportion of randomized patients that complete the patient assessment at 
week 5. We will estimate the confidence interval using the normal approximation to the binomial 
distribution. We will accept this hypothesis if the two-sided confidence interval (alpha=0.05) for 
the primary endpoint excludes 0.66. 
11.5.2 Group 2  
Qualitative analysis will be performed to explore clinician perceptions of the intervention 
strategies for the primary exploratory endpoint. 
11.6 Analysis of the Secondary Endpoint(s) 

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11.6.1 Group 1  
We will calculate the proportion of randomized patients that received all implementation 
components to which they were randomized in the appropriate time frame. We will estimate the 
confidence interval using the normal approximation to the binomial distribution. We will accept 
the hypothesis if the two-sided confidence interval (alpha=0.05) for the secondary endpoint 
excludes 0.66. 
 
11.7 Exploratory Analyses 
11.7.1 Group 1  
Exploratory analyses will mainly consist of descriptive analyses using cross-tabulations, means, 
standard deviations and proportions. The accuracy, positive predictive value, and negative 
predictive value will be calculated for antiplatelet use, PPI use, and “medication optimization” at 
multiple time points, comparing the EHR medication list to self-report (reference standard).  
11.7.2 Group 2  
Exploratory analyses will mainly consist of descriptive analyses using cross-tabulations, means, 
standard deviations and proportions. 
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 (Both Group 1 and Group 2) 
The types of quality improvement strategies (clinician notifications and patient educational 
handouts) described in this document are routinely used by the anticoagulation clinic as part of 
clinical care to improve the safety of patients using warfarin. The quality improvement strategies 
used in this pilot trial were 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 quality improvement strategies. 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 intent of the pilot 
quality improvement trial is to evaluate the feasibility of a large scale quality improvement 
project, which would not include informed consent, i.e., if patients were consented, the pilot 
would diminish the validity of the results. 
12.1.1.2 Patient assessment #1 (Group 1 only)  
Obtaining informed consent from patient and clinician participants prior to delivery of the 
implementation strategies could harm the integrity of the study by priming participants to 
respond to communications or notifications from the anticoagulation service or initiate a 
medication change for bleeding risk reduction.  
Patients and clinicians will not be consented prior to receipt of any implementation strategies 
delivered as part of the quality improvement project in an attempt to reduce reactivity and the 
Hawthorne Effect and ensure integrity of the study. Additionally, we request a waiver of 
informed consent for assessment #1 with patients. Patient assessment 1 will consist of a one-
time phone questionnaire anticipated to take 10 minutes or less to complete and 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 to assess whether the patient-facing 

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implementation strategy (activation tool) was received by the patient. Accurate patient 
medication information in MiChart and knowledge of whether the tool was received by the 
patient are necessary to correctly identify patients at high-risk for adverse events associated 
with warfarin use and ensure that patient education and activation materials can be delivered in 
a timely-fashion, and as such are in-line with quality improvement efforts. 
As consenting patients and/or clinicians prior to their randomization or receipt of the 
implementation strategies may result in unintended reactivity or the Hawthorne Effect which 
could harm the integrity of the study and influence study results, the study team will seek a 
waiver of informed consent from the IRB at the University of Michigan for patient assessment 
#1.  
12.1.1.3 Patient Assessment #2 (Group 1 only)  
Patients who, during patient assessment #1, self-report having had a conversation with a 
clinician about strategies to reduce bleeding risk or who were randomized to receive the patient 
activation guide will be invited at the end of assessment #1 to participate in patient assessment 
#2. Patients who agree to participate in assessment #2 will be provided with an IRB approved 
informed consent document prior to the interview and will be required to provide verbal consent 
to participate in the assessment before any interview questions are asked. Patients who agree 
to complete assessment #2 at week 5-8 will receive a $20 gift card as remuneration. 
Remuneration gift cards will be sent to patients by mail through the human subject incentives 
payment program. As these interviews will be conducted over the phone or zoom and will not 
deal with any sensitive or stigmatized subjects, the study team will seek a waiver of written 
informed consent from the IRB at the University of Michigan for patient assessment #2. Patients 
will not be required to consent to video or audio recording in order to complete assessment #2, 
though interviews will be recorded for all patients who do consent to audio or video recording.  
12.1.1.4 Patient Assessment #3 (Group 1 only)  
All patients who complete patient assessment #1 will be asked at the end of assessment #1 
whether the research team can contact them for a brief, 15-20 minute follow-up questionnaire 
approximately 10-12 weeks after assessment #1. Patients who agree to participate in 
assessment #3 at week 15-17 of the study will be provided with an IRB approved informed 
consent document prior to initiation of assessment #3  and will be required to provide verbal 
consent to participate in the assessment before any assessment questions are asked. Patients 
who agree to complete assessment #3 at week 15-17 will receive a $10 gift card as 
remuneration. Remuneration gift cards will be sent to patients by mail through the human 
subject incentives payment program. As this assessment will be conducted over the phone or 
zoom and will not deal with any sensitive or stigmatized subjects, the study team will seek a 
waiver of written informed consent from the IRB at the University of Michigan for patient 
assessment #3. Patients will not be required to consent to video or audio recording in order to 
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12.1.1.5 Clinician Qualitative Semi-Structured Interviews (Group 1 and 2)  
Any Michigan Medicine clinicians who participate in the research interview will be provided with 
an IRB approved informed consent document, reminded that their decision to participate or not 
participate will not impact their employment at Michigan Medicine in any way, given the 
opportunity to ask any questions, and asked to provide written informed consent using SignNow 
prior to the start of the interview. All clinician interviews will be completed during normal work 
hours at a time convenient to the clinician. Michigan Medicine clinicians will receive a $100 gift 
card incentive to promote participation in these semi-structured interviews. Remuneration gift 
cards will be sent to patients by mail through the human subject incentives payment program. 
12.1.1.6 Anticoagulation Clinic Staff Qualitative Semi-Structured Interviews (Group 1 
Only)  
Any anticoagulation clinic staff members who participate in this interview will be provided with 
an IRB approved informed consent document, reminded that their decision to participate or not 
participate will not impact their employment at Michigan Medicine in any way, given the 
opportunity to ask any questions, and asked to provide written informed consent using SignNow 
prior to the start of the interview All staff interviews will be held during normal work hours at a 
time that is convenient to the staff member. As this project is being done in collaboration with 
the anticoagulation clinic service and staff members are delivering the implementation strategies 
as part of normal clinic activities, no remuneration will be offered to clinic staff .  
12.1.1.7 Chart Review for Randomized Participants (Group 1 and 2)  
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.  
12.1.1.8 Chart Review for All Anticoagulation Clinic Patients who Meet Eligibility Criteria 
at Baseline (other than having a participating clinician) (Group 1)  
No outreach will be made to patient participants whose charts will be reviewed for this portion of 
the study and this data would solely be used to assist with planning for a future large-scale trial 
to test the same implementation strategies trialed in this pilot study. As review of patient’s charts 
to assess their bleeding risk with warfarin is a minimal risk to participants and the knowledge 
obtained from this data will be used to promote future patient safety efforts, a waiver of informed 
consent and a waiver of HIPAA authorization will be sought from the IRB. 
12.1.2 Consent Procedures and Documentation  
 
All patient participants will be required to provide verbal consent before beginning the patient 
assessment #2 or patient assessment #3 and will be provided with an IRB approved informed 
consent document for their records no later than 2 business days after the associated 

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assessment is completed. Michigan Medicine clinicians and staff members will be required to 
provide written consent using SignNow to participate in the qualitative semi-structured phone 
interviews prior to the start of the interview. An informed consent document will be provided to 
all participants prior to any of the aforementioned assessments, and this script will address the 
voluntary nature of participation, participants’ rights, the risks of participation, limits to 
confidentiality, and procedures for reporting complaints and/or adverse events to the 
investigators, the UM IRB, and the funding agency. Consent will occur over the phone or zoom 
with a trained study team member following reading of a comprehensive informed consent 
script. All participants will be given the opportunity to ask any questions or voice any concerns 
prior to participation and will be asked to provide verbal consent before any interview or 
assessment questions are asked. While a waiver of documentation of consent is sought from 
the IRB for patient assessments #2 and #3, documentation of the consent process will be 
entered into the RedCap database to allow the study team to track and verify that consent was 
obtained from all patients who participate in the research interview components of the study. 
A waiver of documentation of written informed consent for patient assessment #2 and patient 
assessment #3 is justified as the clinic provides all of its care to patients virtually and no patients 
are physically seen in the clinic to allow for written informed consent during a patient visit. 
Additionally, the clinic's patient population is generally older and less technologically savvy, 
resulting in concerns about the use of SignNow software for patient participants. The study team 
previously conducted a preliminary evaluation of the patient activation guide to be used in this 
study and recruited patients who used antithrombotic medications from the 
UMHealthResearch.org website to participate in semi-structured zoom interviews in which the 
patient was provided with the activation guide and asked to provide feedback on the guide by 
"thinking aloud". During this study, the research team found that despite recruiting from the 
UMHealthResearch.org site where participants were generally more technologically savvy as 
they had to use the internet and complete screening questions to indicate their interest in 
participating, it was difficult for many of the participants to use the SignNow software. Many of 
the participants in the prior study either could not figure out how to complete the consent form 
on SignNow, while others were able to complete the form but incorrectly filled out certain lines 
(i.e., patient entered correct month and date for birthday, but left the current year [2021] in the 
birth date line), requiring the team to re-do consent multiple times and placing a burden on the 
patient. Due to difficulties encountered with the consent process, some participants ended up 
not completing the interview. We believe that a waiver of written informed consent for patient 
assessments #2 and #3 will allow the study team to obtain a better response rate and prevent 
any unnecessary burden on the behalf of the patients being contacted. 
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. During the 
conduct of the observational study, an individual participant can choose to withdraw consent to 
have their data stored for future research. 

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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 from other researchers 
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 
jkurland@umich.edu 
12.5 Clinical Monitoring 
N/A 
12.7 Data Handling and Record Keeping 
The source materials will include self-report questionnaires completed during phone encounters 
and audiotapes of qualitative interviews. Each study subject will be given a unique numeric 
identifier upon study entry. We will have audiotapes transcribed, and any identifying information 

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will be removed. 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 as long as 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.  
12.8 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 to ensure accurate 
interpretation of the data. 
12.9 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.  
12.10  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 
as any noncompliance with the clinical trial protocol, related only to the research evaluation 
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. Since the proposed research is a formative pilot study that will inform the design of a 
future larger quality improvement trial, the design of the pilot may be modified during the study 
period if feasibility issues are identified early on. 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 on page 6 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 

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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 assessments.  During each assessment, 
the study team member conducting the phone or zoom call will ask the participant whether they 
have experienced any negative reactions or adverse events since the time when they entered 
the study and document and review any reported events with the PI. 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 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. Any participants who complete patient assessment #1 but not 
any further assessments will be considered lost to follow-up and no data will be recorded for 
future assessments for that participant, though chart review may still be completed to assess 
appropriateness of antiplatelet therapy unless the participant explicitly requests that their data 
not be accessed. Data completeness is one outcome for this feasibility pilot trial and will be 
evaluated at the end of the study period.  

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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  
● Obtaining informed consent from participants 
● Collection of study data through chart review, patient 
surveys, and qualitative interviews  
● 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  
● Obtaining informed consent from participants 
● Collection of study data through chart review, patient 
surveys, and qualitative interviews  
● 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  
● Obtaining informed consent from participants 
● Collection of study data through chart review, patient 
surveys, and qualitative interviews  
● 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 

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been randomized  
● Perform statistical analyses  
● Develop and present routine reports throughout the trial 
period for review by the DSMP 
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 anti-platelet 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 
1 

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PCI for 
stable 
CAD 
PCI 6-12 months 
ago 
Continue antiplatelet drug 
Consider switch to 
aspirin 81mg 
PCI >12 months 
ago 
Stop antiplatelet drug 
  
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 
Stop antiplatelet drug 
  
Treatment of coronary artery disease with venous thromboembolism (VTE) 
PCI for 
stable 
CAD 
PCI <3 months 
ago 
Continue antiplatelet 
Clopidogrel preferred 
1 
PCI 3-6 months 
ago 
Continue antiplatelet drug 
-Clopidogrel preferred 
-Consider stopping 
anticoagulant if reversibly 
provoking risk factors 
PCI >6 months 
ago 
Continue antiplatelet drug 
-Consider switch to 
aspirin 81mg 
-Consider stopping 
anticoagulant if reversibly 
provoking risk factors 
PCI >12 months 
ago 
Stop antiplatelet drug 
-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 
ACS +/- PCI <3 
months ago 
Continue antiplatelet drug 
Clopidogrel preferred 

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syndrome 
(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 
Stop antiplatelet drug 
-Consider stopping 
anticoagulant if reversibly 
provoking risk factors 
Cerebrovascular disease 
History of TIA, CVA, or CEA 
Stop antiplatelet drug 
  
1 
Carotid stent ≤ 3 months ago 
Continue antiplatelet drug 
Clopidogrel preferred 
Carotid stent > 3 months ago 
Stop antiplatelet drug 
  
Peripheral arterial disease 
Endovascular intervention or 
surgical repair ≤ 1-3 months 
ago 
Continue antiplatelet drug 
Clopidogrel preferred 
1 
Endovascular intervention or 
surgical repair > 1-3 months 
ago 
Stop antiplatelet drug 
  
Valve replacement 
Mechanical Heart Valve 
Stop antiplatelet drug 
unless another indication is 
present 
  
2 
Bioprosthetic Heart Valve    ≤ 
3 months ago 
Continue aspirin 81mg 
only if high 
thromboembolic risk 
  
Bioprosthetic Heart Valve    > 
3 months ago 
Stop aspirin 
  
TAVR ≤ 3 months 
Continue antiplatelet drug 
only if high 
thromboembolic risk 
  
3 
TAVR > 3 months 
Stop antiplatelet drug 
  

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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 
  
  
PCI=Percutaneous coronary intervention. 
 
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 
15  ABBREVIATIONS AND SPECIAL 
TERMS 
Abbreviation 
Term 
CAT 
Combination Antithrombotic 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 

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IRB 
Institutional Review Board 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
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 
  
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Lamberts M, Staerk L, Olesen JB, et al. Major Bleeding Complications and Persistence 
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