Anticoagulation in Post MI LV Thrombus Trial in Nepal

Official title

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.

Overview

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

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.

Interventions

• Drug Rivaroxaban
  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.
• Drug Warfarin
  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

Primary outcome measures

• LV thrombus resolution [Time frame: 3 months]

Secondary outcome measures (2)

• Major bleeding events [Time frame: 3 months]
• Embolic events [Time frame: 3 months]

Eligibility criteria

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.

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

Single blind

Primary purpose

Treatment

Study locations

Nepal · 1 center

• Nepal Health Research Council — Kathmandu

Publications

• Bhattarai S, Aryal A, Pyakurel M, Bajracharya S, Baral P, Citrin D, Cox H, Dhimal M, Fitzpatrick A, Jha AK, Jha N, Karmacharya BM, Koju R, Maharjan R, Oli N, Pyakurel P, Sapkota BP, Shrestha R, Shrestha S, Spiegelman D, Vaidya A, Shrestha A. Cardiovascular disease trends in Nepal - An analysis of global burden of disease data 2017. Int J Cardiol Heart Vasc. 2020 Jul 31;30:100602. doi: 10.1016/j.ij PMID 32775605
• Adhikari, C. M., Acharya, K. P., Manandhar, R., Sherpa, K., Tamrakar, R., Bogati, A., Singh, S. K., Kansakar, S., Yadav, D. N., Dhungana, M., Dhungel, S., Baniya, B., Joshi, S., Rajbhandari, S., Pandey, R., Raut, R., Prajapati, D., KC, S. S., Adhikari, J., Adhikari, A., Gautam, B., Najmy, S., Poudel, R., Timalsina, B. K., Karki, P., Poudel, S., Thakur, K. K., Limbu, D., Nepal, H. P., Sharma, M., R
• Gottdiener JS, Gay JA, VanVoorhees L, DiBianco R, Fletcher RD. Frequency and embolic potential of left ventricular thrombus in dilated cardiomyopathy: assessment by 2-dimensional echocardiography. Am J Cardiol. 1983 Dec 1;52(10):1281-5. doi: 10.1016/0002-9149(83)90588-x. PMID 6650417
• Gottdiener JS, Massie B, Ammons SB, et al. Prevalence of left ventricular thrombus in dilated cardiomyopathy: the WATCH trial. J Am J Cardiol 2003;41:202.
• Srichai MB, Junor C, Rodriguez LL, Stillman AE, Grimm RA, Lieber ML, Weaver JA, Smedira NG, White RD. Clinical, imaging, and pathological characteristics of left ventricular thrombus: a comparison of contrast-enhanced magnetic resonance imaging, transthoracic echocardiography, and transesophageal echocardiography with surgical or pathological validation. Am Heart J. 2006 Jul;152(1):75-84. doi: 10. PMID 16824834
• Keeley EC, Hillis LD. Left ventricular mural thrombus after acute myocardial infarction. Clin Cardiol. 1996 Feb;19(2):83-6. doi: 10.1002/clc.4960190203. PMID 8821415
• Pizzetti G, Belotti G, Margonato A, Carlino M, Gerosa S, Carandente O, Chierchia SL. Thrombolytic therapy reduces the incidence of left ventricular thrombus after anterior myocardial infarction. Relationship to vessel patency and infarct size. Eur Heart J. 1996 Mar;17(3):421-8. doi: 10.1093/oxfordjournals.eurheartj.a014875. PMID 8737217
• Bhatnagar SK, al-Yusuf AR. Effects of intravenous recombinant tissue-type plasminogen activator therapy on the incidence and associations of left ventricular thrombus in patients with a first acute Q wave anterior myocardial infarction. Am Heart J. 1991 Nov;122(5):1251-6. doi: 10.1016/0002-8703(91)90563-w. PMID 1659166

Identifiers

NCT: NCT05794399 · SGNHC-RCT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗