This is the first systematic review and meta-analysis quantitatively and systematically evaluate the efficacy and safety between NOACs and VKAs in the treatment of ventricular thrombus. There were no significant differences in ventricular thrombus resolution, systemic embolism, bleeding events and all-cause death between NOACs and VKAs, though the data are of low quality due to a limited sample size of our studies. What is more, our findings found that NOACs group showed more than two times higher thrombus resolution rate than VKAs group in studies with rivaroxaban predominantly or only rivaroxaban in the NOACs group. And patients who chose rivaroxaban for ventricular thrombosis had a 32% lower risk of systemic embolism than those who did not. Nevertheless, because of the very low numbers of patients with NOACs it is difficult to draw conclusions about the most favorable results with individual NOACs. But when considering the disadvantages of VKAs such as slow onset of action, susceptibility to food, drugs and genetic polymorphisms, narrow therapeutic window, frequent monitoring of the International Normalized Ratio and poor treatment compliance, NOACs may be a better choice for clinics and patients to apply in the treatment of ventricular thrombus.
Since we had only eight eligible studies which met cretiria to conduct an analysis, in order to provide further evidence, we also analyzed two single-arm studies which showed that NOACs led to ventricular thrombus resolution in 83–100%. One single-center retrospective study in 2019 included 35 patients with left ventricular thrombus who received NOACs and had a follow-up transthoracic echocardiography (TTE), and 83% of patients had achieved thrombus resolution with a mean duration of 264 days, 1 (2.8%) patient had stroke or systemic embolism (SSE), 4 (11.4%) patients had bleeding events and 3 (8.6%) patient suffered from all-cause death. According to different NOACs, 16 (45.7%),17 (48.6%) and 2 (5.7%) patients received apixaban, rivaroxaban and dabigatran had a 93.75%, 76.5%, 50% ventricular thrombus resolution separately after a follow-up TTE[27]. Another study in 2019 which was a tertiary care center experience enrolled 15 patients with left ventricular thrombus who received dabigatran. Overall, all of patients achieved ventricular thrombus resolution after 6-months follow-up, with 1 bleeding event (6.7%) and no SSE [28] .
A meta-analysis conducted by Robinson et al in 2016 revealed that left ventricular thrombus was a universal complication after myocardial infarction [29]. Therefore thrombosis remains one of the most frequent complications after myocardial infarction, and its all-cause death and disability rates remain high. However, 2020 Sedhom et al [30] published a systematic review which collected studies of direct oral anticoagulants for treatment of left ventricular thrombus from January 1st, 2009 till April 25th. Among the 85 patients who were included in the case reports and case series, seventy-four patients (87%) were prescribed a NOAC and had follow-up imaging which showed complete resolution in 69 patients (93.2%). Three patients (3.5%) died during follow-up, 5 patients (5.9%) suffered from SSE and 3 patients (3.5%) had bleeding events. They concluded that the routine use for the treatment of left ventricular thrombus cannot be recommended, but this review included case reports and case series which were liable to publication bias and lacked a thorough data analysis. And our meta-analysis included observational studies aiming to provide a stronger evidence to support our result.
To represent the best evidence to explore the efficacy of NOACs for ventricular thrombus, we also analyzed 52 case reports or series describing 90 cases, which were found by searching Medline, Embase, Cochrane Library Web of Science and Pubmed databases from inception to August 2020. Among the 90 cases, rivaroxaban (n = 46,51.1%) was the most common used NOACs, and 28.9%(n = 26), 17.8%(n = 16), 2.2%(n = 2) patients received apixaban, dabigatran and edoxaban. At a median follow-up period of 60(28–111) days, 92.5% (74/80) patients had complete thrombus resolution. Patients who were treated with dabigatran and edoxaban achieved 100% ventricular thrombus resolution, while those with apixaban and rivaroxaban therapy had 88.4% and 95.8% resolution dependently. There was a total of 5(5.5%) embolic events and 3(3.3%) deaths while being treated with rivaroxaban and dabigatran, and 3(3.3%) bleeding events only occurred in the rivaroxaban group. Those cases indicated that, the application of NOACs showed a great complete resolution of thrombus, with few thromboembolism or hemorrhagic events.
The strength of this meta-analysis resided in the creativity and timing. First, this article was the first international meta-analysis comparing the effectiveness and safety of NOACs and VKAs in the treatment of ventricular thrombus, and based on the results of observational studies, we added existing case series or case reports to provide further evidence for the use of NOACs in the treatment of ventricular thrombus. Second, the studies included in the article covered both domestic and international, and 62.5% (5/8) of the articles published in 2020 included the most recent observational findings. Third, we not only analyzed the effectiveness of different oral anticoagulants but also predicted the prognosis of thrombosis by stratified analysis or meta-regression, which had significant public health implications.
Our meta-analysis presents several limitations. Firstly, only observational studies were included in the current study due to the lack of relevant randomized controlled trials at present, which may have resulted in a lack of strength of evidence for the article. However, we will continue to keep track of the results of the latest clinical trials to add more robust persuasion. Secondly, the sample size of studies included were small owing to the limits of the relatively low incidence of ventricular thrombus in clinical practice. Finally, the diagnosis of ventricular thrombus were inconsistent given no authoritative guideline providing uniform criteria. Echocardiography which may have a lower sensitivity and specificity for detection compared with other imaging modalities, such as cardiac magnetic resonance imaging (MRI)[31]. Among our included studies, the echocardiography was utilized to detect ventricular thrombus amongst five studies, and the others applied MRI as well. It is difficult to evaluate the accuracy and precision in the diagnosis of ventricular thrombus because of the high heterogeneity of the different methods.
With the increasing use of NOACs in clinical practice, it is reasonable to believe that NOACs will gradually be favored by physicians and patients in the treatment of ventricular thrombus, achieving high rates of thrombus cure, rapid regression, few adverse events, and good patient compliance. In addition, NOACs may not only promote thrombus regression, but may also have a protective effect against some cardiac diseases. Recently, Jumeau et al 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 improve left ventricular remodeling while reducing left atrial size and left ventricular diameter, the latter of which could further promote thrombus regression [32].
To date, the therapeutic effect of NOACs on ventricular thrombus has not been formally evaluated in validated randomized controlled trials, which may be linked with the small number of patient cases and difficulty in enrollment. The optimal type, dose and duration of treatment of NOACs is therefore unclear. In light of the 2016 CHEST practice guidelines for the treatment of venous thromboembolism, an updated version may expand the use of loading doses of NOACs for the treatment of intracardiac thrombosis [11]. Four randomized trials, currently in the pilot phase, aim to evaluate the efficacy of rivaroxaban versus warfarin (EARLY-MYO-LVT trial)[33], and dabigatran vs warfarin (NCT 03415386) for the treatment of left ventricular thrombus respectively. Another two ongoing prospective clinical trials randomly assign patients with left ventricular thrombus to treatment of either warfarin or apixaban. One study enrolls 50 patients with acute STEMI and left ventricular thrombus. The primary efficacy end-point is the existence and dimensions of left ventricular thrombus as assessed by TTE. The secondary outcomes are SSE, bleeding, or all-cause death at 3 months[34]. The other study includes 40 patients diagnosed with left ventricular thrombus. The primary outcome is the reduction of left ventricular thrombus size at 3 months. The secondary outcomes are reduction of left ventricular thrombus size by > 50%, the occurrence of cardioembolic stroke, or life-threatening bleeding at 3 months[35]. We hope these upcoming results will provide more reliable data and further insight into the effectiveness of the application of NOACs and safety to expand the therapeutic prospects of NOACs. Overall, the results with NOACs appear to be favorable, which is an encouraging sign for broader researches to better assess their feasibility.