Multicenter Trial of Antithrombotic Strategies in Acute Coronary Syndrome With Coronary Artery Ectasia

Official title

Dual Antiplatelet Therapy Versus Antiplatelet Monotherapy Plus Anticoagulation in Patients With Acute Coronary Syndrome and Coronary Artery Ectasia: A Multicenter Randomized Clinical Trial

Overview

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.

Detailed description

Coronary artery ectasia (CAE) is defined as an abnormal dilatation of a coronary artery segment measuring at least 50% greater than the diameter of the adjacent normal segment. Although relatively uncommon, CAE represents a clinically relevant phenotype of coronary artery disease. Its reported prevalence ranges from 0.3% to 4.9% worldwide; however, higher frequencies have been described in certain populations. At the National Institute of Cardiology "Ignacio Chávez" (INCICh) in Mexico, a prevalence of approximately 10.3% has been documented among patients presenting with ST-segment elevation myocardial infarction (STEMI), highlighting the importance of studying this condition in the Mexican population.

The pathophysiology of CAE involves abnormal coronary blood flow dynamics, including turbulent flow and blood stasis within dilated segments. These changes may promote thrombus formation through multiple mechanisms, including platelet activation, local inflammatory processes, endothelial dysfunction, and potential prothrombotic states. Genetic susceptibility and molecular pathways related to vascular remodeling may also contribute to the development and progression of the disease. Clinically, patients with CAE have been associated with a higher risk of angina, myocardial infarction, distal embolization, and complications during percutaneous coronary intervention.

Despite its clinical significance, the optimal antithrombotic strategy in patients with acute coronary syndrome (ACS) and CAE remains uncertain. Dual antiplatelet therapy (DAPT), typically consisting of aspirin and a P2Y12 inhibitor, is the most commonly used treatment. However, given the propensity for thrombus formation related to abnormal flow conditions in ectatic coronary segments, anticoagulation has been proposed as a potentially beneficial therapeutic strategy.

The exploratory OVERTIME trial conducted at INCICh compared an antithrombotic regimen consisting of antiplatelet monotherapy plus a direct oral anticoagulant (clopidogrel 75 mg plus rivaroxaban 15 mg daily) with standard dual antiplatelet therapy (aspirin 100 mg plus clopidogrel 75 mg daily) in patients with ACS and CAE. Although limited by sample size, the study demonstrated a numerical reduction in major adverse cardiovascular events and a shorter endogenous fibrinolysis time among patients receiving the combination of antiplatelet therapy and anticoagulation, without a significant increase in bleeding events.

These findings support the hypothesis that anticoagulation combined with antiplatelet therapy may improve clinical outcomes in this high-risk population. However, larger randomized studies are needed to confirm these results and provide definitive evidence to guide clinical management.

The OVER-TIME II trial is a multicenter, randomized clinical trial designed to compare two antithrombotic strategies in patients with ACS and angiographically confirmed CAE: (1) standard dual antiplatelet therapy and (2) antiplatelet monotherapy combined with oral anticoagulation. The primary objective is to evaluate whether the addition of anticoagulation reduces major cardiovascular events without significantly increasing bleeding risk.

In addition to the clinical trial component, the study will incorporate a translational research arm. Peripheral blood samples will be collected to investigate genetic variants and DNA and RNA expression profiles that may be associated with susceptibility to CAE, disease progression, and differential response to antithrombotic therapy. These analyses aim to improve the understanding of the biological mechanisms underlying CAE and to identify potential biomarkers that could inform future personalized treatment strategies.

Interventions

• Drug Aspirin 100 mg
  Participants receive aspirin 100 mg once daily
• Drug Clopidogrel 75 mg
  Participants receive clopidogrel 75 mg once daily
• Drug Rivaroxaban 15 mg
  Participants receive oral anticoagulation using rivaroxaban 15 mg once daily

Primary outcome measures

• Time to First Major Adverse Cardiovascular Event (MACE) [Time frame: 12 months]
• Time to First Bleeding Event According to the BARC Classification [Time frame: 12 months]

Secondary outcome measures (2)

• Individual Components of the Major Adverse Cardiovascular Event Composite [Time frame: 12 months]
• Individual Bleeding Events According to the BARC Classification [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Adults aged 18 to 80 years, of either sex, hospitalized with acute coronary syndrome (ACS) with or without ST-segment elevation.
• Recent ACS within 7 days prior to enrollment, defined by all of the following:
• Clinical presentation consistent with acute coronary syndrome.
• Elevated high-sensitivity cardiac troponin above the 99th percentile.
• Presence or absence of persistent ST-segment elevation.
• Coronary artery ectasia in the culprit coronary artery, defined by all of the following:
• The presence of ectasia will be determined by agreement of two expert interventional cardiologists, and will be confirmed by quantitative coronary angiography (QCA).
• Identification of a culprit artery consistent with the electrocardiographic territory involved (in cases with ST-segment elevation) or with angiographic features suggestive of an atherothrombotic event, such as the presence of thrombus or reduced coronary flow.
• Hospital admission lasting more than 24 hours.
• Management with either percutaneous coronary intervention or medical therapy, as determined by the treating medical team. Intracoronary interventions such as stent implantation, balloon angioplasty, or thrombus aspiration are permitted.
• Ability and willingness to provide written informed consent and to participate in the study.

Exclusion criteria

• Pregnant women.
• Current indication for temporary or long-term anticoagulation therapy at the time of enrollment.
• Severe chronic kidney disease, defined as KDIGO stage G4 or higher (estimated glomerular filtration rate \[eGFR\] <30 mL/min/1.73 m²).
• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² at hospital discharge.
• History of major bleeding, active bleeding, or high bleeding risk, including but not limited to gastrointestinal bleeding, intracranial hemorrhage, or other conditions considered by the treating physician to confer a high risk of bleeding.
• Advanced heart failure, defined as left ventricular ejection fraction (LVEF) <30% plus at least one of the following:
• More than two hospitalizations or unplanned emergency department visits for heart failure in the past year, or
• NYHA functional class III or IV symptoms despite optimal medical therapy at enrollment or within the previous 3 months.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Mexico · 1 center

• Instituto Nacional de Cardiologia "Ignacio Chávez" — Mexico City

Publications

• Solis-Jimenez F, Esparza XL, Guzman-Solorzano HP, Villalobos-Pedroza M, Morales-Villamil LA, Diaz-Herrera BA, Hernandez-Pastrana S, Gopar-Nieto R, Arias-Sanchez EA, Marroquin-Donday LA, Jimenez-Rodriguez GM, Sierra-Lara D, Araiza-Garaygordobil D, Arias-Mendoza A. Anticoagulant versus Antiplatelet Therapy After Acute Coronary Syndromes in Patients with Coronary Artery Ectasia: A Retrospective Cohor PMID 40991139
• Araiza-Garaygordobil D, Gopar-Nieto R, Sierra-Lara Martinez JD, Mullasari AS, Belderrain-Morales N, Najera-Rojas NA, Diaz-Herrera BA, Sarabia-Chao V, Alfaro-Ponce DL, Briseno-De la Cruz JL, Ruiz-Beltran M, Martinez-Rios MA, Pina-Reyna Y, Latapi-Ruiz Esparza X, Grimaldo-Gomez FA, Cortina-De la Rosa E, Romero-Arroyo MO, Sierra-Gonzalez de Cossio A, Gonzalez-Pacheco H, Arias-Mendoza A. A randomized t PMID 39615618
• Doi T, Kataoka Y, Noguchi T, Shibata T, Nakashima T, Kawakami S, Nakao K, Fujino M, Nagai T, Kanaya T, Tahara Y, Asaumi Y, Tsuda E, Nakai M, Nishimura K, Anzai T, Kusano K, Shimokawa H, Goto Y, Yasuda S. Coronary Artery Ectasia Predicts Future Cardiac Events in Patients With Acute Myocardial Infarction. Arterioscler Thromb Vasc Biol. 2017 Dec;37(12):2350-2355. doi: 10.1161/ATVBAHA.117.309683. Epub PMID 29051141
• Iwanczyk S, Lehmann T, Cieslewicz A, Malesza K, Wozniak P, Hertel A, Krupka G, Jagodzinski PP, Grygier M, Lesiak M, Araszkiewicz A. Circulating miRNA-451a and miRNA-328-3p as Potential Markers of Coronary Artery Aneurysmal Disease. Int J Mol Sci. 2023 Mar 18;24(6):5817. doi: 10.3390/ijms24065817. PMID 36982889
• Lu TP, Chuang NC, Cheng CY, Hsu CA, Wang YC, Lin YH, Lee JK, Wu CK, Hwang JJ, Lin LY, Yeh SS, Chien KL, Juang JJ. Genome-wide methylation profiles in coronary artery ectasia. Clin Sci (Lond). 2017 Apr 1;131(7):583-594. doi: 10.1042/CS20160821. Epub 2017 Jan 31. PMID 28143891
• Dogan A, Tunc B, Ergene O, Ozaydin M, Nazli C, Altinbas A, Gedikli O. Evaluation of overall fibrinolytic activity in patients with coronary artery ectasia: global fibrinolytic capacity. Int J Cardiovasc Imaging. 2003 Dec;19(6):465-71. doi: 10.1023/b:caim.0000004339.30038.8d. PMID 14690185
• Nunez-Gil IJ, Cerrato E, Bollati M, Nombela-Franco L, Terol B, Alfonso-Rodriguez E, Camacho Freire SJ, Villablanca PA, Amat Santos IJ, de la Torre Hernandez JM, Pascual I, Liebetrau C, Camacho B, Pavani M, Albistur J, Latini RA, Varbella F, Jimenez-Diaz VA, Piraino D, Mancone M, Alfonso F, Linares JA, Rodriguez-Olivares R, Jimenez Mazuecos JM, Palazuelos Molinero J, Sanchez-Grande Flecha A, Gomez- PMID 31378382
• Gunasekaran P, Stanojevic D, Drees T, Fritzlen J, Haghnegahdar M, McCullough M, Barua R, Mehta A, Hockstad E, Wiley M, Earnest M, Tadros P, Genton R, Gupta K. Prognostic significance, angiographic characteristics and impact of antithrombotic and anticoagulant therapy on outcomes in high versus low grade coronary artery ectasia: A long-term follow-up study. Catheter Cardiovasc Interv. 2019 Jun 1;93 PMID 30393992

Identifiers

NCT: NCT07511257 · 26-1556

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗