Direct Oral Anticoagulant Use for Left Ventricular Thrombus Treatment

Left ventricular thrombus (LVT) is a severe complication of acute myocardial infarction (MI) and non-ischemic cardiomyopathies. In the United States, there are approximately 1 million MIs each year. The incidence of LVT after anterior ST-segment elevation MI (STEMI) varies widely in different reports ranging from 4% to 39%. Furthermore, the incidence of LVT in dilated cardiomyopathy (DCM) may be anywhere between 2% and 36%. Despite the improvement of reperfusion therapies, the risk of LVT in these patients remains significant.^1,2 It is important for practitioners to be familiar with the different treatment options for LVT.¹

LVT primarily occurs through the interplay of the 3 components of Virchow’s Triad: stasis attributable to reduced ventricular function, endocardial injury, and hypercoagulability. After severe cardiac events, multiple aspects of Virchow’s Triad may be present leading to the formation of LVT. For example, an acute MI may contribute to a significant reduction in left ventricular ejection fraction (LVEF). Decreased function leads to an increase in venous stasis and an increased risk of thrombus formation.1 LVT risk factors include patients with an anterior MI, MI with involvement of left ventricular (LV) apex, LV akinesis, LV dyskinesis, severe diastolic dysfunction, and large infarct size.²

For the prevention and treatment of LVT, it is commonly recommended to treat with an anticoagulant for at least 3 months post-MI. However, there is sparse evidence to direct therapy for optimal anticoagulant agent and corresponding doses in this patient population.¹

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Traditional Treatment Options

Current research suggests that anticoagulation therapy may resolve LVT and lower the risk of systemic embolism.¹ One of the first studies by Kouvars et al reported evaluating the use of anticoagulation therapy in LVT was published in 1990. This trial enrolled 60 patients who survived an acute anterior MI and whom LVT was detected by cross-sectional echocardiography. Patients were randomized into 3 different treatment groups; group A (n=20) was given a full dose of oral anticoagulants, group B (n=20) was given 650mg of aspirin a day, and group C (n=20) received no antithrombotic therapy. The dosing or agent of anticoagulants were not reported in this trial.

Patients were followed between 9 to 24 months with a 3-month interval echocardiography. Outcomes that were studied in this trial included thrombus resolution, change in thrombus size and thrombus recurrence. Twelve patients (60%) in group A, 9 patients (45%) in group B, and 2 patients (10%) in group C had complete thrombus resolution. Additionally, 3 patients (15%) in group A had a greater than 50% decrease in thrombus size during the first follow-up period after acute MI while 4 patients (25%) had significantly diminished thrombus size in the first trimester of follow up. However, in group C with no antithrombotic therapy, 2 patients (10%) had episodes of cerebral ischemic attacks and 1 patient (5%) had a peripheral embolic episode in the femoral artery. Overall, this trial concluded that anticoagulants (group A) and aspirin (group B) were equally effective, and both were superior to no treatment (p < 0.01) in the resolution of left ventricular thrombosis and prevention of emboli after acute anterior MI. This trial established the potential role that anticoagulants may place in the treatment of LVT.³

Since the Kouvaras et al study was published, smaller single centered or observational studies have been published to further evaluate the use of oral vitamin K antagonist (VKA) in LVT treatment. More recently, a study was published in 2018 which analyzed acute MI patients hospitalized between 2001 and 2014. A total of 1850 patients with first MI who discharged alive were followed post-discharge with a median follow-up period of 5.4 years. A retrospective comparative analysis was completed for patients with LVT treated with VKA with time in therapeutic range (TTR) ≥ 50% (n=34) vs TTR < 50% (n=50). Patients with LVT were first treated with continuous heparin infusion followed by vitamin K antagonist treatment with a target prothrombin time-international normalized ratio (PT-INR) range of 1.6 to 2.6 according to the Japanese guidelines for pharmacotherapy of atrial fibrillation (AF).⁴

Nine embolic events occurred in the TTR < 50% group while only one patient developed an embolic event in the TTR ≥ 50% group (18% vs. 2.9%, P=0.036). Additionally, there was no difference in the incidence of major bleeding between the 2 groups (8% vs 9%, P=0.89). These results suggest that appropriate anticoagulation may decrease the incidence of embolic events in patients with LVT without increasing the incidence of bleeding events. Additionally, this study also demonstrated the increased risk factor for systemic embolism that occurs in patients who have a lower TTR.⁴

Guideline Recommendations

The American Heart Association (AHA) recommends the use of anticoagulation with warfarin 3 to 6 months post diagnosis. This recommendation is based on the severity of the disease state and the available clinical data. Although the data surrounding the use of anticoagulants in LVT are limited, the data shows that treatment with anticoagulation is associated with a higher rate of thrombus resolution and lower the risk of embolic events compared to placebo.¹

Warfarin is the agent of choice for LVT treatment with a therapeutic INR range of 2 to 3. This is based off the availability of clinical data relevant to this more specific complication. Direct oral anticoagulants (DOACs) have become widely available since 2010. However, only recently have these agents been studied for the treatment of LVT. Although the data for DOACs in LVT are limited, the AHA recommends DOACs as an alternative for warfarin in patients. DOACs are an appealing alternative because these agents do not require routine lab monitoring, have less drug-drug interactions and do not interact with food. However, because these novel agents help mitigate adherence issues, it is important to analyze the available literature to see if these data can be applied to this patient population.¹

Literature Review

Limited literature exists specifically evaluating the use of DOACs for the treatment of LVT. Two of the more notable studies that show potential benefits of the use of DOACs in LVT are both retrospective observational studies.^5,6

Daher et al performed an observational single-center retrospective study that included patients admitted between January 2010 and August 2019 with LVT. Patients received treatment with either a DOAC or a VKA (n=42). All patients treated with a VKA were initially in the INR range of 2 to 3 and were monitored monthly after achieving the target INR range; no results were published on the number of patients that remained in the therapeutic INR range during this observational study. Patients receiving DOAC therapy received apixaban (n=12, Eliquis; Bristol-Myers Squibb) 2.5 mg or 5 mg twice daily, dabigatran (n=1, Pradaxa; Boehringer Ingelheim Pharmaceuticals) 110 mg or 150 mg twice daily, and rivaroxaban (n=4, Xarelto; Janssen CarePath) 15 mg or 20 mg daily. DOAC doses were adjusted based on the FDA approved labeling.^7-9 The primary outcome, thrombus resolution, did not occur at significantly different rates between DOAC and VKA agents (70.6%vs. 71.4%, p=0.09). Additionally, there was no difference observed with embolic events with patients treated with DOACs and VKA agents (11.8% vs. 9.5%, p = 0.8). The results of this study suggest similar efficacy and safety between the 2 classes of medications for treatment and resolution of LVT. Five patients failed to respond to DOAC therapy and were transitioned to the VKA group with a goal INR range of 3 to 4; all patients in this crossover group had LVT resolution. While these data suggest equal efficacy for DOACs in the treatment of LVT, it is important to note that the DOAC population mostly consisted of apixaban and may not be as equally applicable to patients on rivaroxaban or dabigatran.⁵

A similarly designed, single-center, retrospective study was conducted by Ali et al, and evaluated patients with confirmed LVT that received treatment with either a VKA, DOAC, or enoxaparin. A total of 96 patients received anticoagulation with 60 patients (63%) started on warfarin, 32 patients (33%) on DOACs (18 on rivaroxaban, 13 on apixaban, and 1 on dabigatran), and 4 patients (3%) started on enoxaparin. There was no information provided in this study regarding specific dosing of DOACs nor an analysis on the incidence of adverse outcomes associated with a specific DOAC. However, in contrary to the previous trial, this trial included an analysis on long-term survival data. At 1-year follow up, stroke had occurred in 11 patients on anticoagulation. Nine patients had an ischemic stroke (IS). Of those with an IS, 7 patients were on warfarin (71% of those had subtherapeutic INR) and 2 patients were on a DOAC. Additionally, 5 patients (5.5%) had peripheral embolism while being treated with anticoagulation and were in the warfarin group. The incidence of any stroke or systemic embolism was increased in the warfarin group (26.6%) compared to the DOAC group (26.6% vs. 6%, p = 0.0001). There was not a significant difference with regards to the 1-year risk of any stroke between the warfarin group and the DOACs group (15% vs. 12%, p = 0.33). Furthermore, there was no statistically significant difference between the rate of thrombus resolution between patients treated with either warfarin or DOACs (62% vs. 53%, p=0.85). These data only further support the use of DOAC agents for the treatment of LVT and provides more robust evidence for the use of rivaroxaban that was missing from the previously discussed trial.^5,6

A larger cohort study was conducted by Robinson et al that consisted of 514 patients with LVT who received treatment with either a DOAC or warfarin. This study was performed at 3 tertiary care academic medical centers between October 2013 and March 2019. Three hundred patients initially received warfarin therapy while 185 patients initially received treatment with a DOAC. A therapeutic INR range was not defined and data regarding the time patients remained in the therapeutic INR range was not collected. There was a cohort of 64 patients who switched treatment (therapy-change group) which resulted in 236 patients treated exclusively with warfarin (warfarin-only group) and 121 patients treated exclusively with a DOAC (DOAC-only group). Out of the patients that were switched from warfarin to DOACs, the main indication for these switches consisted of the following: convenience (n = 10; 19.2%), labile INR values (n = 8; 15.4%), or adherence issues (n = 8; 15.4%). Only 2 patients on warfarin (3.8%) were switched to a DOAC due to an efficacy concern. For DOACS, the most common cause of switching to warfarin was due to cost (n=6). There was no DOAC to warfarin switches due to the presence of bleeding events, however 4 patients were switched from DOACs to warfarin due to efficacy concerns including non-thrombus resolution. One hundred and forty-one patients (76.2%) were treated with apixaban, 46 patients (24.9%) were treated with rivaroxaban, and 9 patients (4.9%) were treated with dabigatran; specific dosing information was not reported regarding the use of DOACs. In contrast to the other clinical trials, this trial showed that DOAC treatment was associated with an increased risk in stroke or systemic embolism (p =0.01) with both an unadjusted and a multivariable analysis. This trial consisted of some limitations including failure to obtain data for bleeding events, adherence issues, or dosing information. However, this does challenge the assumption of DOAC equivalency with warfarin for LVT treatment.¹⁰

Due to limited number of large trials regarding this disease state, Kidoet al performed a meta-analysis to aggregate these studies to better compare the efficacy and safety of DOAC and VKA agents in patients with LVT. The researchers searched the Cochrane library, Google Scholar, MEDLINE, and the Web of Science database through January 2021; they included 8 studies evaluating stroke or systemic embolism (SSE), 6 studies for LVT resolution, and 5 studies for bleeding events. There were no statistically significant differences in SSE (p = 0.73) and LVT resolution (p = 0.56) between DOAC and VKA therapy. Additionally, DOAC use was significantly associated with lower bleeding event rates compared to VKA use (p = 0.02).¹¹ Since this meta-analysis was conducted, multiple meta-analyses have been published further evaluating the applicability of DOACs in the treatment of LVT. The largest meta-analysis to date was conducted by the authors of the AHA’s LVT scientific statement. This analysis consistently showed evidence that DOACs were similar to VKA antagonists in terms of the occurrence of stroke or systemic embolism, bleeding events, and all-cause mortality.²

One of the limitations to the available literature for LVT treatment is the lack of reported information regarding DOAC dosing. The DOACs with the most data for this indication were apixaban and rivaroxaban. A literature review and case-series were conducted and showed that most commonly full dose of anticoagulation (5 mg twice daily for apixaban and 20 mg daily for rivaroxaban) and low doses (2.5 mg twice daily for apixaban and 15 mg daily for rivaroxaban) have been used for this indication. However, in the setting of patients on who needed both DAPT therapy and anticoagulant therapy, reduced DOAC dosing was most utilized to minimize bleeding risk. However, regardless of the presence or absence of DAPT therapy there was no reported use of an apixaban nor a rivaroxaban load for this indication.¹²

Conclusions

Although the data regarding the use of DOACs in LVT is limited, data suggests similar efficacy between warfarin and DOACs in LVT resolution and stroke or systemic embolism. Additionally, the meta-analysis suggests that DOACs may be associated with a lower risk of bleeding compared to warfarin for the treatment of LVT.¹¹ This data supports the current scientific statement put forth by the AHA supporting the use of DOACs as an alternative to warfarin even with the lack of large randomized controlled trials.

The available literature has shown some concerns regarding the use of DOACs for LVT treatments with the main concern for failure of thrombus resolution. The prevalence of the patients where this is the case remained small in clinical trials and statistically insignificant.^5,10 However, in patients who are determined to be at high risk of clotting, present with a massive LVT, or failure to respond to DOACs, the preferred treatment should remain warfarin with a target INR range of 2 to 3. There is insufficient evidence to recommend increasing INR goal to 3 to 4 for patients who failed to respond to DOACs.⁵ Clinical judgement should be considered when determining an INR range for patients who are classified as DOAC non-responders.

The alternative use of DOACs can be monumental for increasing the convivence of treatment for patients with LVT. Warfarin requires routine lab monitoring, dietary considerations, and potentially severe drug-drug interactions. Alternatively, DOACs do not require frequent INR monitoring and have less drug-drug interactions. However, not all patients may be considered a candidate for DOAC therapy. Patients with mechanical valves, blood clotting disorders or those with gaps of insurance coverage should not be initiated on DOAC therapy; warfarin should remain the mainstay of treatment for these patients.

In clinical practice, choosing an oral anticoagulant requires consideration of patient specific factors including medical and socioeconomical factors. If a DOAC is decided to be the ideal agent of choice for LVT treatment, the following DOACs and doses are recommended: apixaban 5 mg twice daily or rivaroxaban 20 mg daily with renal dose adjustment as necessary consistent with the nonvalvular atrial fibrillation indication.^1,13,14 A loading dose treatment regimen is not required for either agent or has not been reported in literature for this indication. Ultimately, regardless of the chosen treatment option, the provider should involve the patient in the decision-making process and ensure they understand the proper precautions they must take to ensure adequate treatment of LVT while minimizing any bleeding or thrombosis complications.

About the Authors

Angel-Rose Weber, PharmD, is a PGY1 pharmacy resident at Albany Medical Center in New York.

Emily M Persson, PharmD, is a PGY2 cardiology pharmacy resident at the Albany College of Pharmacy and Health Sciences in New York.

Katelyn Steverson, PharmD, BCPS, CACP, is an anticoagulation management pharmacist at Albany Medical Center in New York.

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