Journal of Clinical and Preventive Cardiology

: 2020  |  Volume : 9  |  Issue : 4  |  Page : 150--154

Apixaban versus Warfarin in Patients with Left Ventricular Thrombus: A Pilot Prospective Randomized Outcome Blinded Study Investigating Size Reduction or Resolution of Left Ventricular Thrombus

W Yus Haniff W. Isa1, Niny Hwong2, Ahmad Khairuddin Mohamed Yusof3, Zurkurnai Yusof1, Ng Seng Loong4, Nadiah Wan-Arfah5, Nyi Nyi Naing6,  
1 Cardiology Unit, Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
2 Cardiology Unit, Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan; Department of Medicine, Hospital Tengku Ampuan Rahimah, Klang, Selangor, Malaysia
3 Imaging Centre, National Heart Institute, Kuala Lumpur, Malaysia
4 Department of Cardiology, Perak Community Specialist Hospital, Ipoh, Perak, Malaysia
5 School of Biomedical Sciences, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Malaysia
6 Community Medicine Unit, Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu, Terengganu, Malaysia

Correspondence Address:
Dr. W Yus Haniff W. Isa
Cardiology Unit, Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan


Background: Treatment of the left ventricular thrombus (LVT) with Vitamin K antagonists (VKAs) such as warfarin may lead to longer hospitalization. Thus, the potential of non-VKA oral anticoagulants as alternative to warfarin need to be explored. This study aims to investigate the size reduction or resolution of LVT with apixaban compared to conventional warfarin. Materials and Methods: This is a pilot, prospective, single-center, randomized, single-blinded outcome study with patients diagnosed with LVT. Patients diagnosed with LVT by echocardiography were randomized into two treatment groups: apixaban or warfarin, with target international normalized ratio 2–3. Echocardiography was repeated at weeks 6 and 12 to assess the LVT size. The percentage of reduction or total resolution during the first 12 weeks was the primary endpoint. Repeated measure ANCOVA was used to evaluate the differences in left ventricular (LV) thrombus size between treatment groups. Results: Twenty-seven patients were recruited: 14 were treated with apixaban and 13 patients with warfarin. Thirteen patients completed treatment in the apixaban arm with one patient lost to follow-up, and one death observed. In the warfarin arm, nine patients completed the study follow-up, and four died during the follow-up. The mean (standard deviation [SD]) reduction in LV thrombus size in apixaban arm was 65.1% (SD 31.3) versus warfarin arm, 61.5% (SD 44.0) at the 12th week follow-up (P = 0.816). Safety outcomes were similar with both treatment arms. Conclusions: This pilot study suggests that apixaban may have similar effectiveness and safety to warfarin for LVT resolution.

How to cite this article:
W. Isa W Y, Hwong N, Mohamed Yusof AK, Yusof Z, Loong NS, Wan-Arfah N, Naing NN. Apixaban versus Warfarin in Patients with Left Ventricular Thrombus: A Pilot Prospective Randomized Outcome Blinded Study Investigating Size Reduction or Resolution of Left Ventricular Thrombus.J Clin Prev Cardiol 2020;9:150-154

How to cite this URL:
W. Isa W Y, Hwong N, Mohamed Yusof AK, Yusof Z, Loong NS, Wan-Arfah N, Naing NN. Apixaban versus Warfarin in Patients with Left Ventricular Thrombus: A Pilot Prospective Randomized Outcome Blinded Study Investigating Size Reduction or Resolution of Left Ventricular Thrombus. J Clin Prev Cardiol [serial online] 2020 [cited 2023 Feb 6 ];9:150-154
Available from:

Full Text


The left ventricular thrombus (LVT) is a well-recognized complication of acute myocardial infarction (AMI) and congestive heart failure, often in association with severely impaired LV systolic function. LVT incidence has been reported to be as high as 30%–40% in patients with an anterior AMI, while in patients with a nonanterior AMI, the risk is lower than 5%.[1] With early revascularization and aggressive anticoagulation, LVT incidence among patients with anterior AMI reduced to 5%–15%.[2],[3],[4] However, some studies reported that despite aggressive revascularization, LVT prevalence may remain high in anterior AMI patients (23.5%).[1],[5],[6] Meanwhile, in patients with dilated cardiomyopathy and congestive heart failure, the reported LVT prevalence varies, from 10% to 30%.[7],[8]

In the Malaysian population, ischemic-induced left ventricular (LV) failure is common, due to the low rate (16.4%) of primary angioplasty.[9] As a result, the LVT prevalence is higher in this population compared with the Western population. Conventionally, the first-line therapy for LVT is the combination of the Vitamin K antagonist (VKA) warfarin and intravenous (IV) heparin. However, this standard therapy often leads to extended hospitalization to achieve the targeted international normalized ratio (INR). Non-VKA oral anticoagulants (NOACs) are potential good alternative, and no anticoagulation monitoring is needed. However, routine NOAC usage in LVT is not recommended due to the lack of evidence. Apixaban is one of the NOACs used in multiple LVT case reports and has shown efficacy, with low bleeding complications.[10],[11],[12],[13]

Our aim was to conduct a pilot prospective randomized single-blinded outcome study investigating the size reduction or resolution of LVT with apixaban compared to conventional warfarin.

 Materials and Methods

The procedures of this study have been approved by the Research Ethics Committee (human) of Universiti Sains Malaysia and conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent. Patients were recruited following set inclusion criteria namely, age 18–80 years old; heart failure diagnosis with newly discovered LV thrombus confirmed on two-dimensional echocardiography by two operators (to obtain average and increase accuracy); and HAS-BLED score of <3. Exclusion criteria included episodes of major bleeding in the past 6 months. Major bleeding was defined as history of significant drop in hemoglobin level of at least 2 g/dL with or without blood transfusion of at least two packed cell units. Other exclusion criteria were as follows: a history of intracranial bleeding or large ischemic stroke; advanced renal and liver disease on cardiac devices; clinically unstable or in shock. In terms of echocardiography findings, old and organized thrombus was excluded based on the two echocardiographers' experience.

Treatment allocation was carried out by permuted block randomization using computer software into two groups. The first arm was given the study drug, apixaban 5 mg twice daily (BD) for 12 weeks, with the dose of 2.5 mg BD chosen for patients with two of the following characteristics: age ≥75 years, weight ≤60 kg, or serum creatinine ≥133 μmol/L. The other treatment arm received the standard therapy of warfarin with initial heparin infusion, aiming for a target INR of 2–3. In the presence of recent acute coronary syndrome and for patients who did not undergo angioplasty, only a single antiplatelet was used concurrently. Postangioplasty patients were placed on triple therapy (apixaban/warfarin + dual antiplatelet therapy).

Echocardiographers were blinded to the patient's treatment, and a previous echocardiography report was made available for reference. The completed echocardiography data entry forms were kept separately out of reach from investigators for blinding purposes. Unblinding of the reports was conducted only when any suspected adverse events occurred. The study visits were scheduled at weeks 0, 1, 2, 3, 6, 9, and not more than 15 weeks. Weeks 0, 6, and 12 were for echocardiography, whereas the other visits were for INR monitoring and to screen for any adverse events. These methods include blood investigations for hemoglobin level and renal or liver function for both arms.

In total, three echocardiographic examinations were conducted to each patient. The size was measured by universal tracing function by Toshiba Aplio 300 (Toshiba Medical System Corporation, Japan) and was reported as area in cm2 [example shown in [Figure 1]]. During the study duration, the treatment (apixaban/warfarin) was continued after total resolution of LVT until the next visit with echocardiography when no contraindication was observed. The purpose was to ensure that the resolution was maintained on two echocardiographic examinations (6 weeks apart). The primary endpoint was the LV thrombus size resolution in percentage after 3 months.{Figure 1}

Where there was residual small thrombus present, all anticoagulants were switched to warfarin as per local protocol after week 15. After 15 weeks had elapsed, follow-up was conducted by every 2 months until the end of the study duration of 24 months. Any major cardiovascular events, including bleeding, stroke and death from any cause, was recorded and analyzed.

For a pilot study, the minimum number per group was 12 using “the rule of 12.”[14] Schoenfeld suggested that in most cases, 25 subjects would be sufficient for a meaningful difference between the groups.[15]

Statistical analysis

Statistical analysis was based on intention to treat analysis. The full analysis set included patients who received at least one dose of medication or had one or more postrandomization, follow-up evaluation (s). For the primary and secondary outcomes, descriptive statistics and 95% confidence intervals were used to summarize the differences between groups. All data were entered into IBM® SPSS® Statistics version 24(IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, New York, United States: IBM Corp). The descriptive statistics of variables was presented as mean and standard deviation (SD) for continuous variables and frequency and percentage for categorical variables.

The comparison of LV thrombus size (cm2) between the warfarin and apixaban treatment groups was analyzed using repeated measures of ANCOVA. Model assumptions for the repeated measures ANCOVA analysis were then checked for normality, homogeneity of variance, and compound symmetry. Homogeneity of variance was tested using Levene's test, and the equal variance assumption was fulfilled. Box test was applied to test covariance (P > 0.05). Compound symmetry was then checked for all of the measurements using Mauchly's test of sphericity. P <0.05 indicates that assumption of compound symmetry was not met. Thus, analysis continued with multivariate test or univariate test with Epsilon correction. When the time and LVT area interaction was significant (P < 0.05), further analysis then produced adjusted means with 95% confidence interval. The analysis was continued with adjusted confidence intervals using Bonferroni adjustment method. Differences exhibiting P < 0.05 was considered statistically significant.


A total of 112 patients were screened. Of these, 20 had organized LVT, 24 had old thrombus, two had advance chronic kidney disease, 10 were in critical clinical condition and 20 refused to participate due to logistical issues. Thus, 27 patients (mean age 55.19, SD 11.01 years) were finally included in this study, with 14 patients in the apixaban arm and 13 patients in the warfarin arm. Mean ejection fraction on echocardiography was 33.5% (SD 5.73) [Table 1].{Table 1}

Thirteen patients completed the treatment in the apixaban arm with one patient lost to follow-up. Two patients died in the apixaban arm at the end of the study period: one was caused by massive ischemic stroke with hemorrhagic transformation, the second by worsening heart failure. Meanwhile, nine patients completed the study, and four died during the first 12 weeks in the warfarin arm.

LVT mean size reduction throughout the study period for both arms is shown in [Figure 2]. Repeated measure ANCOVA analysis showed a statistically significant mean difference in the LVT size reduction when comparing week 0 versus week 6 and week 0 versus week 12 of both arms. Mean difference was greater in the apixaban arm than in the warfarin arm [Table 2]. Repeated measures ANCOVA within group analysis was applied followed by pairwise comparison with 95% confidence interval adjustment by Bonferroni correction. The LVT size from weeks 0 to 12 showed no significant difference of percentage of reduction for both arms [Table 3].{Figure 2}{Table 2}{Table 3}

There were no statistically significant differences in LVT mean size (cm2) between two treatment arms in baseline, week 6 and week 12 [Table 4]. The mean (SD) reduction in LV thrombus size in apixaban arm was 65.1% (SD 31.3) versus warfarin arm, 61.5% (SD 44.0) at the 12th week follow-up (P = 0.816) [Table 5].{Table 4}{Table 5}

In this study, we found safety outcomes were similar with both treatment arms.

Meanwhile, interobserver reliability analysis by intraclass correlation coefficient between the cardiologist and the staff nurse showed the lowest correlation in week 0 (0.72) with higher correlation in both week 6 (0.91) and 12 (0.98).


In this pilot study, apixaban demonstrated similar effectiveness and safety to warfarin for LVT resolution. Further large prospective randomized trials are needed to explore this group of patients.

Multiple case reports have suggested that apixaban and NOACs are efficacious for the treatment of LVT.[16] Robinson et al. reported a single-center study of patients with LVT, in which NOAC was used off label. In their study, NOAC-treated patients had similar systemic embolism-free survival compared with the warfarin-treated patients.[17] The X-TRA study was the only prospective study of NOACs used for intracardiac thrombus, especially within the left atrial appendage.[18] The present study provides unique prospectively collected data for the use of NOACs with LVT.

This study showed consistent LVT size reduction in both treatment groups. Thrombus size upon admission could be one of the predictors of thrombus resolution.[19] The apixaban group had achieved significant size reduction between weeks 0 and 6 and weeks 0 and 12, similar to the outcome in the warfarin group. Similarly, the mean percentage of reduction for LVT was no different between the two groups although the reduction rate was greater in apixaban group for the first 6 weeks. Of note, LVT was diagnosed and monitored by transthoracic echocardiography which is an acceptable measurement tool employed in other case reports for the use of NOAC in LVT. In addition, utilizing echocardiography to measure the LVT volume quantitatively by planimetry measurement has the advantage of intra- and inter-reader reproducibility.[20] The lower intraclass correlation in week 0 could be due to higher measurement variability in early or actively forming thrombus which may appear echo-lucent and highly mobile. In contrast, older and organized thrombus generally has smooth cavitary surface, which may explain the higher correlation toward the end of treatment.

Additional imaging by contrast-enhanced cardiac magnetic resonance could improve the intracardiac thrombus detection and further characterizes the thrombus morphology.[21]

In terms of adverse events, four death in the warfarin arm occurred during 12 weeks while two deaths in the apixaban arm occurred later. All hospitalization was caused by worsening heart failure. The stroke event only occurred in the apixaban arm. The number of deaths was small in both treatment arms for a meaningful interpretation.


This pilot study has many limitations. First, the sample size of the study was small due to the pilot nature of the study, being a single-center strict study and strict exclusion criteria. The high rate of early angioplasty in this center also contributed to the low number of patients with LVT. In addition, many patients with LVT were excluded because of their ill clinical condition on presentation, deranged renal/liver functions on diagnosis, organized or old LVT and other logistic issues. When patients with LVT were newly diagnosed together with deranged liver and/or renal functions, they had to be treated as soon as possible with IV heparin to avoid thromboembolism. Warfarin was usually added as part of the protocol while they were in the ward, and such patients could not be enrolled. Second, wide variation of data for the thrombus size was expected due to high mobility and deformity of early thrombus.[22],[23] This has also been seen in other echocardiographic measurements.[24],[25],[26] A bigger sample size would attenuate this effect and narrow the confidence interval. No further LVT evaluation was observed by cardiovascular magnetic resonance due to limited availability and high cost. Complementing transthoracic echocardiography with additional contrast-enhanced cardiac magnetic resonance imaging may improve these shortcomings.[21]


This pilot study suggests that apixaban may be used with similar effectiveness and safety to warfarin for LVT resolution. Further large prospective randomized trials are needed to explore treatment options in this group of patients.


We would like to thank Professor Gregory Y. H Lip MD, FRCP, DFM, FACC, FESC for his expertise and assistance throughout all aspect of our study. Last but not least to our research officer Mr. Zulkefli Sanip for his help and patience in preparing the manuscript.

Financial support and sponsorship

This study has been funded by our University (Universiti Sains Malaysia) under Short Term Research Grant Scheme (Grant No.: 304/PPSP/61313197).

Conflicts of interest

There are no conflicts of interest.


1Asinger RW, Mikell FL, Elsperger J, Hodges M. Incidence of left-ventricular thrombosis after acute transmural myocardial infarction. Serial evaluation by two-dimensional echocardiography. N Engl J Med 1981;305:297-302.
2Kalra A, Jang IK. Prevalence of early left ventricular thrombus after primary coronary intervention for acute myocardial infarction. J Thromb Thrombolysis 2000;10:133-6.
3Nayak D, Aronow WS, Sukhija R, McClung JA, Monsen CE, Belkin RN. Comparison of frequency of left ventricular thrombi in patients with anterior wall versus non-anterior wall acute myocardial infarction treated with antithrombotic and antiplatelet therapy with or without coronary revascularization. Am J Cardiol 2004;93:1529-30.
4Greaves SC, Zhi G, Lee RT, Solomon SD, MacFadyen J, Rapaport E, et al. Incidence and natural history of left ventricular thrombus following anterior wall acute myocardial infarction. Am J Cardiol 1997;80:442-8.
5Meltzer RS, Visser CA, Fuster V. Intracardiac thrombi and systemic embolization. Ann Intern Med 1986;104:689-98.
6Küpper AJ, Verheugt FW, Peels CH, Galema TW, Roos JP. Left ventricular thrombus incidence and behavior studied by serial two-dimensional echocardiography in acute anterior myocardial infarction: Left ventricular wall motion, systemic embolism and oral anticoagulation. J Am Coll Cardiol 1989;13:1514-20.
7Ciaccheri M, Castelli G, Cecchi F, Nannini M, Santoro G, Troiani V, et al. Lack of correlation between intracavitary thrombosis detected by cross sectional echocardiography and systemic emboli in patients with dilated cardiomyopathy. Br Heart J 1989;62:26-9.
8Gottdiener JS, Gay JA, VanVoorhees L, DiBianco R, Fletcher RD. Frequency and embolic potential of left ventricular thrombus in dilated cardiomyopathy: Assessment by 2-dimensional echocardiography. Am J Cardiol 1983;52:1281-5.
9Wan Ahmad WA. Annual Report NCVD 2014-2015. Kuala Lumpur: National Heart Association of Malaysia; 2017.
10Kawakami T, Kobayakawa H, Ohno H, Tanaka N, Ishihara H. Resolution of left atrial appendage thrombus with apixaban. Thromb J 2013;11:26.
11Mano Y, Koide K, Sukegawa H, Kodaira M, Ohki T. Successful resolution of a left ventricular thrombus with apixaban treatment following acute myocardial infarction. Heart Vessels 2016;31:118-23.
12Yanıkoğlu A, Altıntaş MS, Ekinözü İ. Dissolution of an apical thrombus by apixaban in a patient with old anteroseptal myocardial infarction. Anatol J Cardiol 2015;15:671-2.
13Nakasuka K, Ito S, Noda T, Hasuo T, Sekimoto S, Ohmori H, et al. Resolution of left ventricular thrombus secondary to tachycardia induced heart failure with rivaroxaban. Case Rep Med 2014; 2014: Article ID 814524, 5 pages.
14Griffiths HR, Lip GY. New biomarkers and risk stratification in atrial fibrillation: Simplicity and practicality matter. Circulation 2014;130:1837-9.
15Schoenfeld D. Statistical considerations for pilot studies. Int J Radiat Oncol Biol Phys 1980;6:371-4.
16Berry A, Brancheau D, Zughaib M. Rapid resolution of left ventricular thrombus with apixaban therapy. SAGE Open Med Case Rep 2017;5:1-3.
17Robinson A, Ruth B, Dent J. Direct oral anticoagulants compared to warfarin for left ventricular thrombi: A single center experience. J Am Coll Cardiol 2018;71:A981.
18Lip GY, Hammerstingl C, Marin F, Cappato R, Meng IL, Kirsch B, et al. Rationale and design of a study exploring the efficacy of once-daily oral rivaroxaban (X-TRA) on the outcome of left atrial/left atrial appendage thrombus in nonvalvular atrial fibrillation or atrial flutter and a retrospective observational registry providing baseline data (CLOT-AF). Am Heart J 2015;169:464-7100.
19Bernhardt P, Schmidt H, Hammerstingl C, Lüderitz B, Omran H. Atrial thrombi-a prospective follow-up study over 3 years with transesophageal echocardiography and cranial magnetic resonance imaging. Echocardiography 2006;23:388-94.
20Meenan RT, Saha S, Chou R, Swarztrauber K, Krages KP, O'Keefee-Rosetti M, et al. Effectiveness and cost-effectiveness of echocardiography and carotid imaging in the management of stroke. Evid Rep Technol Assess (Summ). 2002;49:1-10.
21Takasugi J, Yamagami H, Noguchi T, Morita Y, Tanaka T, Okuno Y, et al. Detection of left ventricular thrombus by cardiac magnetic resonance in embolic stroke of undetermined source. Stroke 2017;48:2434-40.
22Ebrahimi M, Fazlinezhad A, Alvandi-Azari M, Abdar Esfahani M. Long-term clinical outcomes of the left ventricular thrombus in patients with ST elevation anterior myocardial infarction. ARYA Atheroscler 2015;11:1-4.
23Niemann M, Gaudron PD, Bijnens B, Störk S, Beer M, Hillenbrand H, et al. Differentiation between fresh and old left ventricular thrombi by deformation imaging. Circ Cardiovasc Imaging 2012;5:667-75.
24Pellikka PA, She L, Holly TA, Lin G, Varadarajan P, Pai RG, et al. Variability in ejection fraction measured by echocardiography, gated single-photon emission computed tomography, and cardiac magnetic resonance in patients with coronary artery disease and left ventricular dysfunction. JAMA Netw Open 2018;1:e181456.
25Bellenger NG, Burgess MI, Ray SG, Lahiri A, Coats AJ, Cleland JG, et al. Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance; are they interchangeable? Eur Heart J 2000;21:1387-96.
26Vignola PA, Bloch A, Kaplan AD, Walker HJ, Chiotellis PN, Myers GS. Interobserver variability in echocardiography. J Clin Ultrasound 1977;5:238-42.