Advancing clinical management of left ventricular thrombosis: prevention, detection and treatment modalities in the modern era

Pathophysiology

Most cases of LVT were associated with ICM, especially after anterior myocardial infarction, while the rest were attributed to NICM, such as dilated cardiomyopathy (DCM), Takotsubo syndrome, left ventricular (LV) myocardial densification insufficiency, eosinophilic myocarditis, perinatal cardiomyopathy, and cardiac amyloidosis.12 The Virchow’s triad, consisting of ventricular wall tissue damage, blood stasis and an inflammatory/hypercoagulable state, represents the primary mechanism for LVT formation (figure 1).13 14 In the settings of ICM, the risk of LVT occurrence is determined by the onset of ischaemic symptoms and the timing and duration of the intervention.15 16 The intensity of myocardial injury is strongly associated with susceptibility to LVT, especially after acute ischaemic events. Blood stasis is primarily attributable to impaired LV function, characterised by reduced LV ejection fraction (LVEF) and diminished or dysfunctional large-scale motion in the LV apex or anterior wall.17 18 These factors collectively contribute to the formation of abnormal blood flow vortexes, ultimately resulting in blood stasis. Additionally, the stagnation of blood flow resulting from overall LV dysfunction may also represent a critical factor in the intraventricular thrombosis of NICM.13

Figure 1

Virchow’s Triad: pathophysiological basis. LV, left ventricular.

The inflammatory response triggered in the local tissue injury, the low shear stress environment in the infarction area, coupled with reduced LVEF, collectively activate the coagulation cascade. This activation leads to fibrin cross-linking and platelet and red blood cell aggregation, ultimately culminating in the formation of fresh thrombus.19 A comprehensive understanding of tissue damage, blood stasis and fibrin cross-linking in the thrombotic process provides a theoretical foundation for prioritising anticoagulation therapy over sole antiplatelet therapy in patients with LVT. Furthermore, some studies also emphasise the key role of proinflammatory and hypercoagulable states in the development of LVT.14 Indeed, the persistent hypercoagulable state following acute myocardial infarction (AMI) can extend for up to 6 months. Elevated levels of inflammatory markers (eg, C reactive protein, fibrinogen) and increased neutrophil-to-lymphocyte ratios in serum on admission have been established as independent predictors of early LVT occurrence following AMI.20 21 Concurrently, the involvement of inflammatory responses, the hypercoagulable nature of blood, and specific disease processes affecting endocardial health (such as amyloidosis and eosinophilic myocarditis), represent significant pathophysiological components of NICM and substantially increase the risk of LVT.22 23

Diagnostic modalities

Transthoracic echocardiography

Transthoracic echocardiography (TTE) remains the primary guideline-recommended imaging technique for assessing the presence, shape and size of LVT. However, the major inherent limitation of TTE in detecting LVT is inaccurate localisation of the LV apex due to abnormal chest anatomy and poor visualisation of the echocardiographic window. TTE demonstrates high specificity and sensitivity in detecting LVT when optimal visualisation of cardiac structures is attainable. TTE criteria for LVT diagnosis include: (1) Well-defined, echogenic intracavitary mass distinct from myocardial tissue, (2) Clear demarcation from surrounding ventricular cavity, (3) Complete separation from endocardium and (4) Persistence throughout the cardiac cycle. Careful differentiation from pseudotendons and trabeculae is essential. Moreover, artefacts (reverberation, lateral flaps, near-field artefacts) can mimic thrombus and should be meticulously excluded to avoid diagnostic errors (figure 2A).24 Additionally, patients with suboptimal chest anatomy, including narrow intercostal spaces, obesity, thoracic deformities, or pulmonary conditions such as emphysema, can pose challenges for TTE in visualising the LV apex and detecting LVT. This limitation may result in diagnostic uncertainty in 10%–46% of LVT cases, compromising sensitivity.25 TTE with contrast can improve endocardial border definition, thereby increasing sensitivity to approximately 64% while preserving specificity comparable to conventional TTE.26 Nevertheless, small or non-protruding LVT may remain undetected even with TTE with contrast.24

Figure 2

Visual representation of left ventricular thrombosis. CMR, cardiovascular MR; DE-CMR, delayed enhancement cardiovascular MR; LV, left ventricular.

Radioactive labelling

In the 1980s, radioactive labelling of blood components within mural thrombus emerged as a potential LVT diagnostic modality.31 32 Indium-111 labelled platelets demonstrated superior imaging performance compared with TTE, achieving 100% specificity and 71% sensitivity in LVT detection.32 However, the time-consuming nature and high cost of this method, and radiation exposure due to this method limited its widespread adoption. Additionally, it is ineffective for small thrombi, requiring active platelet aggregation on the thrombus surface for optimal performance.32 Diagnostic challenges arise in patients with elevated left hemidiaphragms due to potential spleen-apex activity confusion and in those with large LV aneurysms where stagnant blood can mimic thrombus formation, potentially leading to misdiagnosis. Thus this diagnostic modality is currently not widely used in clinical practice.

To optimise the early diagnosis and management for LVT, we propose an algorithm for diagnostic modalities: (1) Routine TTE is performed as the primary diagnostic tool, and contrast TTE is supplemented in case of diagnostic difficulties; (2) If the diagnosis is still not confirmed, use CMR; (3) CT was chosen when CMR was unavailable or not tolerated. In patients with AMI, imaging is performed within 24 hours of the onset of symptoms (figure 3).

Figure 3

Proposed diagnostic modalities for left ventricular thrombosis. AMI, Acute myocardial infarction; CMR, cardiovascular MR; ICM, ischaemic cardiomyopathies; LV, left ventricular; LVEF, left ventricular ejection fraction; NICM, non-ischaemic cardiomyopathies; TTE, transthoracic echocardiography. *Dilated cardiomyopathy, Takotsubo syndrome, left ventricular myocardial densification insufficiency, eosinophilic myocarditis, perinatal cardiomyopathy, or cardiac amyloidosis. #C reactive protein, fibrinogen and the neutrophil-lymphocyte ratio. †Reduced ejection fraction and/or large apical or anterior LV akinesis or dyskinesis (ie, aneurysm) and reduced contractile function facilitating stasis caused by an abnormal vortex.

Prevention and treatment of LVT

Prevention

Prevention focuses on NICM with depressed LV systolic function and AMI. Most of the preventive data on ICM and NICM of LVT originate from retrospective studies. Not enough RCTs have prospectively evaluated OACs for this indication. Consequently, current preventive strategies for high-risk individuals rely heavily on limited data from related fields to inform treatment decisions. In the absence of robust evidence, guideline-directed medical prevention for LVT is currently limited to ST segment elevation myocardial infarction (STEMI) involving anteroapical akinesis/dyskinesis, with vitamin K antagonists (VKA)-related antithrombotic regimens as the current first-line therapy. Specific recommendations on NICM are rare. This educational review summarises the current guidelines and expert consensus documents regarding LVT prevention, as shown in table 1.

Table 1

Guidelines/consensus on the prevention of LVT

In terms of AMI, RCTs from the prethrombolytic and thrombolytic eras (1970s–1990s) provided robust evidence supporting anticoagulation strategies for LVT prevention.33 Meanwhile, a meta-analysis of 11 studies (856 patients) revealed a 5.5-fold increased risk of thromboembolic events in patients with acute anterior myocardial infarction with LVT compared with those without LVT.34 Anticoagulation reduced LVT formation by 68% and decreased systemic embolism risk in these patients. However, these guideline-supporting studies predate the modern reperfusion era, characterised by limited dual antiplatelet therapy (DAPT) use and under-reported postanticoagulation complications. Therefore, carefully evaluating the balance between the benefits and adverse prognostic risks of prophylactic anticoagulation in patients with AMI receiving DAPT is crucial in contemporary practice. Driven by extensive clinical investigations on OAC, recent advancements in antithrombotic strategies have emerged. Concurrently, growing recognition of the heightened bleeding risk associated with VKA therapy challenges the prophylactic use of VKAs in high-risk patients. Le May et al retrospectively analysed 460 patients with postpercutaneous coronary intervention with anterior STEMI and reduced/absent apical motion, comparing outcomes between those receiving and not receiving VKA therapy. Among patients receiving DAPT as baseline antiplatelet therapy for anterior STEMI, the VKA group experienced a significantly higher risk of net adverse clinical events (mortality, stroke, re-infarction, major bleeding) within 180 days compared with the non-VKA group.35 Shavadia et al similarly found no reduction in ischaemic events but increased bleeding rates with prophylactic VKA in 398 patients with anterior STEMI and LV dysfunction. However, the observational nature of these studies predisposes them to significant bias.36 Collectively, historical clinical trials indicate that short-term prophylactic anticoagulation may reduce the risk of LVT in patients with anterior myocardial infarction. However, these trials are underpowered to determine whether this prophylactic anticoagulation leads to a clinically significant reduction in systemic embolism or major adverse cardiovascular events (MACE).

In terms of NICM with depressed LV systolic function, no RCTs support the routine use of OAC for the primary prevention of LVT in these patients. Considering the variety of NICM, current consensus documents also do not enable systematic recommendations for NICM-related LVT prevention. However, there are also documents emphasising that OAC could be considered in patients with specific NICM, such as those with Takotsubo syndrome, LV myocardial densification insufficiency, eosinophilic myocarditis, perinatal cardiomyopathy and cardiac amyloidosis.3 37–39 Notably, the recommended duration for prophylactic OAC in these NICM subtypes remains undetermined when OAC is implemented. The preventive duration requires individualised adjustment by clinicians based on the patient’s condition, undeniably complicating clinical management.

Based on current guidelines and expert consensus documents, we propose an algorithm for LVT prevention (figure 4A). For patients with AMI involving anteroapical akinesis/dyskinesis, prophylactic anticoagulation may be initiated for 1–3 months, if the risk of thrombosis is high. For patients with specific types of NICM, the decision to initiate prophylactic anticoagulation may be determined by a multidisciplinary assessment weighing bleeding risks and benefits, with OAC duration determined by the multidisciplinary team (MDT) on a case-by-case basis.

Figure 4

Proposed prevention modalities for LVT. AMI, acute myocardial infarction; ICM, ischaemic cardiomyopathies; LVT, left ventricular thrombus; MDT, multidisciplinary team; NICM, non-ischaemic cardiomyopathies; OAC, oral anticoagulants. *CT was chosen when cardiovascular MR was unavailable or not tolerated.

Treatment

Indium-111 platelet imaging studies consistently reveal that most LVT, irrespective of age or size, exhibit continuous platelet accumulation on their exterior, which highlights the persistent platelet activity on the thrombus surface and the associated risk of embolism.32 40 Most current international guidelines suggest VKAs as first-line therapy.41 42 However, only limited evidence suggests anticoagulation therapy can effectively mitigate the embolism complications associated with LVT, with the fibrinolytic mechanism inherent in anticoagulants playing a pivotal role in promoting LVT dissolution. The optimal duration of anticoagulation for the treatment of LVT is uncertain, with no RCTs investigating alternative durations of therapy to date. Results from the LEVITATION Survey show that most centres are opting for an anticoagulation duration of 3–6 months.11 This educational review summarises the current guidelines and expert consensus documents regarding LVT treatment, as shown in table 2.

But the present dilemma is the persistence of a proportion of thrombus after 3–6 months of anticoagulation, and evidence on how to deal with persistent LVT is lacking for this particular subgroup. Protruding and mobile thrombus is perceived to be more likely to embolise than immobile, calcified and organised thrombus.43 44 Hence, prolonged anticoagulation and repeated imaging assessment are generally recommended in protruding and mobile thrombus until LVT total regression; on the other hand, in patients with immobile, calcified and organised thrombus, the risk of embolisation may be low, and discontinuation of anticoagulation is probably a reasonable option after a MDT risk-benefit discussion. However, due to the lack of high-quality evidence, decisions regarding the modality and duration of anticoagulation should be made on a case-by-case basis. Additionally, there are insufficient data that surgical excision for persistent LVT has net efficacy, which is performed only in extreme clinical cases (eg, intolerance of anticoagulation with high risk of cardiogenic embolisation).12

Lastly, based on current relevant guidelines and expert consensus documents, we propose an algorithm for LVT treatment, as shown in figure 4B.

New OACs

Given their established efficacy in treating atrial fibrillation (AF) and venous thromboembolism, it is reasonable to explore the potential benefits of new OACs (NOACs) in the management of LVT. While several guidelines recommend NOACs as a promising alternative to VKAs and are increasingly used for LVT, their efficacy and safety in this setting remain uncertain due to limited and contradictory evidence.

Regarding the treatment, the RED VELVT observational study is, to date, the largest study comparing NOACs to VKAs for the treatment of LVT. In this multicentre cohort study of anticoagulation strategies for LVT, NOAC treatment was associated with a higher risk of systemic embolism compared with VKA use, even after adjustment for other factors.45 These results challenge the previous assumption of equivalence of NOACs with VKAs for LVT and highlight the need for prospective RCTs to determine the most effective treatment strategies for LVT. However, the retrospective nature of this study also predisposes it to result bias. Subsequently, three small-scale RCTs found NOACs to be non-inferior to VKAs.8–10 Further meta-analyses confirmed the findings of the above RCTs.46 47 These studies highlight that NOACs versus VKAs perhaps provide at least equivalent benefit-risk profiles in clinical settings where LVT exists. Yet, owing to the conflicting results of the RED VELVT and current RCTs,45 no consensus on the issue was formed. Regarding prevention, RCTs specifically focusing on the use of NOACs for primary prevention in patients at high risk for LVT are rare. Most RCTs have been conducted to evaluate the optimal antithrombotic regimen for the prevention of major adverse events in other similar clinical settings, such as heart failure or acute coronary syndromes. Similarly, the results vary. Results from the COMMANDER HF Trial indicate that very low dose rivaroxaban was not associated with a significantly lower rate of death, myocardial infarction or stroke than placebo among patients with worsening chronic heart failure, reduced LVEF, coronary artery disease and no AF.48 Conversely, results from the ATLAS ACS 2-TIMI 51 Trial indicate that in patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite endpoint of death from cardiovascular causes, myocardial infarction, or stroke and did not increase the risk of fatal bleeding.49 These varying results potentially indicate that differences in thrombosis in the various clinical settings may reasonably translate into differences in antithrombotic activity, resulting in different anticoagulant responsiveness. Recently, our team performed a modest-sized single-centre, open-label randomised trial of 279 patients and specifically examined whether low-dose anticoagulation (rivaroxaban 2.5 mg two times per day for 30 days) in addition to DAPT could decrease the risk of LV thrombus compared with DAPT alone.7 The addition of low-dose rivaroxaban compared with no such therapy lowered the risk of LV thrombus formation, as well as net adverse clinical events, without increased bleeding. This strategy on NOACs seems promising for use in such selected patients, but the limitations (eg, single-centre, isolated, open-label) of the trial also affected the generalisability. We summarise the still ongoing RCTs of NOACs for the treatment and prevention of LVT (table 3), and expect that future publication of these data will provide new insights for this area.

Future

A critical unmet need in the management of LVT is the development of a systematic, stratified approach to predicting individual patient risks. Previous studies have identified several potential predisposing factors, including ventricular aneurysm, low LVEF, and alterations in coagulation and inflammatory markers. The relative weight of these factors in influencing LVT risk remains poorly understood. Quantifying and integrating LVT predisposing factors to stratify individual risk can significantly enhance the effectiveness of preventative interventions aimed at preventing life-threatening complications. Despite its clinical importance, there is currently a lack of established guidelines for LVT risk stratification. While Weinsaft and Holzknecht have proposed two simple risk prediction scores, their limited sample sizes necessitate further validation before widespread clinical adoption.26 50

The role of prophylactic anticoagulation in preventing LVT remains a subject of ongoing debate. While major guidelines, including the 2012 American College of Chest Physicians, 2013 American College of Cardiology/American Heart Association (AHA) STEMI, and 2014 American Stroke Association/AHA stroke guidelines6 41 51 have historically recommended VKA anticoagulation for patients at high risk of LVT, the 2017 European Society of Cardiology guidelines on STEMI notably completely fail to mention this recommendation,4 potentially reflecting evolving perspectives on limitations of VKA. Over the past 5 years, diagnostic and treatment protocols for LVT have largely overlooked the potential benefits of prophylactic anticoagulation. Despite limited research, the incidence of MACE in patients following LVT remains substantial, reaching up to 37.1%.1 This underscores the urgent need for RCTs to evaluate the efficacy of prophylactic anticoagulation in this population.

Finally, there is a lack of high-quality evidence to guide optimal therapy selection for patients with LVT. Additionally, the appropriate dosage of NOACs for patients with LVT, especially those receiving DAPT, remains unclear. The lack of definitive evidence poses a challenge for clinicians when selecting an antithrombotic regimen for LVT. Careful consideration of the risks and benefits is crucial.