Dual Antiplatelet Therapy Versus Antiplatelet Monotherapy Plus Anticoagulation in Patients With Acute Coronary Syndrome and Coronary Artery Ectasia: A Multicenter Randomized Clinical Trial
Phase: PHASE4
Conditions: Coronary Artery Ectasia, Acute Coronary Syndromes (ACS), STEMI - ST Elevation Myocardial Infarction, NSTEMI - Non-ST Segment Elevation Myocardial Infarction (MI)
Sponsor: Instituto Nacional de Cardiologia Ignacio Chavez

Official Title  
Dual Antiplatelet Therapy Versus Antiplatelet Monotherapy Plus Anticoagulation in Patients 
With Acute Coronary Syndrome and Coronary Artery Ectasia: A Multicenter Randomized 
 
Brief Title  
Multicenter Trial of Antithrombotic Strategies in Acute Coronary Syndrome With Coronary 
Artery Ectasia 
 
Acronym  
OVER-TIME II 
 
Study Type  
Interventional 
 
Study ID and Approval Number 
26-1556 
 
Principal Investigator 
Diego Araiza-Garaygordobil  
 
Investigator Official Title  
Attending Cardiologist at the Coronary Care Unit and Emergency Department 
 
Investigator Affiliation  
Instituto Nacional de Cardiologia Ignacio Chavez 
 
Document Date 
March 30th, 2026 
 
 
 
This document includes: Study Protocol and Statistical Analysis Plan 
 
 

Brief Summary 
Coronary artery ectasia (CAE) is a condition in which a coronary artery becomes abnormally 
dilated, measuring at least 50% larger than the adjacent normal segment. Although relatively 
uncommon, CAE is clinically important because it can lead to abnormal blood flow and increase 
the risk of blood clot formation. Patients with CAE are at higher risk of angina, myocardial 
infarction, and complications during coronary interventions. Despite these risks, the optimal 
antithrombotic treatment for patients with acute coronary syndrome (ACS) and CAE remains 
uncertain.Dual antiplatelet therapy (aspirin plus clopidogrel) is currently the most commonly used 
treatment. However, the abnormal blood flow patterns observed in CAE may promote clot 
formation through mechanisms that could potentially be better addressed with anticoagulant 
therapy.The OVER-TIME II trial is a multicenter randomized clinical trial designed to compare 
two antithrombotic strategies in patients with ACS and CAE: standard dual antiplatelet therapy 
versus antiplatelet monotherapy combined with anticoagulation. The study aims to determine 
whether the addition of anticoagulation reduces major cardiovascular events without significantly 
increasing bleeding risk. 
 
 

Introduction 
 
Coronary artery ectasia (CAE) is defined as an abnormal dilation of the coronary artery in which 
the length of the dilated segment is ≥50% greater than the adjacent diameter (1,2). CAE is an 
uncommon but clinically relevant entity, and its therapeutic management remains controversial. 
The reported prevalence of CAE ranges from 0.3% to 4.9% across different international series (1, 
3–9). However, a study conducted by our research group showed that in a consecutive series of 
angiograms in patients with ST-elevation myocardial infarction (STEMI), the prevalence of CAE 
was 10.3%, a figure notably higher than previously described (10), highlighting the heterogeneity 
of its distribution and the importance of studying it in the Mexican population. 
 
The most common etiology of CAE is atherosclerosis, accounting for approximately 50% 
of cases (11). Other causes include connective tissue diseases, coronary trauma (including 
iatrogenic injury during percutaneous coronary interventions), infectious arteritis, Kawasaki 
syndrome, and congenital forms (12). 
 
From a pathophysiological standpoint, CAE promotes thrombosis due to alterations in 
coronary hemodynamics characterized by slow flow or blood stasis (13). Elevated levels of 
prothrombotic and inflammatory biomarkers (such as P-selectin, platelet factor 4, D-dimer, and 
fibrinogen) have been described in patients with CAE compared to controls (14–16). Additionally, 
these patients exhibit changes in the expression of genes involved in the inflammatory response, 
as well as in microRNA-mediated regulation of transcription and subsequent translation of factors 
associated with angiogenesis and vascular remodeling. These findings suggest the involvement of 
genetic and molecular mechanisms in the pathophysiology of the disease (17, 18). 
 
Currently, evidence regarding the optimal treatment of acute coronary syndrome (ACS) in 
patients with CAE is limited, and there are no guidelines defining a clear therapeutic strategy. 
Management is often left to the discretion of the treating team, with dual antiplatelet therapy 
(DAPT: acetylsalicylic acid 100 mg and clopidogrel 75 mg) being the routinely recommended 
regimen (6–9). However, given the previously described prothrombotic pathophysiology and the 
presence of marked dilation and slow flow, anticoagulants have been proposed as a strategy to 
improve outcomes. A retrospective Japanese study in patients with CAE and acute myocardial 
infarction showed that those treated with warfarin and maintaining therapeutic INR >60% of the 
time had fewer cardiac events compared to those without adequate anticoagulation (0% vs 33%, p 
= 0.03) (19). Likewise, a systematic review of cases found that recurrences were concentrated 
among patients treated with DAPT, whereas those receiving anticoagulation (8/13) had better 
outcomes, even though most were only receiving a single concomitant antiplatelet agent (20). Even 
the use of potent P2Y12 inhibitors has not satisfactorily prevented thrombosis in this group (7). 
 
In this context, the OVER-TIME study was conducted at our Institute, an exploratory 
clinical trial led by the principal investigator of the present proposal (21). This study compared the 
use of SAPT+DOAC (clopidogrel 75 mg + rivaroxaban 15 mg) versus standard DAPT in patients 
with ACS and CAE. Despite its exploratory nature and limitations related to sample size, the 
results were clinically relevant: the SAPT+DOAC group showed a numerical reduction in major 
cardiovascular events, a lower rate of ischemic recurrence, and a favorable safety trend, without a 
significant increase in bleeding events. Additionally, a significant reduction in clot lysis time was 

observed in patients receiving SAPT+DOAC, suggesting improved fibrinolytic activity and 
providing mechanistic evidence for the potential benefit of anticoagulation in this setting. 
 
However, it remains unknown whether, beyond the effects on hemostasis, treatment 
response is associated with genetic, post-transcriptional, or translational modifications, an aspect 
that warrants further investigation. The findings generated at our center support the hypothesis that 
anticoagulation may play a key role in these patients. OVER-TIME thus represents the strongest 
available preliminary evidence and the ideal platform to propose a larger-scale trial with 12-month 
follow-up aimed at definitively confirming these findings and establishing evidence-based 
therapeutic recommendations. Furthermore, this project will explore the genetic and molecular 
profile of these patients to assess potential changes during disease progression or in response to 
treatment, consolidating a unique and necessary line of translational research in this field. 
 
Arms and Interventions 
 
Active Comparator: Dual Antiplatelet Therapy 
 
Description: Participants receive standard dual antiplatelet therapy consisting of aspirin 100 mg 
once daily plus clopidogrel 75 mg once daily. 
 
Experimental: Antiplatelet Monotherapy Plus Anticoagulation 
 
Description: Participants receive antiplatelet monotherapy with clopidogrel 75 mg once daily 
combined with oral anticoagulation using rivaroxaban 15 mg once daily. 
 
Outcomes  
 
Primary Outcomes 
 
1. Time to First Major Adverse Cardiovascular Event (MACE) 
Time to first occurrence of the composite of cardiovascular death, non-fatal myocardial infarction, 
or repeat coronary revascularization in patients with coronary artery ectasia following acute 
coronary syndrome, according to the assigned antithrombotic treatment strategy (dual antiplatelet 
therapy versus clopidogrel plus rivaroxaban). 
 
2. Time to First Bleeding Event According to the BARC Classification 
Time to first occurrence of a composite of major or minor bleeding events defined according to 
the Bleeding Academic Research Consortium (BARC) classification in patients with coronary 
artery ectasia following acute coronary syndrome, according to the assigned antithrombotic 
treatment strategy (dual antiplatelet therapy versus clopidogrel plus rivaroxaban). 
 
Secondary Outcomes 
 
1. Individual Components of the Major Adverse Cardiovascular Event Composite 
Incidence of each individual component of the primary efficacy composite endpoint 
(cardiovascular death, non-fatal myocardial infarction, and repeat coronary revascularization) in 

patients with coronary artery ectasia following acute coronary syndrome, according to the assigned 
antithrombotic treatment strategy. 
 
2. Individual Bleeding Events According to the BARC Classification 
Incidence of individual bleeding events according to the Bleeding Academic Research Consortium 
(BARC) classification in patients with coronary artery ectasia following acute coronary syndrome, 
according to the assigned antithrombotic treatment strategy. 
 
Exploratory Outcomes 
 
1. Genetic Variants and Gene Expression Profiles Associated With Coronary Artery Ectasia 
and Treatment Response 
 
Analysis of genetic variants and gene expression profiles, including DNA, RNA and circulating 
microRNA obtained from peripheral blood samples collected at randomization and at 12 months 
of follow-up. These analyses aim to identify molecular signatures associated with susceptibility to 
coronary artery ectasia, disease progression, and differential response to antithrombotic therapy. 
This exploratory analysis will be performed in an approximately 30% subset of the study 
population. 
 
Methodology 
 
Study design 
Randomized, multicentric, open-label clinical trial  
 
Description of the study population 
- Target population 
Patients with coronary artery ectasia and acute coronary syndrome. 
- Eligible population 
Patients with coronary artery ectasia and acute coronary syndrome presenting to the National 
Institute of Cardiology for care, without any other indication for concomitant anticoagulation. 
 
Inclusion criteria 
Patients with coronary artery ectasia: 
1. Patients of both sexes, aged 18–80 years, hospitalized for acute coronary syndrome with 
or without ST-segment elevation. Operational criteria include ALL of the following: 
A. Acute coronary syndrome within 7 days prior to recruitment, with or without persistent 
ST-segment elevation; with high-sensitivity cardiac troponin above the 99th percentile. 
B. Coronary ectasia in the infarct-related artery and one- or two-vessel coronary artery 
disease. 
Definitions 
of 
ectasia 
include: 
a. Theoretical definition: coronary ectasia is defined as dilation >1.5 times the diameter 
of an adjacent normal coronary segment or the expected normal diameter according to sex-
based 
distribution. 
b. Operational definition: after review by two expert observers (interventional 
cardiologists), supported by quantitative coronary angiography (QCA), the presence of 
coronary ectasia is determined unanimously. In case of disagreement, a third observer 

(interventional 
cardiologist) 
will 
adjudicate. 
c. The infarct-related artery is defined as the artery corresponding to the affected 
electrocardiographic territory (in cases with ST elevation) or showing signs of an 
atherothrombotic event such as thrombus (TIMI I–V) or reduced flow on coronary 
angiography. 
2. Hospital admission lasting >24 hours. 
3. Percutaneous revascularization or medical treatment, as deemed appropriate by the treating 
team. Intracoronary interventions such as stent angioplasty, balloon angioplasty, or 
thrombus aspiration are allowed. 
4. Signed informed consent and willingness to participate voluntarily. 
 
Exclusion criteria 
1. Pregnant women. 
2. Patients with any indication for temporary or permanent anticoagulation at recruitment. 
3. Chronic kidney disease KDIGO stage IV or higher (eGFR <30 ml/min/1.73 m²). 
4. eGFR at hospital discharge <30 ml/min/1.73 m². 
5. History of major bleeding (upper gastrointestinal bleeding, intracranial hemorrhage, etc.) 
or high bleeding risk determined by the treating physician. 
6. Advanced heart failure defined as LVEF <30% plus one of the following: 
I. More than two hospitalizations or unplanned ER visits in the past year and/or 
II. NYHA class III or higher despite optimal medical therapy at recruitment or within the 
past 3 months. 
 
Elimination criteria 
1. Discharge diagnosis other than acute coronary syndrome with or without ST elevation. 
2. Failure to provide or withdrawal of informed consent. 
 
Sample size 
Based on the exploratory OVER-TIME trial (Araiza-Garaygordobil et al., 2025), sample size was 
calculated with 80% power, alpha 0.05, 5% crossover, event rate of 87.5% in the DAPT group and 
96.7% in the anticoagulation + SAPT group. A total of 326 patients (163 per arm). 
 
Of these, 126 patients are expected to be recruited at our Institute, based on recruitment patterns 
observed in the OVER-TIME study (2021–2025). The study will begin as single-center and later 
expand to a multicenter design including: 
• 
Hospital Juárez de México 
• 
Centro de Estudios Clínicos de Querétaro S.C. 
 
Specification of variables 
 
Independent variable: treatment group 
• 
DAPT group: aspirin 100 mg + clopidogrel 75 mg 
• 
SAPT+DOAC group: rivaroxaban 15 mg + clopidogrel 75 mg 
 
Dependent variable: primary composite endpoint of major cardiovascular events 

• 
Defined as: composite of cardiovascular death, nonfatal recurrent myocardial infarction, 
and repeat revascularization/repeat coronary angiography (per international definitions for 
RCTs). 
 
Dependent variable: co-primary bleeding endpoint 
• 
Defined as: composite of minor and major bleeding events according to the Bleeding 
Academic Research Consortium (BARC) scale. 
 
Dependent variable: gene expression profiles in patients with CAE and ACS 
• 
Defined as total DNA and RNA extracted from peripheral blood, including differentially 
expressed genes, gene signatures, and microRNA profiles. 
 
Data collection methods 
 
Patients will be recruited from the Emergency Department and Coronary Care Unit of the National 
Institute of Cardiology. After eligibility confirmation, they will be randomized 1:1 to DAPT vs. 
SAPT+DOAC. Treatment will continue for 12 months. 
Follow-up visits will occur at 30 (±3) days and 12 months, with telephone follow-up at 
months 3 and 6. Clinical data, outcomes, and objective documentation of events will be recorded, 
and peripheral blood samples will be collected for analysis at the INMEGEN Cardiovascular 
Diseases Laboratory. 
 
Case Report Form (CRF) 
A standardized CRF will ensure uniform data collection across centers, including: 
1. Demographics and baseline characteristics 
2. ACS clinical data 
3. Angiographic characteristics 
4. Treatment allocation and adherence 
5. Major cardiovascular events 
6. Bleeding events (BARC classification) 
7. Clinical follow-up data 
8. Biological samples (DNA/RNA) 
9. Exclusion/elimination during follow-up 
 
Statistical analysis plan 
 
All statistical analyses will be performed using Stata version 14.1 (StataCorp, College Station, TX, 
USA). A two-sided p-value <0.05 will be considered statistically significant. 
 
Analysis populations 
• 
The intention-to-treat (ITT) population will be the primary analysis set and will include all 
randomized patients, analyzed according to their assigned treatment group. 
• 
A per-protocol (PP) analysis will also be conducted as a sensitivity analysis, including 
patients with adequate adherence and no major protocol deviations. 
• 
A safety population will include all patients who received at least one dose of the assigned 
treatment. 

 
Descriptive analysis 
Baseline characteristics will be summarized by treatment group. Continuous variables will be 
reported as mean ± standard deviation (SD) or median with interquartile range (IQR), depending 
on distribution (assessed using the Shapiro–Wilk test). Categorical variables will be expressed as 
frequencies and percentages. 
 
Between-group comparisons at baseline will be performed using: 
• 
Student’s t-test or Wilcoxon rank-sum test for continuous variables 
• 
Chi-square test or Fisher’s exact test for categorical variables 
 
No formal statistical testing of baseline differences will be used to guide adjustments. 
 
Primary efficacy endpoint 
The primary endpoint is a composite of cardiovascular death, nonfatal recurrent myocardial 
infarction, and repeat revascularization/repeat coronary angiography. 
• 
Time-to-event will be defined from randomization to first occurrence of any component of 
the composite endpoint. 
• 
Patients without events will be censored at the time of last follow-up. 
• 
Event-free survival will be estimated using Kaplan–Meier curves and compared using 
the log-rank test. 
• 
Cox proportional hazards regression models will be used to estimate hazard ratios (HRs) 
with 95% confidence intervals (CIs). 
• 
The proportional hazards assumption will be assessed using Schoenfeld residuals and 
graphical methods. 
 
Adjusted analyses will be performed including clinically relevant covariates (e.g., age, sex, 
diabetes, baseline renal function, Killip class) if imbalance is observed or pre-specified. 
 
Co-primary safety endpoint (bleeding) 
The co-primary endpoint is a composite of major and minor bleeding events according to 
the BARC classification. 
• 
Time-to-first bleeding event will be analyzed using Kaplan–Meier methods and Cox 
regression. 
• 
Additionally, bleeding incidence rates will be compared using chi-square tests. 
• 
A net clinical benefit analysis (composite of ischemic and major bleeding events) may be 
performed as an exploratory endpoint. 
 
Secondary analyses 
• 
Individual components of the primary endpoint will be analyzed separately using time-to-
event methods. 
• 
Recurrent events may be analyzed using Andersen–Gill models or negative binomial 
regression, if applicable. 
• 
Subgroup analyses will be performed for predefined groups (e.g., STEMI vs NSTEMI, 
presence of multivessel disease, sex, diabetes), including interaction testing. 
 

Biomarker and genetic analysis 
• 
Differential gene expression analyses will be performed using appropriate normalization 
methods (e.g., DESeq2/edgeR pipeline if RNA-seq is used). 
• 
Associations between gene expression profiles and clinical outcomes will be explored 
using multivariable regression models. 
 
Handling of missing data 
• 
Efforts will be made to minimize missing data through active follow-up. 
• 
Missing baseline covariates may be imputed using multiple imputation by chained 
equations (MICE) if missingness exceeds 5%. 
• 
For time-to-event analyses, censoring will be applied at last known follow-up. 
• 
Sensitivity analyses will be conducted to assess the impact of missing data. 
 
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