Conditions: Bleeding Complications
Keywords: Antiplatelet medications Blood thinners Stent thrombosis Percutaneous Coronary Intervention
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 98
Healthy volunteers: no

Brief summary:
The goal of this research is to show that a shorter duration of two antiplatelet medications (compared to the standard of care) is safe and effective while reducing the risk of bleeding complications. Bleeding complications can cause significant problems (hospitalizations, need for blood transfusions, and even death) for patients on antiplatelet medications after coronary stents. Researchers hope to show that reducing the time on two antiplatelet agents in patients at high risk for these bleeding complications will reduce the number of bleeding events while not causing any increase in cardiovascular complications (heart attack, stent malfunction, death).

Detailed description:

Arms:
arm 1: Subjects with high bleeding risk (HBR) on dual antiplatelet therapy (DAPT) with clopidogrel and aspirin, that have undergone successful percutaneous coronary intervention (PCI) will be stratified by the CYP2C19 loss-of-function (LOF) allele within one week of DAPT initiation. In this group, subjects identified as CYP2C19\*2 or\*3 LOF allele carrier will be given prasugrel or ticagrelor monotherapy. arm 2: Subjects with high bleeding risk (HBR) on dual antiplatelet therapy (DAPT) with clopidogrel and aspirin, that have undergone successful percutaneous coronary intervention (PCI) will be stratified by the CYP2C19 loss-of-function (LOF) allele within one week of DAPT initiation. In this group, subjects identified as CYp2C19\*2 or\*3 LOF allele non-carriers will continue with clopidogrel monotherapy.

Interventions: intervention 1: Clopidogrel intervention 2: Prasugrel intervention 3: Tricagrelor
Intervention descriptions: intervention 1: 75 mg/day intervention 2: 60 mg bolus then 10 mg daily intervention 3: 180 mg bolus then 90 mg twice daily

Protocol document:
Prot_SAP_001.pdf: 
 
 
Clopidogrel Monotherapy in High Bleeding Risk 
Patients Undergoing Percutaneous Coronary 
Interventions: 
A Safety Assessment, Pilot Study to Reduce 
Post-Discharge Bleeding 
 
NCT05223335 
 
May 1, 2023 


1 
 
Clopidogrel Monotherapy in High Bleeding Risk Patients Undergoing Percutaneous Coronary Interventions: 
A Safety Assessment, Pilot Study to Reduce Post-Discharge Bleeding 
 
CHAMP Study: Clopidogrel with High bleeding risk and Adverse events with Monotherapy in patients undergoing 
Percutaneous coronary interventions 
 
 
Short Title: 
 
 
Clopidogrel monotherapy in patients with high bleeding risk 
 
Co-Investigators  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mandeep Singh, MD, MPH1 [Principal Investigator and Mentor] 
 
 
Affiliations:  
 
 
Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota (1) 
Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota (2) 
Lab Genetics and Genomics, Mayo Clinic, Rochester, Minnesota (3) 
 
Corresponding Author:  
Mandeep Singh, MD, MPH 
Mayo Clinic, 200 First Street SW, Rochester, MN 55905. 
Tel: 
 
  
 
 
 
Fax: 
  
Email: Singh.Mandeep@Mayo.edu 
 
Disclosures: 
 None. 
 
Key words:  
 
 
Stent thrombosis, percutaneous coronary intervention, bleeding 
 
Protocol Number (IRBe)  
21-011053 
 
Initial version: November 2, 2021 Version (1.0)  
Revised: 
January 10, 2022 Version (2.0) 
Revised: 
April 12, 2022 Version (3.0) 
Revised: 
September 13, 2022 Version (4.0) 
Revised: 
May 1, 2023 Version (5.0) 
 
 
 


 
2 
 
Proposal Summary 
Clopidogrel Monotherapy in High Bleeding Risk Patients Undergoing 
Percutaneous Coronary Interventions: A Safety Assessment, Pilot Study to Reduce 
Post-Discharge Bleeding 
 
CHAMP Study: Clopidogrel with High bleeding risk and Adverse events with Monotherapy in 
patients undergoing Percutaneous coronary interventions 
 
What We Know 
• 
High bleeding risk is common (30%) among patients undergoing PCI at Mayo Clinic, Rochester. 
• 
Most bleeds occur within 30 days of PCI. 
• 
Current studies analyzing shortened DAPT regimens exclude the crucial first 30 days. 
 
What This Study Adds 
• 
Genotype-based stratification of patients receiving antiplatelet therapy after PCI.  
• 
Evaluation of the safety and efficacy of clopidogrel monotherapy with deescalation from DAPT within the first week. 
• 
Clopidogrel monotherapy provides an inexpensive regimen with lower bleeding risk compared to alternative agents and 
regimens. 
• 
First study to evaluate antiplatelet monotherapy within 7 days of PCI. 
 
 
 


 
3 
 
Post-discharge bleeding (PDB) with dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary interventions 
(PCI) is associated with increased morbidity and mortality.1-5 Approximately 1 in 20 post-PCI patients following DAPT are readmitted 
for bleeding, with the highest incidence occurring within 30 days of discharge. Patients with PDB are also at increased risk for 
subsequent death or myocardial infarction (MI), with the highest risk occurring within the first 60 days after a bleeding-related 
hospitalization.6, 7 The bleeding hazard further increases with newer P2Y12 inhibitors and oral anticoagulants. The risk of bleeding is 
modifiable and attempts at reduction in PDB provides an opportunity to improve safety of PCI. In that regard, reduction in PDB has 
been demonstrated following early aspirin discontinuation and shortened DAPT duration. The Ticagrelor with or without Aspirin in 
High-Risk Patients after PCI (TWILIGHT) trial demonstrated a doubling of major bleeding risk in patients randomized to ticagrelor 
with aspirin as compared to ticagrelor alone without an increase in ischemic endpoints with ticagrelor monotherapy.8 More recently, 
two randomized trials demonstrated the safety of P2Y12 monotherapy (mainly clopidogrel) following one and three months of DAPT 
in low-risk patients receiving drug-eluting stents (DES).9, 10 Similarly, Acetyl Salicylic Elimination Trial (ASET) confirmed the safety 
of prasugrel monotherapy following DES in stable coronary artery disease.11 These studies excluded patients with high bleeding risk 
(HBR), however, the results were consistent in demonstrating reduction in PDB without any increase in the ischemic events. The 
MASTER DAPT trial demonstrated noninferiority of 1 month of DAPT in HBR patients compared to standard DAPT for 2 or more 
months in terms of net adverse events and major cardiac/cerebral ischemic events. There was also a lower rate of major or clinically 
significant minor bleeds in the group receiving only a month of DAPT.12 
 
Approximately 15% patients undergoing PCI have HBR and are generally excluded or underrepresented in the DES trials.13, 14 These 
patients will benefit from shorter duration of DAPT. However, contemporary clinical trials are done with newer stent designs 
(polymer-free)13 include older adults with no inclusion criteria that denote HBR15 or have prespecified subgroup with HBR16 
significantly limiting the generalizability. The decline in the rates of stent thrombosis with newer generation stents coupled with 
paucity of data to guide clinical decision-making in this high-risk group highlights the importance to develop simple treatment 
protocols to lower their bleeding risk. Early bleeding hazard with aspirin coupled with time-dependent increase in major bleeding 
events underscores the need to aggressively deescalate DAPT, albeit not at the expense of heightened ischemic risk. Such reduction in 
concomitant ischemic events can be achieved with genotype guidance. A post-hoc analyses of TAILOR PCI demonstrated an almost 
80% risk reduction for ischemic events with genotype guidance in the first 3 months after PCI, the highest risk period following PCI. 
Potential advantages of genotype-guided P2Y12 inhibitor therapy in which a large number of patients receive clopidogrel (given an 
approximate 50% to 70% prevalence of CYP2C19 noncarriers) and the remainder receive more potent alternative P2Y12 inhibitors is 
lower cost and lower risk for bleeding for this group as compared with patients receiving either ticagrelor or prasugrel. Furthermore, 
reduction in ischemic events with newer P2Y12 inhibitors could only be demonstrated among CYP2C19 loss-of-function (LOF) 
carriers, underscoring the utility of upfront genetic testing prior to routine DAPT prescription in patients with HBR undergoing PCI. 
Our specific aims of the present pilot and safety study are: 
Specific Aim 1: Test the hypothesis that clopidogrel monotherapy is safe following successful PCI among 100 consecutive patients 
with HBR and meeting the inclusion criteria (100 active patients, excluding patients who have been enrolled then withdrawn for 
various reasons such as starting an additional blood thinner, patient preference, etc.). To ensure that we have data on 100 active 
patients that complete their 1 month visit, we will plan to accrue up to 150 patients. The primary safety end point will be showing 
noninferiority of clopidogrel monotherapy in reducing ischemic events stratified by presence or absence of CYP2C19 LOF allele 
(QuantStudio with Chemagic DNA extraction). All patients will receive clopidogrel (600 mg load & 75 mg maintenance) and aspirin 
(324 mg load & 81 mg maintenance) for the first week. Those with CYP2C19  *
2 
or
 *
3 
LOF allele (CYP2C19 LOF carriers)] will be 
prescribed prasugrel or ticagrelor [prasugrel 60 mg load, maintenance 10 mg or 5 mg (for patients ≥ 75 years or < 60 kg) daily or 
ticagrelor 180 mg load, maintenance 90 mg twice daily (dose escalation with bolus will occur regardless of the timing of the last 
clopidogrel dose)]. Non-carriers (or those with inconclusive results) will continue with clopidogrel 75 mg daily maintenance dose. 
Aspirin will be stopped in all patients once CYP2C19 results are available. 
Specific Aim 2: Among participants enrolled in aim 1, aim 2 will determine the incidence of BARC 3 or 5 bleeding events. Other 
secondary endpoints are post-dismissal all-cause death, any MI up to 180 days, repeat revascularization, or any other BARC bleeding 
episodes.  
 
SIGNIFICANCE 
Reduction in PDB following PCI is a Major Unmet Need: PDB is common and is seen in approximately 5%; and 20% of those bleeds 
manifest in the first month following PCI. The increase in complexity of patients undergoing PCI and the concerns for late stent 
thrombosis led to prolongation of duration of DAPT following PCI. Coincidentally, patients with HBR were excluded, 
underrepresented, or were given bare metal stents. Recent trials have demonstrated superiority of DES over bare metal stents in 
patients with HBR and showed safety and efficacy of one-month DAPT. The duration of DAPT for at least 30 days, even among HBR 
patients, is still the standard of care even as most bleeding risk following PCI resides within the first month. Further reduction in 
duration of DAPT needs to be carefully weighed against heightened ischemic risk, especially among patients presenting with acute 


 
4 
 
coronary syndrome. The challenges in defining the optimal management of HBR patients undergoing PCI include heterogeneity in its 
definition and paucity of relevant clinical data.  
Proposed Strategy to Reduce PDB through Genotype-Guided Clopidogrel Monotherapy: Reduction in the ischemic risk with current 
generation of DES, modulation of atherothrombotic risk with guideline-directed therapy and shift in patient case-mix towards greater 
noncardiac morbidity and mortality have identified strategies to lower bleeding without compromising anti-ischemic efficacy. In that 
regard, trials have shown superiority and safety of DES over bare metal stents with 1 month of DAPT. Most PDB occurs early and 
underscores the need to abbreviate further the duration of DAPT. More recently, aspirin-free prasugrel therapy following successful 
stenting in patients with stable coronary artery disease has demonstrated safety. The limitations of that pilot study were use of 
prasugrel that is associated with higher bleeding (1 patient died with massive intracranial bleed), inclusion of only stable CAD, and no 
genotype guidance. Our study is a natural, provocative iteration of aspirin-free, clopidogrel monotherapy guided by genotype 
stratification and will include participants with ACS. 
Proposed Strategy to Reduce Ischemic Hazard: Cardiac mortality due to MI dominates in the first week after PCI, and the mortality 
risk is relatively high for 2 weeks after PCI.17 The risk of acute or subacute stent thrombosis with current generation stents is low. 
Utilization of CYP2C19 genotype–guided prescription of oral P2Y12 inhibitor therapy after PCI may improve that ischemic risk by 
individualizing antiplatelet therapy according to the CYP2C19 LOF allele status.18, 19 The potential benefit of this precision medicine 
approach by individualizing antiplatelet therapy may be more relevant early after PCI. In a post hoc analysis from the TAILOR-PCI, 
80% risk reduction in ischemic events with genotype-guided oral P2Y12 inhibitor therapy was seen in the first 3 months after PCI.20 
High prevalence (50%-70%) of non-carriers of CYP2C19 allows very early deescalation into clopidogrel monotherapy in most patients 
with HBR and tailors newer P2Y12 inhibitors with higher bleeding risk only to patients with CYP2C19 LOF allele. PDB and ischemic 
PCI data will be actively monitored and entered from same number of controls deemed to have HBR. The central goal of our proposal 
is to address the unmet need of an effective P2Y12 inhibitor protocol among patients with HBR who undergo PCI to lower their 
incidence of PDB by leveraging the information from their CYP2C19 genotype. This will allow individualizing antiplatelet treatment 
while potentially lowering their bleeding and ischemic hazards. 
 
APPROACH: Methodology – General Methods 
1. Design Overview. For Aim 1, up to 150 participants with HBR on DAPT with clopidogrel and aspirin, who have undergone 
successful PCI will be stratified by the CYP2C19 LOF allele within one week of DAPT initiation. If present, participants will be 
given prasugrel or ticagrelor monotherapy, and non-carriers will continue with clopidogrel monotherapy. The primary safety 
endpoint will be a composite of post-dismissal cardiac death/spontaneous MI <30 days or stent thrombosis <90 days of discharge. 
For Aim 2, the same subjects will undergo post-dismissal assessment for BARC 3 or 5 bleeding, all-cause death, any MI, and/or 
repeat revascularization up to 180 days. Informed consent followed by genotype assessment will be obtained prior to discharge. 
Loading dose of clopidogrel (600 mg) will be given to all patients and maintenance dose of 75 mg daily will be given, as 
indicated. We will allow patients to be given loading dose (324 mg) of aspirin either before or at the time of PCI. The choice of 
stents, access site and treatment site will be at the discretion of the treating physician (Figure 1).  
2.  Clopidogrel and prasugrel/ticagrelor administration. This study will be single-center, single-arm, open label, first-in-human, and a 
proof-of-concept, pilot and safety 
study. All participants in the first 
week will receive clopidogrel bolus 
(600 mg) and maintenance (75 mg) 
and aspirin bolus (324 mg, if not on 
aspirin) and 81mg maintenance. 
Participants with HBR who meet the 
inclusion criteria will be stratified by 
CYP2C19 LOF allele. Non-carriers 
(or those with inconclusive results) 
will continue with maintenance dose 
of clopidogrel monotherapy at 75 mg 
daily. If LOF allele is present, they 
will be prescribed either prasugrel or 
ticagrelor monotherapy [prasugrel 60 
mg load, maintenance 10 mg daily; 
ticagrelor 180 mg load, maintenance 
90 mg twice daily; dose escalation 
with bolus regardless of timing of the 
last clopidogrel dose]. Prasugrel will be the preferred agent except when absolutely contraindicated (history of stroke/transient 
ischemic attack or active bleeding). Patients ≥ 75 years or < 60 kg will receive prasugrel at a reduced dose of 5 mg daily. If there is 


 
5 
 
a relative contraindication to prasugrel (as determined by the treating physician), the participant will be given ticagrelor. 
Maintenance aspirin will be discontinued in both arms once genotype testing has been confirmed. (Figure 1). 
3. Medication adherence, provision of prasugrel/ticagrelor and follow-up: Each enrolled participant will be carefully followed, pre-
dismissal education about medication compliance and potential switch to prasugrel or ticagrelor will be given to each participant. 
A phone call by the study coordinator informing the participant about the results of genotype will be made within the first week of 
PCI. Study coordinator will mail 3-month supply of prasugrel or ticagrelor to patients with CYP2C19 LOF allele and contact them 
for the receipt of the medication and will instruct initiation of the loading and maintenance dose. The number of remaining tablets 
(pill count) at 3-month follow-up will be counted and recorded to assess adherence using a drug accountability report at 3 months. 
Non-carriers will continue clopidogrel monotherapy. Our main aim is to ensure safety of the participants. Close monitoring and 
follow-up of each patient will be done. Study-related events will be assessed by the study coordinator at hospital discharge and at 
1 and 3 months after PCI by telephone. If patients could not be reached by telephone after multiple attempts, the site coordinator 
will conduct a medical record review to assess follow-up. All cardiovascular-related end points and hospitalizations will be 
reviewed and adjudicated by an independent committee blinded to study groups and P2Y12 inhibitor received by the patient. Only 
study-related events confirmed by the adjudication committee will be included in the analysis. 
4. Trial Duration: 90 days. This is based on the observations that the highest bleeding and ischemic risk following PCI is within first 
90 days. Importantly, a post-hoc analysis demonstrated an almost 80% risk reduction for ischemic events with genotype guidance 
in the first 3 months after PCI. 
5. Definitions and Role of Data and Safety Monitoring Board (DSMB): All deaths will be considered cardiac unless a clear 
noncardiac cause can be ascertained. Spontaneous MI will be defined according to the fourth universal definition.21 Periprocedural 
MI (< 48 hours post-PCI) will be defined according to the 2013 definition of the Society for Cardiovascular Angiography and 
Interventions.22 Stent thrombosis will be defined and classified according to the Academic Research Consortium–2 definition.23 
BARC bleeding will be defined as previously reported.24 All endpoints will be independently adjudicated by the clinical event 
committee. An independent DSMB will oversee the individual and collective safety of the patients in the study during enrollment 
and follow-up. To provide the steering committee with timely feedback on potential safety issues, the DSMB will review the data 
3 times during the trial: (1) When the 25th patient is enrolled, (2) when the 50th patient is enrolled, (3) when the 100th patient is 
enrolled, and (4) when the 100th actively enrolled patient completes 1-month follow-up.  
6. Subjects 
a) Inclusion Criteria: Informed consent after successful 
PCI [no non-fatal MI/stroke/repeat target 
revascularization/bleeding/acute kidney injury] and 
academic research consortium-high bleeding risk (ARC-
HBR) score ≥4. 
b) Exclusion Criteria: Chronic use of warfarin or direct oral 
anticoagulant (DOAC), unsuccessful PCI (see above), 
lesions with angiographic thrombus, prior PCI within 6 
months (except for staged PCIs within the same 
hospitalization or within 7 days of initial PCI, in which 
case enrollment will occur following the final 
planned/staged PCI), planned PCI greater than 7 days but 
less than 6 months following index PCI,  planned 
surgical intervention to treat any cardiac or noncardiac 
condition within 6 months (excluding transcutaneous 
valve interventions and pacemakers), high risk 
lesion/stent characteristics (>50% unprotected left main 
disease, bifurcation disease requiring 2 stents technique, 
rotational atherectomy, vein graft, unprotected left main 
intervention, or history of definite stent thrombosis), 
women of child-bearing age unless negative pregnancy 
test is done, life expectancy <1 year, known drug/alcohol 
dependence, and assessment that the patient will not be 
compliant with the study protocol. 
c) Subject Accrual Plan: The recruitment will be drawn 
from the Earl Wood Cardiac Catheterization Laboratory 
(>1,500 PCIs/year) and Cardiology inpatient services at 
St. Mary’s Hospital. Day 1 will include screening 
following successful PCI, bleeding risk calculation 
(ARC-HBR), enrollment, informed consent, and clinical 
CYP2C19 assay collection. On day 30, a study 
coordinator phone call will occur to assess ischemic 
symptoms, readmission, and bleeding. On day 90, a 
study coordinator phone call will again assess ischemic 
symptoms, readmissions, and bleeding. All encounters 
will include drug education and assurance of 
compliance. 
d) Reassessment: The study coordinator will make phone 
calls at one and three months to inquire about ischemic 
symptoms, readmissions at other hospitals with MI, or 
any bleeding. 
 
7. Control Cohort: A cohort of similar patients will be identified from the Mayo Clinic catheterization laboratory PCI 
registry to determine rates of ischemic and bleeding events in a cohort of HBR post-PCI patients reveiving standard of 
care DAPT after PCI. These patients will be identified by registry review, and we will utilize ICD diagnosis codes to 
identify bleeding and ischemic events. Retrospective chart review will verify the clinical situation to ensure the validity 
of the coded diagnoses (to minimize errors inherent to diagnosis coding). There will be no direct patient contact, and 
patients who refused registry research participation will be excluded from this study. We aim to obtain the following 


 
8 
 
data: 
 
A. Events 
• 
Event type (category below); diagnosis codes selected from Mayo Clinic database of ICD codes 
(https://intranet.mayo.edu/charlie/quantitative-health-sciences-groups/rochester-epidemiology-
project/index-of-possible-codes-for-specific-conditions-diseases/) 
• 
Date of ischemic/bleeding event 
• 
Bleeding Categories 
o 
Hemorrhage, gastrointestinal 
o 
Stroke (hemorrhagic) 
o 
Disease, cerebrovascular (hemorrhagic) 
o 
Hematuria 
• 
Ischemic Categories 
o 
Infarction, myocardial 
o 
Disease, cerebrovascular (TIA, ischemic stroke) 
 
B. Inclusion 
• 
Successful PCI 
• 
Approx. 1 year date range TBD (n = 1500 patients; targeting contemporary PCI patients within the last 2 
years). 
 
C. Exclusion 
• 
Enrolled in CHAMP Trial 
 
D. Demographic/Procedure Info to Capture from PCI Registry 
• 
Age/DOB 
• 
Sex 
• 
Race 
• 
Event type (STEMI, NSTEMI/unstable angina, chronic CAD) 
• 
PCI date 
• 
Hemoglobin at time of PCI 
• 
Hemoglobin at time of bleeding event (obtain from chart review; not available in registry) 
• 
Creatinine and eGFR at time of PCI 
• 
Use of clopidogrel, prasugrel, ticagrelor 
• 
Use of oral anticoagulant (warfarin, apixaban, rivaroxaban) 
 
Aim 1: Detailed Approach 
The objective of aim 1 is to determine 
if clopidogrel monotherapy following 
successful PCI is safe among non-
carriers of CYP2C19 LOF allele. The 
hypothesis is that carriers of CYP2C19 
LOF genotype are unable to 
metabolize clopidogrel effectively to 
an active drug that blocks P2Y12 
receptors and inhibit platelet 
aggregation and are therefore at 
heightened ischemic risk following 
PCI. We will reduce bleeding risk by 
giving clopidogrel monotherapy only 
to non-carriers. Our approach to test 
this hypothesis is stratifying HBR 
patients after successful PCI into those 
with CYP2C19 LOF allele and those 
with inconclusive results or who are 


 
9 
 
non-carriers. Within first week of DAPT initiation, non-carriers will receive clopidogrel monotherapy, and prasugrel/ticagrelor 
will be given to patients with CYP2C19 LOF allele. The rationale for this aim is to individualize antiplatelet therapy and to 
reduce bleeding risk by stratifying P2Y12 pharmacotherapy by the CYP2C19 LOF genotype. Large number (50%-70%) of 
patients are non-carriers and in them clopidogrel monotherapy would suffice and the remainder will receive prasugrel or 
ticagrelor thereby lowering bleeding risk, cost, and unique adverse effects related to ticagrelor (e.g., bradycardia, dyspnea) or 
excess bleeding related to prasugrel. Recruitment should not be a challenge at Mayo Clinic, Rochester where 30% of PCI 
patients are HBR. 
Background. The highest risk for readmissions for bleeding is within 30 days of discharge, and those with PDB are also at 
heightened ischemic risk for death/MI within the first 60 days of bleeding-related hospitalization. These findings suggest a 
critical period after bleeding events when patients are most vulnerable for further adverse events. Contemporary studies have 
abbreviated the DAPT duration (1-3 months) or have deescalated the intensity of P2Y12 inhibitors only after this critical period 
is over. There is an urgent need to test early antiplatelet deescalation leveraging CYP2C19-LOF allele-based stratification. 
Preliminary Studies. HBR patients represent 30% 
of all patients who underwent PCI in the Mayo 
Clinic, Rochester catheterization laboratory 
between January 2010 and July 2021. Role of 
genotyping in reducing the incidence of major 
bleeding following PCI: TAILOR PCI 
demonstrated a 34% risk reduction of ischemic 
events (HR 0.66, 95% CI 0.43-1.02, p=0.06) at 12 
months with genotype guided P2Y12 inhibitor 
therapy.20 Importantly in that trial, a post-hoc 
analysis demonstrated an almost 80% risk reduction 
(p=0.001) for ischemic events with genotype 
guidance in the first 3 months after PCI, the highest 
risk period following PCI. A recent meta-analysis 
using data from 7 randomized control trials with 
15,949 patients demonstrates a 30% risk reduction in ischemic events (95% CI 0.59-0.83) in CYP2C19LOF allele patients with 
the use of ticagrelor/prasugrel vs clopidogrel and a RR of 1.0 (95% CI 0.80-1.25) in wild-type or no LOF patients indicating 
that CYP2C19 genotype played a significant role in driving the benefit of ticagrelor/prasugrel.25  
Research Design  
1. Assessment of high bleeding risk: Academic Research Consortium (ARC) defined 1-year high bleeding risk as a BARC 3 or 
5 risk of ≥4% or a risk of intracranial hemorrhage of ≥1%.26 The variables included in this risk model are listed in Table 1. 
Twenty clinical criteria were chosen as major or minor, and patients are at high risk for bleeding if at least 1 major or 2 
minor risk criteria are met. This model successfully identified high bleeding risk patients following PCI.27  
2. Assessment of CYP2C19LOF Allele: Clinical CYP2C19 assay will be run on QuantStudio with Chemagic DNA extraction 
that assesses CYP2C19 (*2, *10, *17, *35) The results will be expected within 72 hours of receipt of the samples. Once 
received, the results will be communicated to the participants and clopidogrel monotherapy will be initiated or samples of 
prasugrel or ticagrelor will be mailed.  
 
Expected Outcomes. From these data, we will determine whether there is increased ischemic risk in HBR non-carriers of 
CYP2C19 LOF genotype receiving clopidogrel monotherapy post-PCI. Close monitoring of participants receiving clopidogrel 
monotherapy or prasugrel/ticagrelor monotherapy for any cardiac deaths, spontaneous MI and stent thrombosis will be done. 
Potential Problems and Alternative Strategies. The results of genotype-based assay will be available at or following the 
participant’s discharge. To ensure compliance with clopidogrel monotherapy or switch among participants with CYP2C19 LOF 
allele, the study coordinator will call them with the results, mail the 90-day prescription for prasugrel or ticagrelor and ensure its 
receipt and initiation. Based on the expert consensus, pharmacodynamic data, escalation in 
patients with CYP2C19 *
2 
or
 *
3 
LOF allele will require stopping clopidogrel and switching to 
60 mg loading dose of prasugrel or 180 mg loading dose of ticagrelor regardless of the timing 
of the last dose of clopidogrel followed by standard maintenance dose of prasugrel 10 mg daily 
(5 mg if age ≥ 75 years or weight < 60 kg) or ticagrelor 90 mg twice daily. We have elected to 
exclude patients on chronic warfarin or DOAC. While this is an ARC major criterion for HBR, 
aspirin is already being discontinued frequently post-PCI in many patients to avoid triple 
therapy, and we want to ensure that this study is truly evaluating antiplatelet monotherapy and 
is not confounded by use of chronic anticoagulants. Patient enrollment is another potential 
problem, but our group has a strong track record of successfully enrolling participants into 


 
10 
 
clinical trials, including genotype-directed randomization for the TAILOR PCI trial. We will approach potential participants for 
informed consent before dismissal following the PCI procedure. For participant with same-day dismissal, we will approach 
them either before coronary angiography or pre-dismissal once the sedation from the procedure wears off.  
Aim 2: Detailed Approach  
Aim 2 includes participants enrolled in Aim 1, and this data will determine the incidence of post-discharge BARC 3 or 5 
bleeding events. Other secondary endpoints are post-dismissal all-cause death, any MI up to 180 days, repeat revascularization, 
or any other BARC bleeding episodes. The rate of death or MI post-PCI at Mayo Clinic, Rochester is presented in Table 2. 
Introduction. PDB is common and is seen in approximately 5% and 20% of those bleeds manifest in the first month following 
PCI. Longer observation is needed to accurately define its incidence, source, severity, and time dependency. The ischemic 
hazard usually follows admission due to PDB and is likely due to interruption or discontinuation of DAPT. Insights into its time 
course, relationship with antecedent bleeding, type of MI (STEMI vs. NSTEMI) and prognosis are equally relevant. 
Prolongation of observation is critical to delineate time course of both bleeding and ischemic hazards. The objectives of Aim 2 
are to determine the frequency, time course, type, severity, and prognosis of both ischemic and bleeding events till the end of 6 
months. The working hypothesis is that most PDB and ischemic events occur early after PCI, however, increase in both 
ischemia and bleeding may continue, especially among participants with ACS. We further hypothesize that participants 
receiving clopidogrel monotherapy will continue to demonstrate lower incidence of bleeding as compared to the standard of 
care with DAPT. Our approach to test this hypothesis will be to do extended period of observation till 6 months and record both 
bleeding and ischemic events. The rationale for this aim is that the main driver for increase in PDB and consequent ischemia is 
the intensity and duration of DAPT, however most bleeds and ischemia occur early, questioning the need to extend the duration 
of DAPT. After successful completion of the proposed studies for Aim 2, it is our expectation that using a prospective design, 
we will have identified predictors of PDB and ischemia. 
Background. Recent randomized trials have investigated different antithrombotic strategies, including monotherapy with a 
P2Y12 inhibitor, aiming to assess the best balance between ischemic and bleeding risks after PCI. Shortening of DAPT duration 
is safe and has not demonstrated an increase in the incidence of ischemic risk. The limitations of the existing trials are, 1) that 
DAPT is given for 1-3 months, and there is an urgent need aspirin-free P2Y12 inhibition in the first month following PCI that 
overlaps with high risk period for PDB, 2) TWILIGHT trial randomized higher-risk patients only after demonstrating no 
ischemia or bleeding for the initial 3 months following PCI thereby selecting lower-risk patients for PDB, 3) ASET pilot study 
included only low-risk, stable patients who were given prasugrel. Older age is one of the main drivers of bleeding and along 
with prior TIA/stroke, or low body weight will significantly limit the applicability of monotherapy with prasugrel. In that 
regard, individualizing P2Y12 therapy guided by genotyping at the time of PCI allows us to use clopidogrel with lower 
attendant bleeding risk among non-carriers (prevalence of 60%-70%) and limiting the use of newer P2Y12 inhibitors to the rest. 
Accurate assessment and prolongation of period of observation is relevant especially among participants presenting with ACS.  
The central goal of Aim 2 is to study the incidence of PDB and ischemia during the first 6 months following PCI with DES. 
This aim leverages the support from existing Mayo Clinic PCI database in whom all the information is routinely collected 
following a coronary intervention.  
Preliminary Studies. Research Design: Same 150 participants from Aim 1 will be enrolled, however, data for Aim 2 will be 
collected at six months. Our main strategy for this aim is to demonstrate whether clopidogrel monotherapy, guided by genotype, 
is associated with lower bleeding and ischemic events during extended period of observation, especially relevant in participants 
presenting with ACS. Expected Outcomes: Upon completion, we will have comprehensive data on incidence, severity, 
predictors, type, and time trends for both PDB and ischemia. In recent years, several trials have analyzed PCI in HBR patients 
examining DAPT regimens and outcomes to balance the risk of ischemia and bleeding. Table 3 (see supplemental material) 
summarizes these key trials. Extending the period of observation allows us to monitor the participants longer and demonstrate 
the safety of clopidogrel monotherapy.  From this aim we will determine whether clopidogrel monotherapy is safe in all-comers 
following successful PCI, especially among participants presenting with ACS, as the current guidelines recommend at least 6 
months of DAPT. Importantly, with this aim, we will focus on the period between 3 and 6 months for both ischemic and 
bleeding events. The idea is that by providing early deescalation with a P2Y12 inhibitor, clopidogrel will lead to lowering in the 
incidence of PDB. The observation period will continue even beyond 6 months as all participants will be entered into the Mayo 
Clinic database. We expect that subjects receiving clopidogrel monotherapy will have reduced PDB during 6 months of 
observation. If the data confirm our hypotheses, we will expect our hypothesis and will have shown after completion of Aim 2 
that clopidogrel monotherapy is safe and effective during 6 months of observation. 
Potential Problems & Alternative Strategies. Participants may not report minor bleeds. Minor bleeds are generally 
nonactionable and don’t carry the same prognostic connotation as more severe BARC 3 bleeds. We will, however, attempt to 
capture all bleeds, including BARC 2. Participants may be admitted to out-of-network facilities with PDB and/or any ischemic 
event that may not be captured routinely. We have a strong post-PCI surveillance program to contact the participants and 
retrieve such records. Specific adverse events monitored will include death, type I NSTEMI, STEMI, stent thrombosis, upper 
gastrointestinal (GI) bleed, lower GI bleed, GI bleed of unclear source, intracranial bleed (hemorrhagic stroke, subdural 


 
11 
 
hemorrhage, etc.), ischemic stroke, radial artery access site complication, femoral artery access site complication, and/or other 
clinically significant bleeding event. Drug compliance may be an issue. To ensure higher rates of compliance, study 
coordinators will underscore the importance of medication compliance before discharge. 
Statistical Considerations: Sample size estimation: Due to the exploratory nature of the study, no formal sample size 
calculations will be performed. Continuous variables will be expressed as mean ± SD or as median with interquartile range. 
Categorical variables will be expressed as frequencies and percentages. Stoppage Rule: On the basis of prior pilot studies with 
similar designs and more recently the ASET study, a sample size of 100 active patients is planned with a similar safety stopping 
rule based on the presence of definite stent thrombosis.11, 28-30 In the present study, if we observe more than 2 cases of definite 
stent thrombosis, the study will be halted and further recruitment will be terminated. The cutoff rates for definite stent 
thrombosis is determined based on the incidence of stent thrombosis (1.2% at 30 days and 1.7% at 1 year, in the Bern-
Rotterdam registry).29 
Project Timeline & Budget: Year 1 will include IRB submission/approval. Patient recruitment and conducting the study will 
occur in year 1 and year 2 if necessary. Statistical analysis and manuscript preparation/submission will occur in year 2. The 
budget for this project is $100,000 ($99,987 – see attached budget). 
Future Directions: The incidence of PDB following PCI is associated with significant morbidity and mortality, and the 
incidence will continue to grow with the aging population. Safe, early deescalation of inhibitors P2Y12 remains the cornerstone 
of management.31 Stratification based on the CYP2C19 LOF allele allows us to use clopidogrel monotherapy with less bleeding 
compared to newer (ticagrelor or prasugrel). Upon completion of this project, we will have identified whether clopidogrel 
monotherapy among non-carriers of this allele can lower the incidence of PDB without compromising safety. This holds great 
potential to allow for a much larger population of patients at HBR to benefit from this protocol.  If this study confirms our 
hypothesis, the next steps will be to test clopidogrel monotherapy in a large multicenter trial to determine whether its 
administration is safe and lowers the incidence of PDB. Further study would also be warranted to evaluate the underlying 
mechanisms of improvement and to demonstrate whether longer-term treatment (beyond 3 months) is safe.  Finally, other doses 
and combinations can be tested along with further research to define the optimal dosing duration and schedule. Prior to 
proceeding to these future studies, our study will test the concept hypothesis that clopidogrel monotherapy is safe and effective 
to reduce PDB among participants undergoing PCI with DES. If our hypotheses are not confirmed, future directions will 
include testing of alternative ways to reduce PDB. In addition, routine use of PPI can be considered to optimize their safety and 
effectiveness. Our goal is to better understand the PDB bleeding among patients undergoing PCI with DES. If correct, our 
hypothesis will impact future trial designs and future practice. 
Supplemental Material 
 
Key 
1° = primary 
2° = secondary 
AD = absolute difference 
BARC = Bleeding Academic Research Consortium 
BioFreedom (BioSensors Interventional 
Technologies) = polymer-free umirolimus/biolimus 
A9 drug-coated stent 
BMS = bare metal stent 
CAD = coronary artery disease 
CI = confidence interval 
CV = cardiovascular 
DAPT = dual antiplatelet therapy 
DCS = drug coated stent 
DES = drug eluting stent 
HBR = high bleed risk 
HR = hazard ratio 
MACE = major adverse cardiac event 
MI = myocardial infarction 
mo. = months 
n = number of participants in study 
pts = patients 
RCT = randomized controlled trial 
RD = risk difference 
Resolute Onyx (Medtronic) = durable-polymer, slow-
release zotarolimus-eluting stent 
RR = relative risk 
ST = stent thrombosis 
TVR/TLR = target vessel/lesion revascularization 
E-ZES = Zotarolimus-Eluting Endeavor Sprint Stent 
 
References 
LEADERS FREE13 
ZEUS-HBR32 
SENIOR15 
LEADERS FREE II (Presented by Krukoff TCT 2018) 
TWILIGIGHT8 
STOP-DAPT-210 
XIENCE 28 (Presented by Valgimigli TCT Connect 
2020) 
XIENCE 90 (Presented by Mehran TCT Connect 2020) 
ONYX ONE33 
EVOLVE SHORT TAPT34 
MASTER DAPT12 
 
 
 
 


 
19 
 
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