The RELEVENT trial is a pragmatic international, multicenter, prospective randomized open label blinded endpoint trial that will recruit at least 216 patients with newly diagnosed LV thrombus. Participants will be randomized 1:1 to either a DOAC or dose adjusted warfarin to test the noninferiority of the former for the primary outcome of resolution of LV thrombus without cardiovascular death, stroke, systemic embolization or major bleeding at 3 months ( Figure 1 ).

Flow diagram of RELEVENT trial including primary and secondary outcomes.

The trial is recruiting in 16 secondary and tertiary care cardiology centers in Australia and New Zealand (Supplementary Table I).

Eligible participants include patients aged 18 or over, with a new diagnosis of LV thrombus and regarded by the treating clinician to be suitable for treatment with either warfarin or a DOAC. Exclusions have been kept to a minimum ( Table 1 ).

The trial is funded in New Zealand by a grant from the Greenlane Research and Education Fund [ 17/42/4135] and in Australia by a grant from the National Heart Foundation of Australia [ VG104989]. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

The trial has been prospectively registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12618001254280, Universal Trial Number U1111-1216-0447).

The RELEVENT trial is designed to closely mirror standard clinical practice. Thus, the clinical imaging used to diagnose LV thrombus will also confirm study eligibility. Imaging may be by echocardiography preferably using a contrast-enhancing agent, cardiac computerized tomography (CT) or CMR. Left ventriculography alone is not sufficient. Image quality must be adequate to confirm the presence of LV thrombus, and the use of echocardiographic contrast or tomographic imaging is encouraged.

The follow-up imaging method will be specified prior to randomization and will be the same method as was used to definitively diagnose the LV thrombus. For example, if a LV thrombus was suspected on echocardiography but required CMR for confirmation, repeat CMR would be required at 3 months.

In addition to evaluating the presence of the LV thrombus, its size (maximal diameter) and shape (laminar or protuberant) are recorded, as is the LV ejection fraction and whether there is localized or global systolic dysfunction. Baseline and follow-up images are transferred to a core laboratory for review blinded to treatment allocation.

Clinical and demographic variables are collected at baseline, along with the EQ-5D-5L questionnaire, the Questionnaire for Verifying Stroke-Free Status (QVSFS) and the WHO Disability Assessment Schedule (WHODAS) 2.0.

Patients are randomized using a web-based system, 1:1 to either warfarin or DOAC, stratified by the underlying mechanism (acute MI [within 4 weeks] or cardiomyopathy) and country. Due to the nature of the intervention, blinding of participants and their treating clinicians is not feasible. Study outcomes are assessed independently by observers blinded to treatment allocation.

Participants randomized to a DOAC can be treated with either a factor Xa inhibitor (apixaban or rivaroxaban, but not edoxaban which is not approved for use in Australia or New Zealand) or a direct thrombin inhibitor (dabigatran). The choice of DOAC is made according to local availability and preference and is specified prior to randomization.

The dose of DOAC is the same as recommended by the manufacturer for stroke prevention in atrial fibrillation, with appropriate adjustment for age, body weight, creatinine clearance and bleeding risk. Recommended doses for DOACs for stroke prevention in atrial fibrillation are Apixaban, standard dose 5 mg bd, reduced dose 2.5 mg bd; Rivaroxaban, standard dose 20 mg od, reduced dose 15 mg od, Dabigatran, standard dose 150 mg bd, reduced dose 110 mg bd.

For patients randomized to warfarin, the target INR is 2.5, with a range between 2.0 and 3.0. INR monitoring and warfarin dose adjustment is as for usual care and a record of INR levels is collected to determine time in therapeutic range for each participant. When initiating treatment, either low molecular weight heparin or unfractionated heparin are recommended until the INR is ≥2.0.

The use of all other nonrandomized medications is at the discretion of treating clinicians, in accordance with standard practice and national and international guidelines. These are recorded at baseline and 3-month follow-up. It is recommended that where patients are receiving 2 antiplatelet agents in addition to their randomized anticoagulant the duration of such ‘triple therapy’ is minimized, and only in exceptional circumstances is this continued for more than 30 days. ^, When a single antiplatelet agent is used longer term in combination with oral anticoagulation, clopidogrel is recommended and in all patients on a combination of an antiplatelet agent and oral anticoagulation the use of a proton pump inhibitor is encouraged. ^,

Participants are phoned at 1 month to ensure they are taking and tolerating their randomized study medication. After approximately 12 weeks of randomized treatment, participants have a follow up assessment and repeat imaging (as above) to determine the resolution of their LV thrombus. At this follow-up visit, participants will complete the same questionnaires as at baseline (EQ-5D-5L, QVSFS and WHODAS 2.0). Further clinical follow-up (without mandatory repeat imaging), with completion of the same questionnaires is performed at 12, 24 and 36 months. A flow chart of the study design is shown in Figure 1 and an assessment schedule in Supplementary Table II.

The primary outcome is resolution of the LV thrombus, without cardiovascular death, stroke, systemic embolization or major bleeding, at 3 months. Secondary outcomes and other outcomes of interest are outlined in Table 2 .

De-identified baseline and 3-month follow-up images are reviewed by 2 independent expert observers. Both adjudicate the presence of LV thrombus and rate this as certain, probable, possible or absent. In addition, in each participant 1 adjudicator also measures the maximal diameter and area of the LV thrombus and determines if it is laminar or protuberant. Where the 2 observers disagree that a thrombus is certain or absent a third observer assesses the image. If 2 of 3 observers agree it is certain or probable it is designated as being present, whereas if 2 of 3 find it to be absent or possible it is designated as not being present. A secondary sensitivity analysis will be performed only including patients with certain or probable LV thrombus (as determined by the core lab) at baseline.

Clinical outcomes (cardiovascular death, stroke, systemic embolism or severity of bleeding) are adjudicated by 2 independent expert observers blinded to treatment allocation. If they disagree a third adjudicator reviews the case, and the majority decision is recorded. Standard definitions of these endpoints are used, as outlined in the supplementary material. Bleeding events are adjudicated according to the Bleeding Academic Research Consortium criteria, with major bleeding defined as type 3 or greater.

Reported rates of LV thrombus resolution range from approximately 50% to 90% of patients following acute MI, with the majority resolving within the first few weeks. ^,, In a meta-analysis of recent studies that have compared echocardiography with CMR, resolution rates at 3 to 6 months were 88%, using the latter imaging modality. Clinical events (cardiovascular death, stroke and systemic embolism) are key indicators of efficacy and important components of the composite primary endpoint. They are, however, relatively rare among contemporary patients receiving OAC therapy (∼5%-10% at 3 months), and are likely to occur more often in patients with persisting thrombus. Likewise, although clinically relevant bleeding events are reported to be approximately 20% lower in patients receiving DOACs, compared to those treated with warfarin, the absolute incidence over 3 months is expected to be low ( Table 3 ). Thus, if we assume a 76% “success rate” (ie, 76% of participants do not die from cardiovascular causes and have resolution of LV thrombus with no stroke, systemic embolization or major bleeding) in warfarin treated patients and 82% in those randomized to a DOAC then 204 participants are required to be 80% sure that the upper limit of a one-sided 97.5% confidence interval (CI), or equivalently a 95% two-sided CI, will exclude a difference in favor of the standard group (warfarin) of more than 10%. Assuming a loss to follow-up of 5%, 216 patients will be recruited into the trial.

Table 3

Previous randomized comparisons of warfarin versus direct oral anticoagulants in the treatment of left ventricular thrombus.

Study	Study population	Number randomized	Number completing 3m follow-up	DOAC used		Other thrombus related outcomes reported	Stroke/systemic embolism rates (3m)	Major bleeding rates (3 m)
Isa et al.	Any newly diagnosed LVT	27 (14 DOAC/ 13 warfarin)	22 (13 DOAC/ 9 warfarin)	Apixaban 5mg bd*	Not reported	Mean reduction in LVT size: DOAC 65.1% v warfarin 61.5%	1 CVA in DOAC arm only	Not reported
Abdelnabi et al.	Any newly diagnosed LVT	79 (39 DOAC/ 40 warfarin)	79 (39 DOAC/ 40 warfarin)	Rivaroxaban 20mg od	77% DOAC v 68% warfarin	Resolution at 1 m: 72% DOAC v 48% warfarin	0 DOAC/ 6 warfarin	2 DOAC/ 6 warfarin
Alcalai et al.	Post-MI only	35 (18 DOAC/ 17 warfarin)	32 (17 DOAC/ 15 warfarin)	Apixaban 5mg bd*	94% DOAC v 93% warfarin	Nil reported	0 DOAC/ 1 warfarin	0 DOAC/ 2 warfarin
Youssef et al.	Post-MI only	55 (27 DOAC/ 28 warfarin)	50 (25 DOAC/ 25 warfarin)	Apixaban 5mg bd*	76% DOAC v 80% warfarin	20% regression at 3 m (without resolution) in both groups	Nil in either group	Nil in either group †
Jenab et al.	Post-MI only	50 (25 DOAC/ 25 warfarin)	49 (25 DOAC/ 24 warfarin)	Rivaroxaban 15mg od	76% DOAC v 54% warfarin	Nil reported	Nil in either group	Nil in either group ‡
Shah et al.	Post-MI only	261 (171 DOAC/ 90 warfarin)	252 (165 DOAC/ 87 warfarin)	Rivaroxaban 20mg od	96% DOAC v 97% warfarin	Resolution at 1 m: 20% DOAC v 8% warfarin	DOAC 6 CVAs (3.5%)/ warfarin 1 CVA (1.1%)	4 DOAC (2.3%)/ 1 warfarin (1.1%)

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