Rationale and design of a prospective multi-center randomized trial of EARLY treatment by rivaroxaban versus warfarin in ST-segment elevation MYOcardial infarction with Left Ventricular Thrombus (EARLY-MYO-LVT trial)

Jie He, Heng Ge, Jian-Xun Dong, Wei Zhang, Ling-Cong Kong, Zhi-Qing Qiao, Ying Zheng, Song Ding, Fang Wan, Long Shen, Wei Wang, Zhi-Chun Gu, Fan Yang, Zheng Li, Jun Pu, Jie He, Heng Ge, Jian-Xun Dong, Wei Zhang, Ling-Cong Kong, Zhi-Qing Qiao, Ying Zheng, Song Ding, Fang Wan, Long Shen, Wei Wang, Zhi-Chun Gu, Fan Yang, Zheng Li, Jun Pu

Abstract

Background: Left ventricular thrombus (LVT), a common complication of acute ST-segment elevation myocardial infarction (STEMI), is associated with increased risk of systemic embolism and high mortality. Current STEMI guidelines recommend adding anticoagulant therapy to dual antiplatelet therapy (DAPT) if early-formulated LVT were detected, for which vitamin K antagonist (VKA) is the standard anticoagulant agent. The role of non-VKA oral anticoagulants (NOACs) in this scenario is uncertain.

Methods: The EARLY-MYO-LVT study will be a prospective, multi-center and randomized trial designed to investigate the efficacy and safety of rivaroxaban versus warfarin in the treatment of post-STEMI LVT. It will enroll 280 patients with STEMI who have developed LVT within the first month of symptom onset. They will be randomized at 1:1 ratio into the group of rivaroxaban 15 mg daily or VKA treatment (with targeted INR 2-2.5) on the basis of standard DAPT (100 mg daily aspirin plus 75 mg daily clopidogrel) for 3-6 months. The primary efficacy endpoint will be the probability of LVT resolution after 3-month triple therapy, and the principal safety outcome will be the incidence of major bleeding events during the treatment.

Discussion: The described study will systemically assess the efficacy and safety of NOACs-based anticoagulant therapy in the treatment of LVT subsequent to STEMI.

Trial registration: The EARLY-MYO-LVT trial (Clinical trial number: NCT03764241).

Keywords: Bleeding; embolism and thrombosis; myocardial infarction; rivaroxaban.

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

2020 Annals of Translational Medicine. All rights reserved.

Figures

Figure 1
Figure 1
Study flowchart. STEMI, ST-elevation myocardial infarction; VKA, vitamin K antagonist; DAPT, dual antiplatelet therapy (DAPT is composed of 100 mg daily aspirin and 75 mg daily clopidogrel).
Figure 2
Figure 2
Manifestations of left ventricular thrombus (LVT) on CMR. LVT (white star) appears as a hypo-signal mass in the left ventricular in both the gadolinium perfusion (upper row) and late enhancement (lower row) imaging. Endo- and epi-cardium is delineaed by green and blue dash line, respectively. LGE, late gadolinium enhancement; LAX, long axis; SAX, short axis.

References

    1. Pu J, Ding S, Ge H, et al. Efficacy and Safety of a Pharmaco-Invasive Strategy With Half-Dose Alteplase Versus Primary Angioplasty in ST-Segment-Elevation Myocardial Infarction: EARLY-MYO Trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment-Elevation Myocardial Infarction). Circulation 2017;136:1462-73. 10.1161/CIRCULATIONAHA.117.030582
    1. Ding S, Lin N, Sheng X, et al. Melatonin stabilizes rupture‐prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα‐dependent manner. J Pineal Res 2019;67:e12581. 10.1111/jpi.12581
    1. Keren A, Goldberg S, Gottlieb S, et al. Natural history of left ventricular thrombi: their appearance and resolution in the posthospitalization period of acute myocardial infarction. J Am Coll Cardiol 1990;15:790-800. 10.1016/0735-1097(90)90275-T
    1. Mooe T, Teien D, Karp K, et al. Left ventricular thrombosis after anterior myocardial infarction with and without thrombolytic treatment. J Intern Med 1995;237:563-9. 10.1111/j.1365-2796.1995.tb00886.x
    1. Domenicucci S, Chiarella F, Bellotti P, et al. Early appearance of left ventricular thrombi after anterior myocardial infarction: a marker of higher in-hospital mortality in patients not treated with antithrombotic drugs. Eur Heart J 1990;11:51-8. 10.1093/oxfordjournals.eurheartj.a059592
    1. Solheim S, Seljeflot I, Lunde K, et al. Frequency of left ventricular thrombus in patients with anterior wall acute myocardial infarction treated with percutaneous coronary intervention and dual antiplatelet therapy. Am J Cardiol 2010;106:1197-200. 10.1016/j.amjcard.2010.06.043
    1. Kouvaras G, Chronopoulos G, Soufras G, et al. The effects of long-term antithrombotic treatment on left ventricular thrombi in patients after an acute myocardial infarction. Am Heart J 1990;119:73-8. 10.1016/S0002-8703(05)80084-5
    1. Cregler LL. Antithrombotic therapy in left ventricular thrombosis and systemic embolism. Am Heart J 1992;123:1110-4. 10.1016/0002-8703(92)91069-D
    1. Ram P, Shah M, Sirinvaravong N, et al. Left ventricular thrombosis in acute anterior myocardial infarction: Evaluation of hospital mortality, thromboembolism, and bleeding. Clin Cardiol 2018;41:1289-96. 10.1002/clc.23039
    1. Chen PF, Tang L, Yi JL, et al. The prognostic effect of left ventricular thrombus formation after acute myocardial infarction in the contemporary era of primary percutaneous coronary intervention: A meta-analysis. Eur J Intern Med 2019. [Epub ahead of print].
    1. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127:e362-425.
    1. Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45):3754-832.
    1. Delewi R, Nijveldt R, Hirsch A, et al. Left ventricular thrombus formation after acute myocardial infarction as assessed by cardiovascular magnetic resonance imaging. Eur J Radiol 2012;81:3900-4. 10.1016/j.ejrad.2012.06.029
    1. Meurin P, Brandao Carreira V, Dumaine R, et al. Incidence, diagnostic methods, and evolution of left ventricular thrombus in patients with anterior myocardial infarction and low left ventricular ejection fraction: a prospective multicenter study. Am Heart J 2015;170:256-62. 10.1016/j.ahj.2015.04.029
    1. Kristensen SD, Aboyans V. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2018;39:119-77. 10.1093/eurheartj/ehx393
    1. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e44S-88S.
    1. Lip GYH, Collet JP, Haude M, et al. 2018 Joint European consensus document on the management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous cardiovascular interventions: a joint consensus document of the European Heart Rhythm Association (EHRA), European Society of Cardiology Working Group on Thrombosis, European Association of Percutaneous Cardiovascular Interventions (EAPCI), and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA). Europace 2019;21:192-3. 10.1093/europace/euy174
    1. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213-60. 10.1093/eurheartj/ehx419
    1. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330-93. 10.1093/eurheartj/ehy136
    1. Schulman S, Angeras U, Bergqvist D, et al. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010;8:202-4. 10.1111/j.1538-7836.2009.03678.x
    1. Kaatz S, Ahmad D, Spyropoulos AC, et al. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015;13:2119-26. 10.1111/jth.13140
    1. Xia JL. Statistical considerations in non-inferiority clinical trials. Chinese Journal of Health Statistics 2012;29:270-74.
    1. ICH Harmonized Tripartite Guideline. Choice of control group and related issues in clinical trials. 2000;E10.
    1. Abdelnaby M, Almaghraby A, Abdelkarim O, et al. The role of rivaroxaban in left ventricular thrombi. Anatol J Cardiol 2019;21:47-50.
    1. Leow AS, Sia CH, Tan BY, et al. A meta-summary of case reports of non-vitamin K antagonist oral anticoagulant use in patients with left ventricular thrombus. J Thromb Thrombolysis 2018;46:68-73. 10.1007/s11239-018-1656-8
    1. Zielinska M, Kaczmarek K, Tylkowski M. Predictors of left ventricular thrombus formation in acute myocardial infarction treated with successful primary angioplasty with stenting. Am J Med Sci 2008;335:171-6. 10.1097/MAJ.0b013e318142be20
    1. Maniwa N, Fujino M, Nakai M, et al. Anticoagulation combined with antiplatelet therapy in patients with left ventricular thrombus after first acute myocardial infarction. Eur Heart J 2018;39:201-8. 10.1093/eurheartj/ehx551
    1. Küpper AJF, Verheugt FW, Peels CH, et al. Left ventricular thrombus incidence and behavior studied by serial two-dimensional echocardiography in acute anterior myocardial infarction: left ventricular wall motion, systemic embolism and oral anticoagulation. J Am Coll Cardiol 1989;13:1514-20. 10.1016/0735-1097(89)90341-0
    1. Kajy M, Shokr M, Ramappa P. Use of Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombus: Systematic Review of Current Literature. Am J Ther 2019. [Epub ahead of print]. 10.1097/MJT.0000000000000937
    1. Makrides CA. Resolution of left ventricular postinfarction thrombi in patients undergoing percutaneous coronary intervention using rivaroxaban in addition to dual antiplatelet therapy. BMJ Case Rep 2016. doi: .10.1136/bcr-2016-217843
    1. Shokr M, Ahmed A, Abubakar H, et al. Use of direct oral anticoagulants in the treatment of left ventricular thrombi: A tertiary center experience and review of the literature. Clin Case Rep 2018;7:135-42. 10.1002/ccr3.1917
    1. Seecheran R, Seecheran V, Persad S, et al. Rivaroxaban as an antithrombotic agent in a patient with ST-segment elevation myocardial infarction and left ventricular thrombus: a case report. J Investig Med High Impact Case Rep 2017;5:2324709617697991. 10.1177/2324709617697991
    1. Summaria F, Sgueglia GA, D'Errico F, et al. Safety and Efficacy of Triple Therapeutic Targets with Rivaroxaban after Acute Myocardial Infarction Complicated by Left Ventricular Thrombi in a Case of Nonvalvular Atrial Fibrillation. Case Rep Cardiol 2018;2018:6503435.
    1. Azizi A, Puricel S, Cook S, et al. Rivaroxaban dissolves postinfarction left ventricular thrombus. Cardiovasc Med 2016;19:25-7. 10.4414/cvm.2016.00381
    1. Smetana KS, Dunne J, Parrott K, et al. Oral factor Xa inhibitors for the treatment of left ventricular thrombus: a case series. J Thromb Thrombolysis 2017;44:519-24. 10.1007/s11239-017-1560-7
    1. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107-15. 10.1016/S0140-6736(12)62177-1
    1. Fiedler KA, Maeng M, Mehilli J, et al. Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol 2015;65:1619-29. 10.1016/j.jacc.2015.02.050
    1. Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med 2016;375:2423-34. 10.1056/NEJMoa1611594
    1. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29-38. 10.1016/S0140-6736(09)60738-8
    1. McCarthy CP, Vaduganathan M, McCarthy KJ, et al. Left Ventricular Thrombus After Acute Myocardial Infarction: Screening, Prevention, and Treatment. JAMA Cardiol 2018;3:642-9. 10.1001/jamacardio.2018.1086
    1. Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51). J Am Coll Cardiol 2013;61:1853-9. 10.1016/j.jacc.2013.01.066
    1. Lip GY, Hammerstingl C, Marin F, et al. Left atrial thrombus resolution in atrial fibrillation or flutter: Results of a prospective study with rivaroxaban (X-TRA) and a retrospective observational registry providing baseline data (CLOT-AF). Am Heart J 2016;178:126-34. 10.1016/j.ahj.2016.05.007
    1. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. 10.1056/NEJMoa1009638

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