IMR Press / RCM / Volume 23 / Issue 7 / DOI: 10.31083/j.rcm2307243
Open Access Systematic Review
A Meta-Analysis Comparing Different Oral Anticoagulation for the Treatment of Ventricular Thrombus
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1 National Clinical Research Center of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 100037 Beijing, China
2 Emergency Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 100037 Beijing, China
3 Department of Endocrinology, Key Laboratory of Endocrinology of the National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100037 Beijing, China
4 Department of Echocardiographic, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 100037 Beijing, China
*Correspondence: fwyy2803@163.com (Yan Liang)
Academic Editor: Fabrizio D’Ascenzo
Rev. Cardiovasc. Med. 2022, 23(7), 243; https://doi.org/10.31083/j.rcm2307243
Submitted: 25 March 2022 | Revised: 14 May 2022 | Accepted: 30 May 2022 | Published: 27 June 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Background: Patients with ventricular thrombus (VT) require anticoagulation therapy and it remains unknown that whether non-vitamin K antagonist oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) are more effective. Objective: We aimed to compare the effectiveness and safety of NOACs with VKAs on the rate of thrombus resolution and clinical outcomes. Methods: MEDLINE, PUBMED, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure Database and Wanfang Database, were searched up to November 22, 2021. The primary outcome was the rate of thrombus resolution, and the secondary outcomes were bleeding, stroke or systemic embolism (SSE), stroke and all-cause death. Odds ratio (OR) and 95% confidential intervals (CI) were used for the pooled results. Results: Eighteen studies with 1755 participants (NOACs, n = 607; VKAs, n = 1148) were included. There were no significant differences in thrombus resolution (OR 0.92, 95% CI 0.68–1.23, p = 0.558), bleeding (OR 0.85, 95% CI 0.54–1.35, p = 0.496), SSE (OR 0.77, 95% CI 0.41–1.43, p = 0.401), stroke (OR 0.65, 95% CI 0.29–1.49, p = 0.312) or all-cause death (OR 1.02, 95% CI 0.63–1.67, p = 0.925) between NOACs and VKAs. Subgroup analyses showed a statistics difference in thrombus resolution between NOACs and VKAs among studies which enrolled patients with or without dabigatran (Yes: OR 0.80, 95% CI 0.59–1.08; No: OR 1.48, 95% CI 1.00–2.19; p = 0.01), while no significances were observed according to baseline characteristics. Conclusions: Our findings showed that NOACs were comparable to VKAs in thrombus resolution as well as clinical outcomes. In studies that enrolled patients without dabigatran, the thrombus resolution seemed to be greater in NOACs group than VKAs group. And in different proportion of baseline left ventricular ejection fraction, history of ischemic cardiomyopathy and combination with antiplatelet, the thrombus resolution among the two groups remained similar.

Keywords
ventricular thrombus
non-vitamin K antagonists
oral anticoagulants
warfarin
1. Introduction

Ventricular thrombus (VT), with an incidence ranging from 2% to 5% [1, 2], can lead to a high rate of embolism to vital organs or mortality [3, 4, 5], which are mostly secondary to severe cardiac systolic dysfunction, myocardial infarction or cardiomyopathy. Treatments and clinical outcomes in patients with VT were inconsistent. According to guidelines, the warfarin use was reasonable for ST elevation myocardial infarction (STEMI) patients with asymptomatic left VT (Class II a, Level C evidence) [6, 7]. Due to the inherent limitations of warfarin, patients might have a poor compliance, making it arduous to guarantee the effective maintenance and control of the therapeutic target of international normalized ratio (INR).

Non-vitamin K antagonist oral anticoagulants (NOACs) have been an attractive anticoagulant choice nowadays in the setting of non-valvular atrial fibrillation and venous thrombotic diseases [8, 9]. Several studies reported that patients with VT who received NOACs had a great rate of thrombus resolution (83% to 100%) [10, 11]. In general, compared with vitamin K antagonists (VKAs), NOACs have several special features such as a rapid onset of action, offering a more predictable and flexible anticoagulant option, and have been increasingly favored in clinical practice [12]. In the guideline of stroke, patients with acute myocardial infarction (AMI) combined with ischemic stroke or transient ischemic attack (TIA) were recommended to use dabigatran, rivaroxaban or apixaban for 3 months to prevent recurrence stroke or TIA (Class II b, Level C evidence) [13]. Similarly, 2017 European guideline suggested that STEMI patients with left VT should maintain anticoagulation therapy for up to 6 months under the guidance of repeated imaging (Class II a, level C evidence) [14]. Up to date, the application of NOACs in patients with VT has not been clearly evaluated and the comparison between NOACs and VKAs in patients with VT remains controversial.

To address the knowledge gaps, we aimed to conduct a systematic review and meta-analysis to compare the effectiveness and safety between NOACs and VKAs, providing more evidence on anticoagulation therapy for patients with VT.

2. Methods

The study was performed under the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [15] and it was registered on PROSPERO as CRD42020205477, which was available from: https://www.crd.york.ac.uk/prospero/#recordDetails.

2.1 Search Strategy

Two reviewers (Q.Y. and L-Y.H.) independently searched seven databases including Cochrane Library, MEDLINE (Ovid), PUBMED, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI) Database and Wanfang Database to identify the studies from inception to November 22, 2021. The reference lists of researches and systematic reviews were also reviewed and retrieved for more trials. Potential gray literature was searched in OpenGrey.eu. The following search terms were used: “ventricular thrombus” or “intraventricular thrombus”, “direct/new/novel oral anticoagulants” or “non-vitamin K antagonists oral anticoagulants”, “warfarin”, “vitamin K antagonists” and combination of these terms as keywords (The detailed search strategy was showed in Supplementary materials).

2.2 Study Eligibility and Selection

Eligible studies met all the following criteria: (1) studies that included participants with VT, regardless of nationality, sex, race, occupation or education; (2) studies that compared NOACs and VKAs for the treatment of VT (NOACs could be rivaroxaban, apixaban, edoxaban, dabigatran, or any other new oral anticoagulants and VKAs could be warfarin, coumadin, phenprocoumon, acenocumarol, fluindione, phenindione or anisindione).

Studies that met the following criteria were excluded: (1) studies that were abstracts, reviews, duplicated publications, case reports or case series; (2) the data were incomplete or not serious, especially the important outcome events missing or not available.

Investigators searched for related literature, imported articles into the database created by Endnote (Endnote X9.3.1; Thomson Reuters, San Francisco, CA), and filtered for duplicates. According to the inclusion and exclusion criteria, our two reviewers (Q.Y. and L-Y.H.) independently screened the titles and abstracts. If appropriate, full texts of the records were reviewed to identify all potentially eligible studies. The selection processes were repeated twice. Conflicts were resolved through discussions with other team members until a consensus was reached.

2.3 Data Collection and Analysis

Data collection was conducted to extract the participant and study characteristics, including study design, baseline information of subjects (age, sex, hypertension, diabetes mellitus, atrial fibrillation, history of thromboembolism, ischemic cardiomyopathy (ICM), dyslipidemia), cardiac imaging data (left ventricular ejection fraction, LVEF), and antiplatelet therapy.

The primary outcome was the rate of thrombus resolution which was confirmed by echocardiogram, computer tomography (CT) or cardiac magnetic resonance imaging (CMR), and the secondary outcomes included bleeding, stroke, stroke or systemic embolism (SSE) events and all-cause death. Stroke events referred to definite ischemic or hemorrhagic stroke, and other uncertain or unknown stroke [16]. SSE events were defined as the stroke or transient ischemic attack, acute coronary emboli (including myocardial infarction) or acute peripheral artery emboli (limb, renal, or digestive arteries) [17]. Bleeding events were defined as International Society on Thrombosis and Haemostasis (ISTH) major bleeding or clinically relevant non-major bleeding events [18, 19]. Two reviewers (Q.Y. and L-Y.H.) extracted the data independently and compared the results to ensure coherence, and an additional reviewer resolved the discrepancies.

2.4 Assessment of Quality in the Included Studies

The Newcastle-Ottawa Scale (NOS) was operated by two reviewers independently to evaluate the quality of studies included [20], which assessed cohort studies for three blocks, including selection, comparability, and outcome evaluation. A study could be awarded a maximum of one star for each numbered item within the selection and outcome categories. A maximum of two stars could be given for comparability. The article quality was evaluated as follows: low quality (0–3); moderate quality (4–6); high quality (7–9). Any disagreement was discussed with other team members until agreement was reached.

2.5 Statistics Analysis

The continuous data were presented as mean and standard deviation (SD) or median and interquartile range (IQR), and the dichotomous outcomes were calculated by the odds ratio (OR) with 95% confidence intervals (CIs) [21]. A random-effects model was used for meta-analysis considering the possible heterogeneity existing in the eligible studies. Heterogeneity was visually assessed with the forest plots and statistically detected by standard Chi-squared test and I2 statistic [22]. I2 test explained the percentage of variation in intervention estimates due to heterogeneity rather than sampling error, with I2 values 0% to 40% being indicative of likely insignificant; 30% to 60%, likely moderate heterogeneity; 50% to 90%, likely substantial heterogeneity; 75% to 100%, substantial heterogeneity [21]. To explore the possible sources of heterogeneity in the thrombus resolution, subgroup analyses were performed (a. Studies with dabigatran vs. studies without dabigatran; b. ICM history 80% vs. <80%; c. LVEF 30% vs. <30%; d. Antiplatelet therapy 90% vs. <90%) according to the baseline characteristics that might be related to the rate of thrombus resolution. The generalized linear model (generalized linear mixed-model, GLMM) was conducted to reduce the bias of classical Meta-analysis caused by continuous correction. Sensitivity analysis was performed by omitting studies one by one. Publication bias was visually evaluated using funnel plot and statistically accessed by Egger’s regression tests [23]. Furthermore, when Egger’s regression tests or funnel plots indicated publication bias, we utilized the trim-and-fill method to identify whether funnel plot asymmetry should be corrected [24]. All comparisons were considered two-sided, and the p < 0.05 was considered as statistical significance. All the analyses were scheduled for completion with R Studio, Version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria).

3. Results
3.1 Literature Search

Fig. 1 represented the process of the literature search. A total of 954 citations were yielded by searching Cochrane Library, MEDLINE, PUBMED, EMBASE, and Web of Science, CNKI and Wanfang Database, of which 809 records remained after removing the duplicates. After reviewing titles and abstracts, 27 citations were remained for the full-text screening and 782 records were deleted owing to irrelevance to our study. Nine articles were deleted due to the inaccessibility of full-text (n = 8) and uncomplete data (n = 1). Finally, we included a total of 18 eligible studies for meta-analysis (17 for retrospective study and one for prospective study) [25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42].

Fig. 1.

Flow chart of literature search strategies.

3.2 Study and Patient Characteristics

Among the eligible studies included, eight studies were conducted in 2021, and the rest were published in recent years. Observational durations ranged from 3 to 172 months, eight of which lasted for 12 months or even longer [27, 28, 29, 38, 40, 41] (Table 1, Ref. [25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42]). Among 1755 patients included, 65% of patients (n = 1148) received VKAs and 35% of patients (n = 607) received NOACs. Rivaroxaban (70.4%, 405/575) was the most commonly used NOACs, followed by apixaban (24.0%, 138/575), dabigatran (5.4%, 31/575), and edoxaban (0.2%, 2/575).

Table 1.Baseline characteristics of studies included.
Study Follow-up, months Comparison Sample size Male, n (%) Mean age, years Mean LVEF, % TTR, % Antiplatelet therapy, n (%) Major medical history, n (%)
Atrial fibrillation Thromboembolisms Ischemic cardiomyopathy
Daher et al., 2020 [25] 3 NOACs 17 14 (82.4) 57 41 - 11 (64.7) - - 15 (88)
VKA 42 35 (83) 61 36 28 (67) - - 36 (74)
Iqbal et al., 2020 [26] 36 NOACs 22 16 (73) 62 31 - 9 (41) 3 (14) 2 (9) 18 (82)
VKA 62 57 (92) 62 35 39 (65) 3 (5) 11 (17.7) 55 (89)
Robinson et al., 2020 [27] 12 NOACs 121 94 (77.7) 58.1 27.7 - 77 (63.6) 30 (24.8) 79 (65.3) 66 (54.5)
VKA 236 170 (72) 58.2 28.2 164 (69.5) 45 (19.1) 123 (52.1) 148 (62.7)
Jones et al., 2020 [28] 24 NOACs 41 33 (80.4) 58.7 33.5 53.5 38 (92.7) 0 21 (55.3) 21 (55.3)
VKA 60 51 (85) 60.8 35.4 55 (91.7) 0 22 (36.7) 22 (36.7)
Guddeti et al., 2020 [29] 12 NOACs 19 15 (79) 60.7 25 - 11 (57.9) 4 (21.1) 11 (57.9) 10 (52.6)
VKA 80 55 (68.8) 61.3 25 54 (67.5) 18 (22.5) 49 (61.2) 48 (60)
Yan et al., 2019 [30] 6 NOACs 11 9 (81.8) 64.2 38.6 - 11 (100) 0 - 11 (100)
VKA 37 34 (91.9) 59 39.6 21 (56.7) 0 - 37 (100)
Chao et al., 2018 [32] 8.3 NOACs 56 45 (80.3) 61.2 46.8 - 56 (100) 4 (7.1) 50 (89.3) 47 (83.9)
VKA 70 55 (78.6) 60.4 35.3 70 (100) 6 (8.6) 67 (95.7) 61 (87.1)
Li et al., 2015 [31] 3 NOACs 15 11 (73.3) 51.6 - - 0 5 (33) 6 (40) 6 (40)
VKA 16 12 (75) 52.4 - 0 4 (25) 7 (43) 7 (43)
Zhang et al., 2021 [38] 24 NOACs 33 24 (72.7) 60.3 42.9 77.4 33 (100) - - 33 (100)
VKA 31 23 (74.2) 61.3 41.4 31 (100) - - 31 (100)
Mihm et al., 2021 [34] 6 NOACs 33 23 (69.7) 63.3 32.58 - 19 (57.6) 13 (39.4) 9 (27.3) 14 (42.4)
VKA 75 54 (72) 60.3 27.95 55 (73.3) 15 (20) 20 (26.7) 72 (96)
Alcalai et al., 2021 [36] 3 NOACs 18 13 (72.2) 55.5 35 60 18 (100) - - 4 (22.2)
VKA 17 15 (88.2) 58.8 36 17 (100) - - 3 (17.7)
Albabtain et al., 2021 [35] 9.5 NOACs 28 24 (85.7) 58.2 26.4 - 19 (67.9) 1 (3.6) 16 (57.1) 16 (57.1)
VKA 35 34 (97.1) 59 27.3 20 (57.1) 2 (5.7) 25 (71.4) 25 (71.4)
Yao et al., 2021 [42] 3 NOACs 42 34 (81) 58.5 42.8 - - - - 25 (59.5)
VKA 58 48 (82.8) 60.1 36.6 - - - 32 (55.2)
Willeford et al., 2020 [40] 172.5 NOACs 22 17 (77.3) 54 - - 5 (22.7) 3 (13.6) 6 15 (68.2)
VKA 129 104 (80.6) 56 - 70 (54.3) 24 (18.6) 46 68 (52.7)
Iskaros et al., 2021 [33] 3 NOACs 32 28 (88) 62 25 - 21 (66) 4 (13) 20 22 (69)
VKA 45 41 (91) 63 25 30 (67) 9 (20) 25 33 (73)
Varwani et al., 2021 [39] 12 NOACs 58 - - - 13.1 - - - -
VKA 34 - - - - - - -
Cochran et al., 2020 [37] 12 NOACs 14 11 (78.6) 51.5 - - - - - 26 (53)
VKA 59 45 (76.3) 62 - - - - 36 (61)
Xu et al., 2021 [41] 2.4 NOACs 25 19 (76) 59.4 33.8 - 11 (44) 20 (80) 4 (16) 18 (72)
VKA 62 47 (75.8) 61.9 37.6 27 (43.5) 50 (80.6) 13 (21) 48 (77.4)
Abbreviations: NOACs, non-vitamin K antagonist oral anticoagulants; VKAs, vitamin K antagonists; LVEF, left ventricular ejection fraction.

Thirteen studies adopted echocardiogram to assess VT [25, 27, 29, 31, 32], three studies using echocardiogram or CMR [14, 28, 34] and two studies adopted all three tools-echocardiogram, CT, CMR-to confirm thrombus resolution [30, 33]. Most of the studies had a higher proportion of men than women. Among the total of 1755 patients, the mean age of participants varied from 51 to 64 years, with a median age of 60.3 years old. Among the included studies, four papers reported time in therapeutic range (TTR) [28, 36, 38, 39], of which two articles indicated that patients met the therapeutic target of INR (TTR 60%) [36, 38], while the rest of fourteen articles reported no tracked data of TTR even though they collected the baseline of INR or highlighted the importance of monitoring the INR range of 2.0–3.0. Fourteen studies reported baseline LVEF which ranged from 25% to 46%, and patients in NOACs group had a median of 33.6% (IQR 28.5%–44.4%) while patients in VKAs group had a median of 35.3% (IQR 28.0%–36.4%). Fifteen studies reported the combination of antiplatelet agents at baseline, with 68.8% (339/493) patients in NOACs group and 68.3% (681/997) in VKAs group (Table 1).

3.3 Quality Assessment

The quality assessment showed that the quality of 11 studies was at high levels while the rest was at moderate levels, and the average score was 7.11 (Supplementary Table 1). All studies had adequacy of follow-up by a description of missing visits. Owing to the retrospective studies, all of them had record linkages. Five studies did not adequately consider the comparability of the exposed and unexposed groups in their design and statistical analysis [25, 29, 30, 31, 32].

3.4 Outcomes of Meta-Analysis
3.4.1 Thrombus Resolution

At a median follow-up period of 8.9 (IQR 3–12) months, 71% (599/842) of patients in the VKAs group and 74% (319/430) in the NOACs group had complete thrombus resolution. Fig. 2 showed no significant difference in thrombus resolution rate between NOACs and VKAs groups (OR 1.09, 95% CI 0.81–1.46, p = 0.558) with insignificant heterogeneity (I2 = 0%) by analyzing 15 retrospective studies and 1 prospective study (Fig. 2).

Fig. 2.

Forest plot of thrombus resolution between NOACs versus VKAs (16 studies). Abbreviation: OR, odds ratio; CI, Confidence interval; NOACs, non-vitamin K antagonist oral anticoagulants; VKAs, vitamin K antagonists.

3.4.2 Bleeding

No significant difference was observed in bleeding rate between NOACs and VKAs groups (OR 0.85, 95% CI 0.54–1.35, p = 0.496, I2 = 0%) according to 17 studies (Fig. 3).

Fig. 3.

Forest plot of bleeding between NOACs versus VKAs (17 studies). Abbreviation: OR, odds ratio; CI, Confidence interval; NOACs, non-vitamin K antagonist oral anticoagulants; VKAs, vitamin K antagonists.

3.4.3 Stroke or Systemic Embolism

A total of 18 studies reported the outcome of SSE and no significant difference was found in the comparison of NOACs and VKAs groups (OR 0.77, 95% CI 0.41–1.43, p = 0.401) with moderate heterogeneity (I2 = 38%) (Fig. 4).

Fig. 4.

Forest plot of SSE between NOACs versus VKAs (18 studies). Abbreviation: OR, odds ratio; CI, Confidence interval; NOACs, non-vitamin K antagonist oral anticoagulants; VKAs, vitamin K antagonists.

3.4.4 Stroke

Apart from analyzing SSE in our included studies, we also extracted the stroke events in 14 studies and there was no significant difference as well (OR 0.65, 95% CI 0.29–1.49, p = 0.312, I2 = 39%) (Fig. 5).

Fig. 5.

Forest plot of stroke between NOACs versus VKAs (14 studies). Abbreviation: OR, odds ratio; CI, Confidence interval; NOACs, non-vitamin K antagonist oral anticoagulants; VKAs, vitamin K antagonists.

3.4.5 All-Cause Death

Fig. 6 graphed that an insignificant difference was observed in all-cause death between NOACs and VKAs groups (OR 1.02, 95% CI 0.63–1.67, p = 0.925) with small heterogeneity (I2 = 0%) in 18 studies.

Fig. 6.

Forest plot of all-cause death between NOACs versus VKAs (18 studies). Abbreviation: OR, odds ratio; CI, Confidence interval; NOACs, non-vitamin K antagonist oral anticoagulants; VKAs, vitamin K antagonists.

Supplementary Table 2 summarized the results for efficacy and safety of NOACs versus VKAs. In order to add the double zero events of outcomes into the analysis, the GLMM was performed to give unbiased results. Supplementary Figs. 1–5 showed the results of thrombus resolution, bleeding, stroke, SSE and all-cause death based on the GLMM, and no significances were observed.

3.5 Subgroup Analysis

Table 2 and Supplementary Figs. 6–9 showed the subgroup analyses on the thrombus resolution according to several interesting baseline characteristics from the clinic knowledge, consensus of experts and international guidelines [6, 7, 13, 14]. Considering the possible differences among the direct thrombin inhibitor dabigatran vs. the other NOACs, we performed the analysis and observed a statistical difference among studies that enrolled patients either with dabigatran or without dabigatran (Yes: OR 0.80, 95% CI 0.59–1.08, I2 = 11%; No: OR 1.48, 95% CI 1.00–2.19, I2 = 0%; p = 0.01). In six studies with the median LVEF 30%, NOACs group showed a similar thrombus resolution rate (OR 0.96, 95% CI 0.53–1.73, I2 = 41%) compared with VKAs group, and the result remained in the other four studies with a median LVEF <30% (OR 0.86, 95% CI 0.56–1.31, I2 = 0%). And to explore the potential effect of antiplatelet therapy combined with anticoagulation in patients with VT, studies were divided into two groups based on a high or moderate rate of combination of antiplatelet therapy. And when analyzing studies with antiplatelet therapy 90%, NOACs had a greater thrombus resolution than VKAs (OR 1.72, 95% CI 0.71–4.19, I2 = 0%) while considering studies with antiplatelet therapy <90%, it came to an opposed result between the two groups (OR 0.86, 95% CI 0.65–1.14, I2 = 9%), though both of which had no statistical significance. Moreover, we conducted a further analysis in different prevalence of ICM history among these included studies, and the result remained non-significant (ICM 80%: OR 1.15, 95% CI 0.73–1.81, I2 = 15%; ICM <80%: OR 1.08, 95% CI 0.70–1.65, I2 = 35%; p = 0.85). Based on the above information, we could subscribe the possible sources of heterogeneity to the baseline LVEF and the history of ICM for the analysis of thrombus resolution, owing to the moderate high I2.

Table 2.Subgroup analyses on the thrombus resolution of NOACs versus VKAs.
Subgroup K Pooled OR (95% CI) Heterogeneity p value*
Dabigatran 0.01
Yes 8 0.80 (0.59–1.08) 11%
No 9 1.48 (1.00–2.19) 0%
Baseline LVEF 0.76
30% 6 0.96 (0.53–1.73) 41%
<30% 4 0.86 (0.56–1.31) 0%
Baseline antiplatelet therapy 0.14
90% 3 1.72 (0.71–4.20) 0%
<90% 11 0.86 (0.65–1.14) 9%
Baseline prevalence ischemic cardiomyopathy 0.85
80% 7 1.15 (0.73–1.81) 15%
<80% 9 1.08 (0.70–1.65) 35%
*Test for subgroup difference (p < 0.05 for statistically significant).
Studies in which the NOACs groups use included dabigatran.
Abbreviations: K, Number of studies; OR, odds ratio; CI, Confidence interval; NOACs, non-vitamin K antagonist oral anticoagulants; VKAs, vitamin K antagonists; LVEF, ventricular ejection fraction.
3.6 Sensitivity Analyses

We conducted sensitivity analyses on the thrombus resolution, SSE, stroke, bleeding and all-cause death, which omitted each study one by one to examine the impacts of any individual study on the final results (SupplementaryFigs. 10–14). The omission of any individual study did not significantly change the overall results.

3.7 Publication Bias

No visible publication bias was found in the study, which was visually exhibited through the trimmed funnel plot (SupplementaryFigs. 15,16). The effect after shearing was OR 0.84 (95% CI 0.46–1.54) which showed that the mild publication bias had no substantial effect on the overall results. Statistical evaluations via Egger’s test showed no significant publication bias (p = 0.601).

4. Discussion

Our systematic review and meta-analysis evaluated the efficacy and safety between NOACs and VKAs in the treatment of VT quantitatively and systematically, which included a large number of full-text prospective and retrospective studies. We found no significant differences in VT resolution, SSE, stroke, bleeding events or all-cause death in the comparison of the two agents, with or without adjusting the confounding.

Researchers have explored the effectiveness of NOACs in the treatment of VT [25, 26, 43]. Tomasoni et al. [44] conducted a summary of single-armed case series, including 52 patients with left VT, 93.2% had complete thrombus resolved in a median follow-up of 180 days. No stroke or embolism events were observed, and only one patient experienced nonfatal bleeding. Numerous studies claimed that NOACs were comparable with or even outweighed VKAs [28, 33, 34, 35, 36, 37, 39, 40, 45, 46, 47], and obviously the most popular or dominant usage of NOACs was rivaroxaban in all studies. It was known that NOACs could be divided into two types targeting various action mechanism-anti-Xa inhibitor (rivaroxaban, apixaban and edoxaban or anti-IIa inhibitors (dabigatran). Compared anti-Xa, dabigatran has low bioavailability and is mainly cleared by the kidney, thus patients with moderate renal function should avoid use. In the field of cardiovascular diseases such as atrial fibrillation or pulmonary embolism, NOAC have all been proven at least as safe and effective as warfarin in large randomized controlled trials [8, 48, 49]. And neither guidelines nor studies have identified the differences in the treatment of VT in anti-Xa inhibitors vs. dabigatran, which may be due to the low proportion of patients included in retrospective studies. From our subgroup analysis, in studies that included patients without dabigatran, the thrombus resolution favored NOACs group over VKAs group. Though there was a statistical significance in studies with dabigatran or without dabigatran, the result needed to be interpreted carefully since the sample of patients who were administered with dabigatran was small in our study. To conclude, patients with VT might obtain inconsistent results with the usage of different NOACs.

Several meta-analyses reported similar results to ours [37, 47, 50, 51, 52]. Dalia et al. [52] included a total of eight studies and reported non-significant differences in thrombus resolution, stroke or SSE, bleeding and mortality in the comparison of NOACs and VKAs, though three of including papers were conference abstracts. Cocharan et al. [37] including six studies also showed that NOACs group was similar to VKAs in the rate of unresolved thrombus, embolic events or bleeding events. Interestingly, Camilli et al. [53] found that NOACs had a lower bleeding rate and an increase in SSE events compared with VKAs. Otherwise, one meta-analysis including the same studies as Camilli et al. [53] concluded no significant difference in each outcome [47]. Whether NOACs could decrease the risk of bleeding or stroke was unknown. And considering patients who had a great adherence or kept the TTR more than 60% could have a reduced risk of bleeding or stroke events, further large randomized controlled trials are required to assess the net safety efficacy profile of NOACs compared to VKAs different in VKAs recipients.

Our meta-analysis had three advantages. Firstly, the current study merged recent full-text articles from various countries comparing the effectiveness and safety of NOACs and VKAs, including both prospective and retrospective observational studies, which offered a global picture of comparative outcomes with NOACs and VKAs in the rate of VT resolution. Then, in order to explore the possible sources of heterogeneity in the thrombus resolution, we performed subgroup analyses based on clinical variables that might be related to the rate of thrombus resolution, and found that, different NOACs targeting various inhibitors produced inconsistent results in the treatment of VT. More importantly, for minimizing the confounding, we conducted the generalized linear mixed-model to give unbiased estimates in the presence of missing data, providing reasonably stable results.

There were several limitations in our paper. Firstly, only observational studies were included which could not make causal inference, though we conducted subgroups to minimize the difference of patient characteristics within the two groups. However, we would continue to keep track of those upcoming clinical trials to add more robust persuasion. Secondly, the imaging tool for the diagnosis of VT was inconsistent, which decreased the accuracy and precision of the assessment of VT. Another problem was that, given the nature of the meta-analysis, we had no more data on INR to better control the equivalence of the two treatment strategies.

With the increasing use of NOACs in clinical practice, NOACs have been gradually favored by physicians in the treatment of VT, except for patients with antiphospholipid syndrome or severe renal insufficiency. Considering the clinical practicability and health economics, VKAs had numerous inherent disadvantages such as the slow onset of action, susceptibility to food and narrow therapeutic window, which notably lead to a poor treatment compliance, and on the other hand, in the era of COVID-19 pandemic, patients with VT obtained more benefits with the treatment of NOACs since it was so formidable to frequently monitor the INR or contact with clinic workers when administering with VKAs, which echoed the recommendation of Thachil et al. [54] and Hermans et al. [55]. Therefore, NOACs can be considered a favorable alternative for clinics and patients especially in patients intolerant to VKAs therapy. In addition, NOACs may not only influence the outcome of thrombus resolution, but also have a protective effect against some cardiac diseases. Recently, Jumeau et al. [56] found that NOACs could slow down the process of atrial dilation by preventing interstitial fibrosis, extracellular interstitial remodeling, and heart failure-associated atrial hypertrophy, and also improve left ventricular remodeling while reducing left atrial size and left ventricular diameter, the latter of which could further promote thrombus regression.

Overall, it is critical to explore the therapeutic effectiveness and safety of NOACs on VT in large randomized controlled trials, as well as to offer the type, dose or duration of treatment of NOACs. Until now, there are four trials in the pilot phase, comparing NOACs versus warfarin (EARLY-MYO-LVT trial [57], NCT 03415386, NCT02982590), which can provide strong evidence for future work on this topic area.

5. Conclusions

Our findings showed that no statistically significant differences were observed in thrombus resolution, SSE, stroke, bleeding events or all-cause death between NOACs and VKAs in patients with VT. In studies that enrolled patients without dabigatran, NOACs group might have a greater thrombus resolution than VKAs group. Further well-designed prospective clinical trials are required to determine the efficacy and safety of the agents.

Abbreviations

VT, ventricular thrombus; NOACs, non-vitamin K antagonist oral anticoagulants; VKAs, vitamin K antagonists; OR, odds ratio; CI, confidential intervals; SD, standard deviation; AMI, acute myocardial infarction; LVEF, ventricular ejection fraction; ICM, ischemic cardiomyopathy; STEMI, ST elevation myocardial infarction; TIA, transient ischemic attack; PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses; CNKI, China National Knowledge Infrastructure; TTR, time in therapeutic range; INR, international normalized ratio; CT, computer tomography; CMR, cardiac magnetic resonance imaging; ISTH, International Society on Thrombosis and Haemostasis; NOS, Newcastle-Ottawa Scale.

Author Contributions

QY and L-YH extracted the data, and L-YH contributed to data analysis. QY drafted the manuscript, L-YH performed the statistical analysis. XQ and YL reviewed and corrected the manuscript. QY and YL discussed the results and contributed to the final manuscript. All authors read and approved the manuscript.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

We are sincerely to thank Xinyue Lang and Yanyan Zhao for help with statistical questions as well as Lulu Wang for helpful comments on the draft.

Funding

This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

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References
[1]
Gianstefani S, Douiri A, Delithanasis I, Rogers T, Sen A, Kalra S, et al. Incidence and predictors of early left ventricular thrombus after ST-elevation myocardial infarction in the contemporary era of primary percutaneous coronary intervention. The American Journal of Cardiology. 2014; 113: 1111–1116.
[2]
Turpie AGG, Robinson JG, Doyle DJ, Mulji AS, Mishkel GJ, Sealey BJ, et al. Comparison of High-Dose with Low-Dose Subcutaneous Heparin to Prevent Left Ventricular Mural Thrombosis in Patients with Acute Transmural Anterior Myocardial Infarction. New England Journal of Medicine. 1989; 320: 352–357.
[3]
Abdelnaby M, Almaghraby A, Abdelkarim O, Saleh Y, Hammad B, Badran H. The role of rivaroxaban in left ventricular thrombi. The Anatolian Journal of Cardiology. 2019; 21: 47–50.
[4]
Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal. 2012; 33: 2569–2619.
[5]
Caldeira D, Costa J, Ferreira JJ, Lip GYH, Pinto FJ. Non-vitamin K antagonist oral anticoagulants in the cardioversion of patients with atrial fibrillation: systematic review and meta-analysis. Clinical Research in Cardiology. 2015; 104: 582–590.
[6]
O’Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, 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. Journal of the American College of Cardiology. 2013; 61: e78–e140.
[7]
2019 Chinese Society of Cardiology (CSC) guidelines for the diagnosis and management of patients with ST-segment elevation myocardial infarction. Zhonghua Xin Xue Guan Bing Za Zhi. 2019; 47: 766–783.
[8]
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine. 2009; 361: 1139–1151.
[9]
Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016; 149: 315–352.
[10]
Fleddermann AM, Hayes CH, Magalski A, Main ML. Efficacy of Direct Acting Oral Anticoagulants in Treatment of Left Ventricular Thrombus. The American Journal of Cardiology. 2019; 124: 367–372.
[11]
Verma B, Singh A, Kumar M. Use of dabigatran for treatment of left ventricular thrombus: a tertiary care center experience. Journal of Family Medicine and Primary Care. 2019; 8: 2656.
[12]
Orenes-Piñero E, Esteve-Pastor MA, Valdés M, Lip GYH, Marín F. Efficacy of non-vitamin-K antagonist oral anticoagulants for intracardiac thrombi resolution in nonvalvular atrial fibrillation. Drug Discovery Today. 2017; 22: 1565–1571.
[13]
Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014; 45: 2160–2236.
[14]
Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal. 2018; 39: 119–177.
[15]
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of Internal Medicine. 2009; 151: 264–269, w264.
[16]
Bosch J, Eikelboom JW, Connolly SJ, Bruns NC, Lanius V, Yuan F, et al. Rationale, Design and Baseline Characteristics of Participants in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) Trial. The Canadian Journal of Cardiology. 2017; 33: 1027–1035.
[17]
Halperin JL, Hankey GJ, Wojdyla DM, Piccini JP, Lokhnygina Y, Patel MR, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation. 2014; 130: 138–146.
[18]
Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Journal of Thrombosis and Haemostasis. 2005; 3: 692–694.
[19]
Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. 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. Journal of Thrombosis and Haemostasis. 2015; 13: 2119–2126.
[20]
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. NewCastle-Ottawa Quality Assessment Scale –Cohort Studies[EB/OL] 2012-06-15. 2012. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (Accessed: 2, December, 2021).
[21]
Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane database of systematic reviews. 2019; 10: ED000142.
[22]
Kriston L. Dealing with clinical heterogeneity in meta-analysis. Assumptions, methods, interpretation. International Journal of Methods in Psychiatric Research. 2013; 22: 1–15.
[23]
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. British Medical Journal. 1997; 315: 629–634.
[24]
DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemporary Clinical Trials. 2015; 45: 139–145.
[25]
Daher J, Da Costa A, Hilaire C, Ferreira T, Pierrard R, Guichard JB, et al. Management of Left Ventricular Thrombi with Direct Oral Anticoagulants: Retrospective Comparative Study with Vitamin K Antagonists. Clinical Drug Investigation. 2020; 40: 343–353.
[26]
Iqbal H, Straw S, Craven TP, Stirling K, Wheatcroft SB, Witte KK. Direct oral anticoagulants compared to vitamin K antagonist for the management of left ventricular thrombus. ESC Heart Failure. 2020; 7: 2032–2041.
[27]
Robinson AA, Trankle CR, Eubanks G, Schumann C, Thompson P, Wallace RL, et al. Off-label Use of Direct Oral Anticoagulants Compared with Warfarin for Left Ventricular Thrombi. JAMA Cardiology. 2020; 5: 685.
[28]
Jones DA, Wright P, Alizadeh MA, Fhadil S, Rathod KS, Guttmann O, et al. The use of novel oral anticoagulants compared to vitamin K antagonists (warfarin) in patients with left ventricular thrombus after acute myocardial infarction. European Heart Journal Cardiovascular Pharmacotherapy. 2020. (in press)
[29]
Guddeti RR, Anwar M, Walters RW, Apala D, Pajjuru V, Kousa O, et al. Treatment of Left Ventricular Thrombus with Direct Oral Anticoagulants: a Retrospective Observational Study. The American Journal of Medicine. 2020; 133: 1488–1491.
[30]
Yan J, Zhou XY, Bian ZY, Xu SC, Tang QZ. Antithrombotic therapy and outcome in patients with ischemic cardiomyopathy complicated by left ventricular thrombus. Chinese Journal of Heart Failure and Cardiomyopathy. 2019: 69–73.
[31]
Li XF, Ge ZR, Paerhati T. Comparative Study of Rivaroxaban and Warfarin for Treating the Patients With Left Ventricular Thrombus. Chinese Circulation Journal. 2015; 30: 559–561.
[32]
Chao P, Li J, Chen XY, Wang Y, Ren P. Incidence of SSE in Patients With Left Ventricular Thrombus After Myocardial Infarction Treated With New Oral Anticoagulants or Vitamin K Antagonists. Chinese Circulation Journal. 2018; 33: 1184–1188.
[33]
Iskaros O, Marsh K, Papadopoulos J, Manmadhan A, Ahuja T. Evaluation of Direct Oral Anticoagulants Versus Warfarin for Intracardiac Thromboses. J Cardiovasc Pharmacol. 2021; 77: 621–631.
[34]
Mihm AE, Hicklin HE, Cunha AL, Nisly SA, Davis KA. Direct oral anticoagulants versus warfarin for the treatment of left ventricular thrombosis. Internal and Emergency Medicine. 2021; 16: 2313–2317.
[35]
Albabtain MA, Alhebaishi Y, Al-Yafi O, Kheirallah H, Othman A, Alghosoon H, et al. Rivaroxaban versus warfarin for the management of left ventricle thrombus. The Egyptian Heart Journal. 2021; 73: 41.
[36]
Alcalai R, Rashad R, Butnaru A, Moravsky G, Leibowitz D. Apixaban versus Warfarin in Patients with Left Ventricular (LV) Thrombus, a prospective randomized trial. European Heart Journal Cardiovasc Pharmacother. 2021; pvab057.
[37]
Cochran JM, Jia X, Kaczmarek J, Staggers KA, Rifai MA, Hamzeh IR, et al. Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombus: a Retrospective, Multicenter Study and Meta-Analysis of Existing Data. Journal of Cardiovascular Pharmacology and Therapeutics. 2021; 26: 173–178.
[38]
Zhang Z, Si D, Zhang Q, Qu M, Yu M, Jiang Z, et al. Rivaroxaban versus Vitamin K Antagonists (warfarin) based on the triple therapy for left ventricular thrombus after ST-Elevation myocardial infarction. Heart and Vessels. 2022; 37: 374–384.
[39]
Varwani MH, Shah J, Ngunga M, Jeilan M. Treatment and outcomes in patients with left ventricular thrombus - experiences from the Aga Khan University Hospital, Nairobi - Kenya. The Pan African Medical Journal. 2021; 39: 212.
[40]
Willeford A, Zhu W, Stevens C, Thomas IC. Direct Oral Anticoagulants Versus Warfarin in the Treatment of Left Ventricular Thrombus. Annals of Pharmacotherapy. 2021; 55: 839–845.
[41]
Xu Z, Li X, Li X, Gao Y, Mi X. Direct oral anticoagulants versus vitamin K antagonists for patients with left ventricular thrombus. Annals of Palliative Medicine. 2021; 10: 9427–9434.
[42]
Yao Y, Cui J, Wang Y, Guan Y, Zhu H, Chen C, et al. The Effect of Novel Oral Anticoagulants in Patients With Heart Failure and Left Ventricular Thrombi[J]. Chinese Circulation Journal, 2021; 36: 379–382.
[43]
Bass ME, Kiser TH, Page RL, McIlvennan CK, Allen LA, Wright G, et al. Comparative effectiveness of direct oral anticoagulants and warfarin for the treatment of left ventricular thrombus. Journal of Thrombosis and Thrombolysis. 2021; 52: 517–522.
[44]
Tomasoni D, Sciatti E, Bonelli A, Vizzardi E, Metra M. Direct Oral Anticoagulants for the Treatment of Left Ventricular Thrombus-A New Indication? A Meta-summary of Case Reports. Journal of Cardiovascular Pharmacology. 2020; 75: 530–534.
[45]
Sedhom R, Abdelmaseeh P, Megaly M, Asinger R. Use of Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombi: a Systematic Review. The American Journal of Medicine. 2020; 133: 1266–1273.e6.
[46]
Burmeister C, Beran A, Mhanna M, Ghazaleh S, Tomcho JC, Maqsood A, et al. Efficacy and Safety of Direct Oral Anticoagulants Versus Vitamin K Antagonists in the Treatment of Left Ventricular Thrombus. American Journal of Therapeutics. 2021; 28: e411–e419.
[47]
Saleiro C, Lopes J, De Campos D, Puga L, Costa M, Gonçalves L, et al. Left Ventricular Thrombus Therapy with Direct Oral Anticoagulants Versus Vitamin K Antagonists: a Systematic Review and Meta-Analysis. Journal of Cardiovascular Pharmacology and Therapeutics. 2021; 26: 233–243.
[48]
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine. 2011; 365: 981–992.
[49]
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England Journal of Medicine. 2011; 365: 883–891.
[50]
Salah HM, Goel A, Saluja P, Voruganti D, Al’Aref SJ, Paydak H, et al. Direct Oral Anticoagulants Versus Warfarin in Left Ventricular Thrombus: A Systematic Review and Meta-Analysis. American Journal of Therapeutics. 2021. (in press)
[51]
Shah S, Shah K, Turagam MK, Sharma A, Natale A, Lakkireddy D, et al. Direct oral anticoagulants to treat left ventricular thrombus—a systematic review and meta‐analysis: ELECTRAM investigators. Journal of Cardiovascular Electrophysiology. 2021; 32: 1764–1771.
[52]
Dalia T, Lahan S, Ranka S, Goyal A, Zoubek S, Gupta K, et al. Warfarin versus direct oral anticoagulants for treating left ventricular thrombus: a systematic review and meta-analysis. Thrombosis Journal. 2021; 19: 7.
[53]
Camilli M, Lombardi M, Del Buono MG, Chiabrando JG, Vergallo R, Niccoli G, et al. Direct oral anticoagulants vs. vitamin K antagonists for the treatment of left ventricular thrombosis: a systematic review of the literature and meta-analysis. European Heart Journal Cardiovascular Pharmacotherapy. 2021; 7: e21–e25.
[54]
Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. DOACs and “newer” hemophilia therapies in COVID‐19: Reply. Journal of Thrombosis and Haemostasis. 2020; 18: 1795–1796.
[55]
Hermans C, Lambert C. Impact of the COVID-19 pandemic on therapeutic choices in thrombosis-hemostasis. Journal of Thrombosis and Haemostasis. 2020; 18: 1794–1795.
[56]
Jumeau C, Rupin A, Chieng-Yane P, Mougenot N, Zahr N, David-Dufilho M, et al. Direct Thrombin Inhibitors Prevent Left Atrial Remodeling Associated with Heart Failure in Rats. JACC: Basic to Translational Science. 2016; 1: 328–339.
[57]
He J, Ge H, Dong JX, Zhang W, Kong LC, Qiao ZQ, et al. 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). Annals of Translational Medicine. 2020; 8: 392.
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