Anticoagulation in Post MI LV Thrombus Trial in Nepal

Study Overview
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Brief Summary
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Introduction: The prevalence of left ventricular(LV) thrombus after acute myocardial infarction has decreased with thrombolysis and primary angioplasty intervention worldwide. However, most of the patients in our country present late after the onset of ischemia resulting in a comparable increase proportion of late presentation MI compared to developed countries. This delayed presentation is associated with the increased incidence of LV thrombus, associated with increased cerebrovascular and cardiovascular events resulting in increased morbidity and mortality. The Vitamin K Antagonist Warfarin is indicated in recent guidelines for the duration of 3-6 months. The use of Warfarin is less in our part of the world due to the requirement of frequent International Normalized Ration (INR) monitoring and dietary restrictions. Novel oral anticoagulants (NOACs) are an alternate option for such hindrance to the treatment of LV thrombus. This research will help assess the safety and efficacy of Rivaroxaban, one of the NOACs compared to warfarin. Objectives: Our aim will be to compare the efficacy of rivaroxaban compared to warfarin in the complete resolution of post-MI LV thrombus. The primary efficacy endpoint of our study will be a resolution of LV thrombus as assessed by cardiac MRI at the end of 3 months of the study period. The secondary endpoint will be the comparison of the safety of both drugs measured by the incidence of major bleeding and embolic events. Methods: The patients who present late after acute MI in our center with LV thrombus will be enrolled in our study. The diagnosis of LV thrombus will be diagnosed by cardiac MRI, which is considered the gold standard for the diagnosis. The patients then will be randomized in a 1:1 ratio to either warfarin or rivaroxaban within 24 hours of diagnosis of LV thrombus. The warfarin group will be prescribed the warfarin in the dose of 5mg daily and the dose titrated according to the INR value to maintain the INR range of 2 to 3. Rivaroxaban group will be prescribed 15 to 20mg according to the indication. The research group consisting of the principal investigator and coinvestigators will be responsible for the recruitment and overall study procedures.

Detailed Description
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Cardiovascular disease is the leading cause of mortality and morbidity among non-communicable diseases worldwide including in Nepal. Myocardial infarction(MI) is the main disease among cardiovascular diseases. [i] MI is also the main reason for hospitalization in the cardiac centers of our country. [ii] There is an additional burden of late presentation of MI in our setting due to lack of proper awareness, limited access to health care and improper referral mechanism. In the hospital-based registry in 2018, more than 65% of acute MI presented after the eligible time frame for primary angioplasty or thrombolysis. [iii] The incidence of the formation of left ventricular (LV) thrombus is increased with the late presentation. Worldwide, the prevalence of LV thrombus before the era of primary angioplasty was around 31-57%. [iv],[v],[vi] After the start of the primary angioplasty techniques, the prevalence of post-MI LV thrombus has decreased to around 15%.[vii] However, it is still associated with increased risks of embolic events and mortality.[viii],[ix],[x] European and American guidelines have recommended using vitamin K antagonist (VKA) for a minimum of 3-6 months as a class IIa, LOE c, with duration individualized to bleeding risk with a target of international normalized ratio (INR) of 2.5 (range of 2 to 3). [xi],[xii] Non-VKA oral anticoagulants (NOACs) in addition to the dual antiplatelet therapy in these patients are attractive alternatives because of their potential efficacy and safety along with ease of administration, lack of requirement for INR monitoring or dietary restrictions resulting in overall improvement of life.[xiii] However, there is no randomized control trial comparing warfarin and NOACs. There are two ongoing trials NCT01556659 and NCT03764241. The recommendation is more relevant to us as there is an overburden of patients presenting late due to various geographical and financial reasons. This study was designed for the evaluation of anticoagulation effects among the acute ST elevation Myocardial Infarction (STEMI) with LV thrombus in complete resolution of LV thrombus. The investigators aim to compare Warfarin to Rivaroxaban in the management of post-myocardial infarction left ventricular thrombus in our part of the world. Data management and Analysis Plan: Independent data safety and monitoring board will be formed and will be responsible for the safety concerns of the research participants. Data will be collected and entered in the computer-based CRF constructed using the password-protected free software at https://www.kobotoolbox.org. The data will be accessed by the principal investigator and the research officer only. The data will be anonymized before statistical analysis which will be performed by the separate coinvestigators responsible for the data analysis. Appropriate statistical tests will be used for measuring association and correlation. A 'P' value of less than 0.05 will be considered to be significant. Dissemination Plan: The findings of the study will be published in a peer-reviewed journal and presented at national and international conferences.

Official Title
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Comparison of Warfarin Versus Rivaroxaban in Management of Post-myocardial Infarction Left Ventricular Thrombus in a Tertiary Cardiac Center of Nepal: a Randomized Control Study.

Conditions
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Left Ventricular Thrombus, Myocardial Infarction

Intervention / Treatment
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* Drug: Rivaroxaban
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged >18 years hospitalized with the diagnosis of acute STEMI and Presence of LV thrombus which is confirmed with cardiac MRI. Exclusion Criteria: Bleeding risk Active bleeding; history of intracranial hemorrhage; clinically significant gastrointestinal bleeding within 12 months before randomization; severe thrombocytopenia (<50×109/L), or anemia (i.e., hemoglobin <90 g/L) at screening or pre-randomization; Liver function Child-Pugh B or C; untreated arterial aneurysm, arterial or venous malformation and aorta dissection; and body weight <40 kg. Undergoing anticoagulation therapy Cardiovascular condition Cardiac shock; uncontrolled blood pressure (SBP ≥180 mmHg); planned CABG within 3 months; suspicious Pseudo-ventricular aneurysm Concomitant diseases Severe chronic or acute renal failure (CrCl <50 mL/min at screening or pre-randomization); significant liver disease; current substance abuse (drug or alcohol) problem; life expectancy to less than 12 months; Known allergies, or intolerance to rivaroxaban; Woman who is currently pregnant, or breastfeeding; and Other hypercoagulable states, such as a malignant tumor, SLE Other conditions adjudicated by investigators to be unsuitable for anticoagulation Pregnant women and participants with any cognitive impairment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1 parallel study design
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban<br>In this arm, the patients with post-myocardial infarction and left ventricular thrombus will be treated with Rivaroxaban 20mg or 15mg as indicated. | Drug: Rivaroxaban<br>* Intervention Group: The patients in the intervention group will be treated with Rivaroxaban 20 mg once daily with the evening meal in patients with a CrCl >50 mL/min OR 15 mg in cases of moderate-to-severe renal impairment dose with the dosing of once daily with the evening meal in patients with a CrCl ≤50 mL/min. The patient in the intervention group will be requested for follow-up after 3 months of commencing the treatment or whenever the signs and symptoms of bleeding events are noted.<br>|
| Active Comparator: Warfarin<br>In this arm, the patients with post-myocardial infarction and left ventricular thrombus will be treated with warfarin with a dose adjusted with the International Normalised ratio range of 2.0 to 3.0. | Drug: Warfarin<br>* Control Group: The patients in the control group will be treated with Warfarin. The dose will be started with 5 mg and will be titrated based on the International Normalized Ratio (INR) which will be targeted at the range of 2.0 to 3.0. The dual antiplatelet duration will be based on the latest guidelines. The patients will be asked for frequent INR monitoring on an OPD basis until the INR is within the therapeutic range, after which patients will be asked for monthly follow-up INR reports. The patients in the control group will not be treated with heparin or low molecular weight heparin before the INR is maintained in the therapeutic range.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LV thrombus resolution | The primary endpoint will be a resolution of LV thrombus as assessed by cardiac MRI in 3 months of study. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major bleeding events | The major bleeding events will be defined according to the definition of major bleeding for non-surgical patients according to the International Society on Thrombosis and Haemostasis (ISTH)/Scientific and Standardization Committee (SSC)[xiv] which is Fatal bleeding. and/or Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome. and/or Bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells. | 3 months | 
| Embolic events | Embolic events will be defined as Cardioembolic stroke that is stroke attributable to arterial occlusion from an embolus that presumably arose in the heart. Ischemic stroke in the vascular distribution of a major intracranial or extracranial artery with >50% stenosis or occlusion on vascular imaging. Clinical findings include those of cerebral cortical involvement or brainstem or cerebellar dysfunction. Cortical and cerebellar lesions and brainstem or subcortical lesions >1.5 cm are considered potentially caused by large artery atherosclerosis. Evidence of a previous TIA or stroke in >1 vascular territory supports a clinical diagnosis of cardioembolic stroke.[xv] | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post Myocardial Infarction, Left Ventricular Thrombus, Warfarin, Rivaroxaban, Nepal