Recurrent Stroke and Progression of Left Ventricular Thrombus During Apixaban Therapy in a Patient with Severe Ischemic Cardiomyopathy: A Case Report

Introduction

Left ventricular thrombus (LVT) is a well-defined complication of myocardial infarction and congestive heart failure and is associated with significant morbidity, mortality, and systemic embolism [1]. Multiple precipitating factors contribute to LVT development, including hypercoagulability, endothelial damage, and blood stasis, often referred to as Virchow’s Triad [2].

Warfarin, a vitamin K antagonist (VKA), has historically been the anticoagulant of choice for the management of LVT. Direct oral anticoagulants (DOACs) have largely replaced VKAs in various medical conditions due to their favorable pharmacokinetics and lack of requirement of routine monitoring [3]. While several studies support the efficacy of DOACs as an alternative to VKAs for LVT resolution [4–8], others have reported cases of failure with DOACs, compared with VKAs [9–11].

According to the American Heart Association (AHA) guideline for ST-elevation myocardial infarction (STEMI), VKAs are recommended for class IIa [12]. Whereas, the AHA guideline for the management of stroke recommends VKAs for class I and highlight the uncertainty of DOAC safety in newly diagnosed LVT (less than 3 months) [13]. More recently, the AHA guideline for the management of LVT acknowledged DOACs as an acceptable alternative in patients unable to maintain a therapeutic international normalized ratio (INR) with warfarin, which is in alignment with the position of the Asian Pacific Society of Cardiology [1,14].

Consequently, current evidence and organizational guidelines reflect ongoing debate regarding the role of DOACs versus VKAs in LVT treatment, highlighting the need for further prospective, randomized trials to clarify the efficacy and safety of DOACs in the management of LVT. In this case report, we present a patient treated with apixaban for LVT who experienced a recurrence of stroke and increase in LVT size while on apixaban.

Case Report

A 62-year-old male patient who was known to have hypertension, diabetes, dyslipidemia, ischemic heart disease, post-percutaneous coronary intervention, chronic kidney disease (CKD), peptic ulcer disease, and heart failure with reduced ejection fraction of 20% to 25% and implantable cardioverter defibrillator placed in 2014 (NYHA class IV) was found to have a large, fixed thrombus on the apical wall of the left ventricle measuring 17.5×9.9 mm, based on echocardiogram in October 2021 (Figure 1). He was on apixaban 2.5 mg twice daily, with dose adjustment due to a creatinine clearance of less than 30 mL/min. He also had a previous ischemic stroke in April 2021, without residual weakness (Figure 2). The patient reported quitting smoking 10 years ago; he used to smoke hookah 2 to 3 times per day for 30 years.

He presented to the Emergency Department in April 2022 with sudden onset of dizziness associated with a right-sided headache. At home, he checked his glucose level, which measured 500 mg/dL (27.7 mmol/L). While seated, he developed dysarthria and left-sided weakness, followed by a fall and head trauma. Additionally, he reported orthopnea, paroxysmal nocturnal dyspnea, cough with yellowish sputum, dysphagia to solids for 4 months, and peripheral neuropathy characterized by bilateral lower limb numbness for 3 months. Prior to the episode of dizziness, he had experienced a 1-hour episode of stabbing right-sided chest pain radiating to the right shoulder, with no clear aggravating or relieving factors, which later resolved spontaneously. Upon presentation, his vital signs were as follows: blood pressure of 189/87 mmHg, heart rate of 81 beats/min, temperature of 36.6°C, and oxygen saturation of 95% on room air. His Glasgow Coma Scale score was 15/15. His physical examination revealed bilateral mid-zone crepitation, dysarthria, and left-sided mouth deviation with an impaired gag reflex. Baseline laboratory investigations were obtained upon presentation to the Emergency Department in April 2022 to evaluate the patient’s clinical status before initiating acute management (Table 1).

He was admitted as a case of recurrent ischemic stroke outside the thrombolytic window, secondary to unresolved LVT, along with the decompensated heart failure, acute kidney injury, and hypertensive emergency. As the patient presented beyond the thrombolytic window, he was started on loading doses of aspirin and clopidogrel, along with a high-intensity, renally adjusted dose of rosuvastatin. A transthoracic echocardiography revealed a large, fixed thrombus on the apical wall of the left ventricle measuring 17.5×16.4 mm (Figure 3), despite the patient’s full adherence to apixaban. As the patient had acute kidney injury, heparin infusion was started initially, with a target activated partial thromboplastin time of 60 to 80 s as a bridge to warfarin 5 mg daily, with a target INR of 2 to 3. During admission, the target INR was achieved, heparin infusion was discontinued, and the patient was discharged in May 2022 on warfarin monotherapy.

Five months later, a follow-up echocardiogram showed a complete resolution of LVT. Therefore, warfarin was discontinued, and aspirin was resumed for lifelong therapy (Figure 4).

Discussion

LVT is primarily associated with increased risks of stroke and systemic embolism [1]. In our case, the patient experienced reoccurrence of stroke and a significant increase in LVT size, as evidenced on echocardiogram, despite strict adherence to apixaban therapy over a 7-month period. In contrast, a complete resolution of LVT was achieved within 5 months after switching to warfarin. This case is particularly complex as the patient had worsened LVT while on apixaban, alongside multiple comorbidities and factors that contributed to a hypercoagulable state, including all components of Virchow’s triad. Additionally, he was at a high risk of bleeding, with a HAS-BLED score of 5, a prior hemorrhagic transformation, and melena that occurred when he received Heparin infusion. Given his creatinine clearance of less than 30 mL/min, the concurrent dual antiplatelet therapy (DAPT, aspirin and clopidogrel), the initial decision was to start on apixaban at a reduced dose of 2.5 mg twice daily without DAPT. At present, DOAC use in LVT is considered off-label, and manufacturers do not provide renal dosing recommendations in this context. Thus, clinicians often extrapolate dosing strategies from non-valvular atrial fibrillation trials [11,15–23].

DOACs are increasingly being used for LVT in clinical practice and reported more frequently in the literature. Apixaban, a direct factor Xa inhibitor, has been reported in multiple case series and reports to be effective for LVT management [4,17,18,21,22], while other cases have shown treatment failure and required switching to warfarin [11,24], similar to our case.

A recent systematic review and network meta-analysis of 19 studies, including 2545 patients with LVT, compared DOACs with warfarin. The findings favored DOACs for LVT resolution. Notably, rivaroxaban was associated with faster resolution within 1 month (2.08, 95% CI [1.10–4.68]), compared with apixaban. However, apixaban demonstrated a rate of stroke or systemic embolism comparable to that of warfarin. Overall, no statistically significant difference in LVT resolution was found between DOACs and warfarin (2.72, 95% CI [0.97–8.52]) [5]. These findings align with previous AHA stroke guideline observations. However, further randomized controlled trials are necessary to confirm these results. This study highlights the variation in time to effect among DOACs, and based on these results, we can infer that our patient would have benefited from an earlier monitoring of the size of LVT while on apixaban. Additionally, a recent meta-analysis of randomized trials involving STEMI patients with LVT showed that 80.8% achieved complete resolution in the DOAC group, compared with 70.5% in the warfarin group (1.14, 95% CI [0.98–1.32]) [4].

Apixaban is primarily cleared by the kidneys, with approximately 25% eliminated renally [25]. At present, patients on DOACs for LVT with advanced CKD or end-stage renal disease are underrepresented or were excluded from clinical trials, and there are no guideline recommendations nor randomized clinical trials addressing DOAC dosing in CKD patients for managing LVT [4]. Therefore, in such a population, the choice of DOAC depends on clinical judgment and shared decision-making [1]. Advanced CKD is considered a risk factor that increases the likelihood of recurrence or increase in LVT size [26]. A reduced dose has been suggested based on extrapolation from previously published clinical trials of patients with frailty, including CKD patients, which should be interpreted with caution [25]. In a reported case of an 87-year-old patient who developed LVT after non-STEMI, dabigatran with a reduced dose (110 mg twice daily) was given alongside DAPT therapy. The authors reported that triple therapy was well tolerated by the patient, with no evidence of bleeding and successful resolution of the LVT within 1 month [19]. In a case series, 6 patients had CKD, with a mean estimated glomerular filtration rate of 40.5 mL/min, and apixaban was administrated for the treatment of LVT. Two patients received the standard dose of 5 mg twice daily, 2 were started on the reduced dose of 2.5 mg twice daily, and the remaining 2 patients began with the reduced dose, which was later changed to 5 mg twice daily following improvement in kidney function. Both of the latter patients had more than 1 LVT. Interestingly, apixaban demonstrated excellent efficacy across all cases, with complete resolution of LVT achieved within 7 to 28 days, irrespective of the initial dosing regimen [27].

On the other hand, multiple studies reported failure of LVT resolution with DOACs. In a retrospective multicenter cohort conducted by Robinson et al [9], 185 patients diagnosed with LVT were treated with oral DOACs, with apixaban being the most commonly prescribed (141 patients). Among those receiving DOACs, 4.9% had an estimated glomerular filtration rate below 30 mL/min. Treatment with DOACs resulted in significantly higher risk of stroke, systemic embolism, or death, compared with warfarin (1.55; 95% CI [1.05–2.30]; P=0.03), a trend that persisted beyond the first year of follow-up (3.10; 95% CI [1.10–8.73]; P=0.03) [9]. Another case described a 50-year-old patient with LVT and end-stage renal disease that progressed to hemodialysis. The patient was treated with apixaban 5 mg twice daily for at least 6 months; however, no significant reduction in LVT size was observed. Consequently, the patient was switched to warfarin, which led to successful resolution of the thrombus within 4 months [28], which is consistent with the findings in our case.

The current literature presents conflicting results, which poses a limitation to the widespread use of DOACs in the management of LVT. A limitation of the present case report is the suboptimal quality of the echocardiographic images, which may have affected the assessment of thrombus size and left ventricular function. However, interpretation was supported by subsequent imaging and clinical correlation.

This case reinforces the need for more robust data, including head-to-head comparisons and subgroup analyses of DOAC performance in CKD populations. Such a complicated case closely resembles the daily cases encountered in clinical practice, making its findings particularly relevant to real-world decision-making. Although apixaban has favorable pharmacokinetic properties, this case adds to the subset of cases reporting that apixaban was associated with treatment failure, as our patient experienced stroke recurrence and worsening thrombus burden despite strict adherence.

Conclusions

We report a case of a successful resolution of LVT on warfarin in a patient who had recurrence of stroke and LVT while on apixaban, with a renally adjusted dose. Close serial echocardiographic follow-up for LVT formation could be beneficial, especially in patients receiving DOAC therapy who have severe ischemic cardiomyopathy and reduced ejection fraction.