The prognostic impact of left ventricular thrombus resolution after acute coronary syndrome and risk modulation via antithrombotic treatment strategies

Abstract Background Left ventricular thrombus (LVT) is a rare but dreaded complication during the acute phase of acute coronary syndrome (ACS). However, profound data on long‐term outcome and associated antithrombotic treatment strategies of this highly vulnerable patient population are scarce in current literature. Methods Patients presenting with ACS were screened for presence of LVT and subsequently included within a prospective clinical registry. All‐cause mortality and the composite of major adverse cardiac events (MACE) and thromboembolic events were defined as primary and secondary endpoint. Results Within 43 patients presenting with LVT, thrombus resolution during patient follow‐up was observed in 27 individuals (62.8%). Patients that reached a resolution of LVT experienced lower incidence rates of death (−23.9%; p = .022), MACE (−37.8%; p = .005), and thromboembolic events (−35.2%; p = .008). Even after adjustment for clinical variables, thrombus resolution showed an independent inverse association with all‐cause death with a hazard ratio (HR) of 0.14 (95% CI: 0.03–0.75; p = .021) and as well with MACE with a HR of 0.22 (95% CI: 0.07–0.68; p = .008) and thromboembolic events with a HR of 0.22 (95% CI: 0.06–0.75; p = .015). Triple antithrombotic therapy (TAT) with ticagrelor/prasugrel showed a strong and independent association with thrombus resolution with an adjusted HR of 3.25 (95% CI: 1.22–8.68; p = .019) compared to other strategies. Conclusion The presented data indicate a poor outcome of ACS patients experiencing LVT. In terms of a personalized risk stratification, thrombus resolution has a strong protective impact on both all‐cause death and MACE with the potential to tailor treatment decisions—including an intensified antithrombotic treatment approach—in this patient population.

with ST-elevation myocardial infarction (STEMI). 1 Incidence rates differ among the observational studies from 1.6% up to 39% indicating that many LVT cases might remain undetected. [2][3][4][5][6][7] This substantial variation in the incidence rate, is caused by varieties in the imaging modality used for diagnosis and the timing and frequency of screening. Additionally, the use of modern revascularization therapies has reduced the occurrence of LV-thrombus formation. [2][3][4][5][6][7] While the prognosis of patients presenting with LVT after ACS has been controversially discussed, it seems intuitive that individuals without thrombus resolution have an increased risk for cardiovascular events and mortality. Thrombus formation is significantly associated with anterior myocardial infarction (MI) and confers an increased risk for thromboembolic events (mostly cerebrovascular). [8][9][10] In the prethrombolytic era, these complications were described in approximately 10% of cases, whereas in the era of thrombolytic therapy embolic events occurred in 2%-3% of cases. [8][9][10] Until now there is scarce evidence regarding the incidence of embolic events in patients treated by primary percutaneous coronary intervention (PCI) that receive dual antiplatelet therapy (DAPT) or even triple antithrombotic therapy (TAT; oral anticoagulation [OAC] plus DAPT) or dual antithrombotic therapy (DAT) as the combination of OAC with only one antiplatelet agent. However, optimal pharmacological therapy-used to reduce complications of LVT-remains challenging. While patients post MI requires DAPT for reduction of atherothrombotic risk, they also need OAC in case of LVT formation for reduction of related complications, with subsequent high risk of bleeding. 11 For patients with large anterior STEMI, DAPT with a potent P2Y 12 inhibitor may even be an attractive option, as potent DAPT has been shown to contribute to a lower incidence of LVT. 12 Considering a strong impact of LVT on patient outcome and the notion that many LVTs remain undetected in clinical practice, patient characteristics that help to identify ACS individuals at risk for the development of LVT with an adverse outcome should be considered in terms of a personalized secondary prevention. However, profound data on long-term outcome of this highly vulnerable patient population are scarce in current literature. Therefore, we aimed to investigate the impact of LVT resolution and associated antithrombotic treatment strategies on patient's outcome from a long-term perspective.

| Data acquisition and patient follow-up
Patient-relevant characteristics were assessed via the patients' electronic medical records of the Vienna General Hospital, as well during a standardized follow-up procedure. Data assessment was performed by specially trained chart reviewers that inserted predefined patient characteristics into a record abstraction form for further analysis of the registry at the time of hospitalization and re-evaluation during the entire hospitalization. Discharge letters of all participants were screened for the antithrombotic treatment approach at the time of discharge.
Patients were invited to the local department for screening of thrombus resolution. The presence of LVT was validated by contrast transthoracic echocardiography (TTE) and/or cardiac magnetic resonance tomography (CMR) of all enrolled individuals. Clinically relevant data, including the antithrombotic treatment and adherence to medication was assessed during the follow-up visit. Thrombus resolution was defined as lack of evidence of thrombus mass in follow-up contrast TTE or CMR.

| Endpoint definition
All-cause death (including death from cardiovascular, renal, and cancer disease) was chosen as primary study endpoint.

| Statistical analysis
Continuous data are presented as median and the respective interquartile range and analyzed using Mann Whitney U test. Categorical parameters are presented as counts and percentages and analyzed using Chi-square test. Univariate and multivariate Cox proportional hazard models were applied to assess the influence of thrombus resolution on primary and secondary endpoints and to assess the impact of a TAT with newer P2Y 12 antagonists on LVT resolution. Results were presented as hazard ratio (HR) and the respective 95% confidence interval (CI). A three-step adjustment approach was followed within the multivariate regression model

| RESULTS
Detailed baseline characteristics for the study population presenting with LVT (n = 43), stratified in individuals with thrombus resolution and without thrombus resolution are summarized in Table 1.
In short, the present study population   (Table 3) LVT resolution proved to be inversely associated with long-term mortality, presenting with a crude HR of 0.18 (95% CI: 0.03-0.93; p = .041). Three different multivariate models (1. patient characteristics, 2. clinical presentation, and 3. laboratory values) were used to analyze whether the prognostic value of LVT was independently associated with mortality, MACE, and thromboembolic events (Table 4). Within the multivariate model 2, LVT resolution remained inversely associated with long-term mortality with an adjusted HR of 0.14 (95% CI: 0.03-0.75; p = .021) ( Table 4).

| Follow-up and outcome analysis
In addition, LVT resolution was also associated with a signifi-   (  Figure 1).   (Table 5).

| DISCUSSION
The current analysis is-to the best of our knowledge-one of the first in literature that investigated the impact of LVT resolution after ACS on cardiovascular events and mortality. The present data illustrates that LVT resolution was independently associated with a favorable long-term outcome and survival free of MACE and thromboembolic events. In addition, our data indicates that TAT with potent P2Y 12 inhibitor might be considered in patients with LVT.
Within the present investigation, we observed an incidence rate of LVT after ACS of 2.5%. Reported incidence rates vary from 1.6% up to 39%. [2][3][4][5][6][7] The principal cause of these variations is rooted in the use of modern revascularization therapies 2-7 Furthermore, different imaging modalities and the timing and frequency of screening may affect the incidence rate. [2][3][4][5][6][7] Within our study, we observed a high prevalence of established Compared with the existing literature, the number of patients with NSTEMI in our study is high. However, because the proportion of NSTEMI patients compared to STEMI patients is increasing significantly in clinical practice, we assume more NSTEMI patients in total.
Optimal pharmacological therapy in this highly vulnerable patient population-used to reduce complications of LVT-remains challenging. Within the present investigation VKA is the primary anticoagulant used with low prescription rates of NOACs, which is probably caused by the lack of evidence in the treatment of LVT. 11  poor with a very high risk of major cardiovascular events and mortality. Furthermore, they could assess that LVT resolution, obtained with different anticoagulant strategies, was associated with reduced mortality, which may serve as a basis for using LVT resolution as a surrogate endpoint in future RCT. 15

| LIMITATIONS
Despite the extended follow-up, several limitations should be addressed.
The major limitations of the present analysis represent its single center setting and the low-sample size. However, considering the rare occurrence of LVT after MI and long screening period, we obtained a clinically relevant sample size for the present investigation. In addition, patients were not followed using a standardized follow-up. Also, laboratory measurements were not available for all patients introducing possible selection bias.
Finally, despite multivariable adjustment for clinical variables and biomarkers, residual confounding is possible.

| CONCLUSION
The presented data clearly highlighted the poor outcome of ACS patients experiencing LVT. In terms of personalized risk stratification, the prognostic value of thrombus resolution on MACE, all-cause death and thromboembolic events can reasonably be considered for risk assessment and treatment decisions in this highly vulnerable patient population. Considering the observation that TAT with more potent P2Y 12 antagonists was associated with a treatment benefit, an intensified antithrombotic treatment approach might be taken into account in patients with persistent LVT and low-bleeding risk. and Christian Hengstenberg critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.