Factors Influencing Left Ventricular Thrombus Recurrence After Resolution

1. Introduction

Left ventricular thrombus (LVT) is a common complication in patients with heart failure due to ischemic or non-ischemic cardiomyopathy[1]. Left ventricular dysfunction has been identified as a significant independent predictor of LVT[2]. Moreover, LVT is closely associated with a high risk of severe systemic thromboembolism, as well as increased morbidity and mortality [3,4]. Currently, anticoagulation therapy remains the primary strategy in the management of LVT [5]. However, some patients experience recurrence of LVT after initial resolution, presenting a great challenge in clinical practice [6,7]. However, the factors influencing LVT recurrence remain unclear.

The current guidelines recommend a duration of anticoagulation therapy for LVT of 3 to 6 months [8,9]. Studies have shown that complete resolution of LVT occurs in approximately 62.3% of patients with smaller thrombus within three months [10]. Although a majority of patients could achieve LVT resolution after appropriate anticoagulation therapy, some patients may still experience recurrence following the discontinuation of treatment [11,12]. Increasing the dose of oral anticoagulants to prevent recurrence may lead to higher bleeding risk, which is not the optimal strategy for managing the LVT recurrence [13,14]. However, there is limited data concerning the recurrence of thrombus following resolution and its potential clinical outcomes [15]. In this study, we aimed to identify the risk factors and clinical outcomes associated with LVT recurrence after resolution and to inform follow-up strategies and treatment approaches in clinical practice.

2. Methods

2.1. Study Design

This was a single-center, retrospective study conducted at the Zhongshan Hospital, Fudan University. We included a total of 98 patients who were diagnosed with LVT resolution from January 1, 2018 to January 1, 2021, who had received anticoagulation therapy for 6 months or more. Exclusion criteria included (1) LVT caused by non-cardiovascular diseases, such as autoimmune disease and malignant tumors, (2) patients in the end stage of various diseases, and (3) patients lost to follow-up after LVT resolution. Patients were categorized into recurrence group and non-recurrence group based on transthoracic echocardiography (TTE) findings. The longitudinal diameter of LVT was measured after the discontinuation of anticoagulant therapy. This study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University and complied with the Declaration of Helsinki.

2.2. Demographic and Clinical Characteristics

Baseline characteristics collected included age, gender, history of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), as well as comorbidities such as hypertension, diabetes, hyperlipidemia, atrial fibrillation (both paroxysmal and persistent), cardiomyopathy, heart failure, stroke, previous myocardial infarction and chronic kidney disease. All patients underwent echocardiographic evaluations, recording left atrial diameter, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left ventricular ejection fraction (LVEF), LVT area (calculated as longitudinal diameter × transverse diameter), and the presence of ventricular aneurysm.

The presence of LVT was assessed using the TTE and defined as hypoechoic masses located near myocardial segments with reduced or impaired left ventricular motion. LVT must be visible in at least two different views throughout the entire cardiac cycle. The location, size, and mobility of LVT were recorded. Echocardiography was repeated 3 months after the initial detection of ventricular thrombus and the size of LVT was evaluated based on the thrombus area obtained from the imaging examination.

Thrombus resolution was defined as the complete disappearance of LVT at follow-up. Ineffective anticoagulation was characterized by an unchanged or increased LVT area. Major adverse cardiovascular events, including ischemic stroke, acute myocardial infarction or acute systemic arterial embolism, major bleeding events, and all-cause mortality, were also recorded.

2.3. Follow-Up

The follow-up duration was defined as the period until the confirmation of LVT recurrence or nonrecurrence, as assessed in the last follow-up echocardiogram after LVT resolution. The median follow-up time was 3.0 years. The enrolled patients completed two or more echocardiographic follow-ups at our hospital.

2.4. Statistical Analysis

The continuous variables were expressed as mean ± standard deviation. The normally distributed variables were compared using the t-test, while non-normally distributed variables were analyzed using the rank-sum test. Categorical variables were presented as percentages, and comparisons were made using the chi-square test or Fisher's exact test. Multivariate logistic regression was utilized to identify independent predictors of ineffective anticoagulation treatment for LVT. ROC curves were generated to determine the optimal critical value, sensitivity, and specificity. A p value of less than 0.05 was considered statistically significant.

3. Results

3.1. Demographic and Clinical Characteristics

A total of 98 patients with LVT resolution were finally enrolled in this study. They were classified into two groups based on the recurrence of LVT, including 26 patients (26.5%) in the recurrence group and 72 patients (73.5%) in the non-recurrence group. Patients in two groups were similar in average age, gender and previous history of hypertension, diabetes, hyperlipidemia, atrial fibrillation, chronic kidney disease and stroke. The recurrence group showed a higher prevalence of prior myocardial infarction (recurrence vs non-recurrence: 84.6% vs 61.1%, p=0.03) and PCI (recurrence vs non-recurrence: 76.9% vs 52.8%, p=0.03). Conversely, patients in the non-recurrence group were more likely to suffer non-ischemic cardiomyopathy (recurrence vs non-recurrence: 11.5% vs 38.9%, p=0.01). Echocardiographically, patients in the recurrence group were more likely to have ventricular aneurysm compared to the non-recurrence group (50.0% vs 22.2%, p = 0.008). Additionally, patients in the recurrence group had a greater longitudinal diameter of LVT (27.7±12.6mm vs 21.4±9.1mm, p = 0.008). There were no significant differences between the two groups regarding the use of warfarin, rivaroxaban and dabigatran. However, the administration of aspirin and clopidogrel was notably higher in the recurrence group (aspirin: 65.4% vs 40.3%, p = 0.03; clopidogrel: 69.2% vs 47.2%, p = 0.05) (Table 1).

3.2. Multivariate Analysis of Predictors for LVT Recurrence

Logistic regression analysis, considering factors such as previous PCI, myocardial infarction, ventricular aneurysm and longitudinal diameter of LVT, revealed that the longitudinal diameter of LVT is an independent risk factor for LVT recurrence (OR 1.058, 95% CI 1.003 - 1.115, p = 0.04). (Table 2)

3.3. Value of LVT Longitudinal Diameter in the Prediction for LVT Recurrence

Using a ROC curve, the optimal cut-off value for LVT longitudinal diameter was determined through the maximum Youden index. The results indicated that the area under the curve (AUC) for LVT longitudinal diameter was 0.647, with an optimal cut-off value of 23.5 mm, a sensitivity of 62%, and a specificity of 64% (Figure 1).

3.4. Follow-Up

After a follow-up of 3.0 ± 2.5 years, no statistical difference in major bleeding, ischemic stroke, or all-cause mortality was observed between the two groups. However, the incidence of non-fatal myocardial infarction and major adverse cardiovascular events (MACE) was significantly higher in the recurrence group compared to the non-recurrence group [(myocardial infarction: 3 (11.5%) vs 1 (1.4%), p = 0.02); MACE: 7 (26.9%) vs 7 (9.7%), p = 0.01] (Table 3).

4. Discussion

LVT is a common complication associated with cardiomyopathy and heart failure, leading to adverse cardiovascular events such as stroke and systemic embolism, which contribute to high mortality and disability. Hypercoagulable state, circulatory stasis, and myocardial injury are the basic components of the LVT formation, also known as Virchow's triad [16]. The prethrombotic state could be reversed by the application of anticoagulants. Nevertheless, the risk of recurrence persists due to ongoing risk factors for thrombosis once the medication is discontinued. Although previous studies have demonstrated that a high resolution rate of LVT with anticoagulation treatment, there are limited reports on the recurrence of LVT following resolution [17]^- [19]. Additionally, the long-term management of these patients remain unclear [20]. Therefore, it is crucial to identify the risk factors for recurrence after LVT resolution to guide the management of high-risk patients and implement intensified follow-up and anticoagulation treatment. Our investigation implicated that percentages of previous myocardial infarction, history of PCI, and the presence of ventricular aneurysm were significantly higher, and the longitudinal diameter of the thrombus were notably larger in the recurrence group.

The formation of LVT is primarily associated with abnormal ventricular wall motion, hemodynamic changes, and a hypercoagulable state induced by cardiac conditions such as myocardial infarction, cardiomyopathy, and valvular heart disease [21]. Continuous anticoagulation treatment is essential to prevent the recurrence of LVT [22,23]. Nonetheless, it cannot eliminate the underlying risk factors for thrombosis formation. Zhou XD et al. found that nearly 25% of patients with LVT resolution experience recurrence within 1 year, with LV aneurysm being a significant factor associated with recurrence [15]. When the risk factors persist, the LVT tends to relapse. In addition, irregular medication adherence and poor patient compliance during the anticoagulation therapy may also contribute to recurrence following the resolution of the thrombus.

Anticoagulation therapy is the primary treatment regimen for LVT. The duration of anticoagulation treatment directly influences the thrombus resolution and the risk of recurrence. Short anticoagulation treatment span is an independent risk factor for recurrence after LVT resolution [7,23]^- [25]. Prolonged anticoagulation has shown to reduce the risk of recurrence, particularly in patients with a larger thrombus diameter [11,12]. Larger thrombus can significantly alter the blood flow dynamics in the left ventricle, leading to decreased local blood flow velocity and vortex formation, which increases the risk of thrombus recurrence [10,26]. Previous studies have indicated that patients with a larger thrombus area are at a higher risk of adverse events such as systemic embolism [27,28]. In a retrospective study involving 159 patients with confirmed LVT recurrence, the presence of LVT was associated with an incredibly high risk of MACE (n = 59, 37.1%) and embolic complications (n = 35, 22.2%). This study also suggested that the anticoagulation treatment lasting more than 3 months is independently associated with lower rates of MACE. The authors emphasized the importance of identifying the predictors of LVT recurrence following resolution. However, the risk of bleeding caused by intensified anticoagulation remains a concern, therefore a comprehensive risk-benefit assessment becomes urgent. This study also revealed that the length of the thrombus was an independent risk factor for recurrence after LVT resolution [10].

In case the length of LVT was greater than 23.5mm, it was recommended to extend the anticoagulation time more actively. This finding represents a novel contribution of our study. Prolonging the anticoagulant treatment for patients at high risk of thrombus recurrence can theoretically help maintain the hypocoagulability of blood and reduce the risk of thromboembolism. However, these findings still need to be further confirmed by the prospective studies with larger sample sizes.

5. Limitations

This is a single-center retrospective study exploring the factors influencing the recurrence after LVT resolution. The sample size was relatively small. Moreover, the two-dimensional planar measurements of a thrombus may not fully represent its three-dimensional structure. In future studies, we will collect relevant case data, expand the sample size, and design prospective multi-center randomized controlled studies. Meanwhile, we will arrange regular follow-ups to further assess the efficacy and safety of anticoagulation duration in patients with LVT.

6. Conclusions

In the present study, we found that previous myocardial infarction, ventricular aneurysm, and larger thrombus diameter are significant high-risk factors for LVT recurrence. It’s worth mentioning that the longitudinal diameter of the thrombus is an independent risk factor for recurrence following LVT resolution. For patients with a LVT diameter greater than 23.5 mm, it is recommended to extend the anticoagulation duration and to actively combine it with comprehensive treatment measures to reduce the risk of recurrence.

Taken together, our research provides a comprehensive summary of the disease characteristics of patients with LVT and analyzes the longitudinal diameter of LVT. These findings can offer a reliable basis for the further conduction of relevant interventional clinical trials and serves as a reference for determining appropriate anticoagulation time in clinical practice, ultimately delivering important therapeutic benefits for patients with LVT.