Left Ventricular Thrombus Therapy With Direct Oral Anticoagulants Versus Vitamin K Antagonists: A Systematic Review and Meta-Analysis

Abstract

Background:

Current guidelines recommend vitamin K antagonists (VKAs) for left ventricular thrombus (LVT) resolution. Direct oral anticoagulants (DOACs) are increasingly evaluated as alternatives to the standard of care in anticoagulation.

Methods:

We performed a systematic review and meta-analysis to assess the use of DOACs vs VKAs for LVT treatment. The occurrence of LVT resolution, systemic embolism (SE) or stroke, and bleeding events were compared during follow-up using random-effects analysis.

Results:

The 5 included studies were all observational (a total of 828 patients). Of these, 284 patients (34%) were treated with DOACs, and 544 (66%) treated with VKAs. Thrombus resolution was similar for both methods (pooled odds ratio [OR], 0.91; 95% CI, 0.47-1.75; I ² = 63%; P = .78). The incidence of SE or stroke was also similar (pooled OR, 1.59; 95% CI, 0.85-2.97; I ² = 0%; P = .14). Clinically relevant bleeding incidence was similar for both groups (pooled OR, 0.66; 95% CI, 0.31-1.40; I ² = 0%; P = .28), although all bleeding events were less frequent in the DOAC group (pooled OR, 0.49; 95% CI, 0.26-0.90; I ² = 0%; P = .02).

Conclusion:

Our systematic review and meta-analysis suggests DOACs were as effective as VKAs for LVT resolution, with a similar risk of systemic embolism/stroke and clinically relevant bleeding. These results, obtained from observational studies, are not definitive and hence randomized controlled trials are needed. Nevertheless, our analysis identifies key experimental features required in future studies.

Keywords

left ventricular thrombus direct oral anticoagulants vitamin K antagonists anticoagulation

Background

The reported incidence of left ventricular thrombus (LVT) ranges from 15% to 25% in patients with anterior myocardial infarction (MI)¹ and as high as 36% with dilated cardiomyopathy when optimal imaging modalities are used.^2,3 LVT is associated with increased risk of cerebral and peripheral ischemic events and subsequent increased mortality.^4,5

Current guidelines for LVT resolution recommend anticoagulant treatment with vitamin K antagonists (VKAs) for 3 months⁶ or 6 months.⁷ Direct oral anticoagulants (DOACs) have emerged as alternatives to the standard of care in anticoagulation for the prevention of SE in atrial fibrillation (AF)^8

-11 and for prevention and treatment of venous thromboembolism.^12

-15 Compared with VKA treatment, DOACs offer the advantage of providing a stable and predictable anticoagulant effect with no need for monitoring. DOACs are also associated with higher medication adherence.¹⁶ In patients with AF, DOACs have a favorable risk-benefit profile; they provide a significant reduction in the risk of intracranial hemorrhage and all-cause mortality.¹⁷

Although there are no randomized clinical trials to assess DOAC treatment of LVT, observational studies have been published.^5,18

-23 In addition, several case reports evaluated off-label use of DOACs for LVT resolution.^24

-31

We performed a systematic review and meta-analysis to assess the effect of different anticoagulation strategies (DOACs versus VKAs) on the resolution of LVT and the prevention of related ischemic and bleeding events.

Methods

We searched MEDLINE and the Cochrane Library databases using the terms “left ventricular thrombus” or “left ventricular thrombi” and “anticoagulation” or “anticoagulants” or “treatment” or “direct oral anticoagulants” or “vitamin K antagonists,” without language or date restrictions. Also, we manually reviewed references cited in the retrieved articles. This meta-analysis of data was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The selection of papers to include followed a 3-step methodology: (1) reading the title and evaluation of its relevance, (2) reading the abstract, and (3) reading the full text.

Articles were considered for inclusion if they described comparison of DOACs and VKAs for LVT treatment and assessed LVT resolution and recorded occurrence of SE and stroke. Observational studies were eligible for inclusion. Exclusion criteria included duplicate publications and studies published only in abstract format.

A total of 269 studies were identified. Of these, 262 were excluded after title and abstract evaluation indicated they did not fulfill the inclusion criteria. Two studies were excluded after full-text reading because, although they compared anticoagulant strategies, adequate data for analysis were not presented.^5,23 Figure 1 shows the selection diagram.

Figure 1.

Diagram of study selection.

Study design and characteristics were collected from each included study. Data on age, sex, and the incidence of hypertension, diabetes mellitus, ischemic cardiomyopathy history, AF diagnosis, LV ejection fraction, and concomitant antiplatelet therapy were also collected when available.

The coprimary endpoints were (1) thrombus resolution and (2) SE or stroke events. The secondary endpoint was clinically relevant bleeding and all bleeding events. The definition of bleeding events varied between studies. Therefore, we employed 2 categories: (1) “clinically relevant bleeding events,” defined as BARC ≥2 (for Bleeding Academic Research Consortium) bleedings or bleeding events requiring cessation in anticoagulation or with need for hospitalization; and (2) all bleeding events. Variable definition by study is shown in Table 1.

Table 1.

Outcomes Definition by Study Included in the Meta-Analysis.

	Thrombus resolution	Systemic embolism or stroke	Bleeding events
Daher et al	Thrombus resolution confirmed on transthoracic echocardiography	Not specified	Not applicable
Guddeti et al	Resolution of thrombus on follow-up echocardiogram	Ischemic stroke confirmed by neuroimaging	Any life-threatening bleeding, drop in hemoglobin ≥2 g/dL, and/or bleeding requiring hospitalization or evaluation by endoscopy
Iqbal et al	No evidence of thrombus or organization of thrombus	Not specified	Any episode of bleeding documented on the hospital medical record including hospitalization, attendance at the emergency department, or described in correspondence during the period of anticoagulation
Jones et al	Resolution of thrombus on follow-up echocardiogram or cardiac magnetic ressonance	Not specified	Defined by BARC criteria
Robinson et al	Thrombus resolution confirmed on echocardiogram	Systemic embolism or ischemic stroke	Bleeding events requiring cessation in anticoagulation

BARC, Bleeding Academic Research Consortium.

Risk of Bias Assessment

We assessed the risk of bias in the studies, following the Newcastle-Ottawa Scale.³² Three quality parameters were evaluated: selection, comparability, and outcome. The maximum score for each study was 9 points; studies with a score of less than 5 were considered to have a high risk of bias.

Statistical Analysis

Continuous variables were expressed as mean ± SD or median and interquartile range (IQR), and categorical variables were expressed as frequencies or percentages. Pooled odds ratios (ORs) and 95% CIs were estimated based on a random-effects meta-analysis and were obtained from the pooled adjusted ORs of the primary studies. The I ² statistic was used to assess statistical heterogeneity across studies (moderate heterogeneity was considered present for values between 30% and 60%). Sensitivity analysis for all outcomes was conducted excluding data from the study with the highest risk of bias. Statistical analyses were performed using RevMan Review Manager, version 5.2 (Nordic Cochrane Centre).

Results

Studies Included and Baseline Characteristics

Five studies were included with a total of 828 patients. The baseline characteristics of the patients stratified by study are shown in Table 2. A total of 284 patients (34%) were treated with DOACs, and 544 (66%) were treated with VKAs. The mean age of the study patients was similar (DOAC, 65 ± 15 years vs VKA, 65 ± 14 years). Sixty-four patients (8%) switched treatment between treatment groups, and the analysis was conducted so that an individual event was counted for each group according to the patient’s treatment at the time of the event. Among DOAC-treated patients, 65% received apixaban, 30% rivaroxaban, 4% dabigatran, and 1% edoxaban. All the studies had observational designs.^18

-22 Table 3 summarizes the studies.

Table 2.

Baseline Population Characteristics by Study.

Author	Medication	Age, y (mean ± SD)	Gender (male)	HTN	Hyperlip.	DM	DVT/PE	AF	LVEF, % (mean ± SD)	Ischemic CM	AAS	P2Y12 inhibitors
Daher et al	DOAC (n = 17)	57 ± 14	14 (82)	10 (59)	5 (29)	2 (12)	–	–	41 ± 8	15 (88)	10 (59)	11 (64)
Daher et al	VKA (n = 42)	61 ± 13	35 (83)	17 (41)	18 (43)	9 (21)	–	–	36 ± 12	36 (74)	28 (66)	17 (40)
Guddeti et al	DOAC (n = 19)	61 ± 13	55 (69)	15 (79)	–	3 (16)	1 (5)	4 (21)	25 (20 -40)	10 (53)	11 (58)	3 (16)
Guddeti et al	VKA (n = 80)	61 ± 12	15 (79)	61 (76)	–	34 (43)	4 (5)	18 (23)	25 (20 -35)	48 (60)	54 (68)	12 (15)
Iqbal et al	DOAC (n = 22)	62 ± 13	20 (91)	9 (41)	4 (18)	19 (86)	N.A.	N.A.	31 ± 13	18 (82)	9 (41)	11 (50)
Iqbal et al	VKA (n = 62)	62 ± 14	55 (89)	18 (29)	9 (15)	19 (31)	N.A.	N.A.	35 ± 13	55 (89)	39 (65)	29 (45)
Jones et al	DOAC (n = 41)	58 ± 14	33 (80)	23 (61)	19 (50)	7 (18)	N.A	N.A.	34 ± 10	–	–	–
Jones et al	VKA (n = 60)	60 ± 14	51 (85)	22 (36)	19 (32)	10 (17)	N.A.	N.A.	35 ± 9	–	–	–
Robinson et al	DOAC (n = 121)	58 ± 15	94 (78)	86 (71)	71 (59)	36 (30)	25 (21)	30 (25)	28 ± 14	66 (55)	56 (46)	–
	VKA (n = 236)	58 ± 15	170 (72)	177 (75)	126 (53)	92 (39)	38 (16)	45 (19)	28 ± 12	148 (63)	109 (46)	–
	Therapy change (n = 64)	56 ± 13	44 (69)	47 (73)	29 (45)	26 (41)	19 (30)	23 (36)	25 ± 12	36 (56)	26 (40)	–

HTN, hypertension; Hyperlip., hyperlipidemia; DM, diabetes mellitus; DVT/PE, deep venous thromboembolism/pulmonary embolism; AF, atrial fibrillation; LVEF, left ventricular ejection fraction; CM, cardiomyopathy; AAS, acetylsalicylic acid; DOAC, direct oral anticoagulants; VKA, vitamin-K antagonists; N.A., not applicable.

Table 3.

Study Designs and Main Characteristics.

Study	Design	No. of patients	DOACs	Follow-up	Outcomes
Guddeti et al (2020) USA	Retrospective multicenter (2012-2019)	99	19 (apixaban [n = 15], rivaroxaban [n = 2], dabigatran [n = 2])	1 year	Stroke occurred in 2 patients in the warfarin group and none in the DOACs group (P = .49). Bleeding events were observed in 4 in the warfarin group and 1 in the DOACs group (P = .96). No difference between patients in the DOACs group compared to the VKAs group (80% vs 81%; P = .9) for thrombus resolution.
Daher et al (2020) France	Retrospective single-center (tertiary referral center) (2010-2019)	59	17 (apixaban [n = 12], rivaroxaban [n = 4], dabigatran [n = 1])	3 months	No difference in thrombus resolution (70.6% vs 71.5%; P = .9). No difference in systemic embolic events (11.8% vs 9.5%; P = .8).
Guddeti et al (2020) US	Retrospective multicenter (2012-2019)	99	19 (apixaban [n = 15], rivaroxaban [n = 2], dabigatran [n = 2])	1 year	Stroke occurred in 2 patients in the warfarin group and none in the DOACs group (P = .49). Bleeding events were observed in 4 in the warfarin group and 1 in the DOACs group (P = .96). No difference between patients in the DOACs group compared to the VKAs group (80% vs 81%; P = .9) for thrombus resolution.
Iqbal et al (2020) UK	Retrospective single-center (tertiary referral center) (2012-2018)	84	44 (rivaroxaban [n = 13], apixaban [n = 8], dabigatran [n = 1])	Mean: 3 years (±1.4 years)	No differences between VKAs and DOACs in rates of stroke (2% vs. 0%, P = .55) or other thromboemboli (2% vs 0%, P = .55). No differences in clinically significant bleeding (10% vs 0%, P = .13). No difference in the rate of resolution of thrombus between groups (76% vs. 65% P = .33), at 233±251 days. Rehospitalization (50% vs. 45%: P = .53) and all-cause mortality (10% vs. 14%; P = .61) were also similar.
Guddeti et al (2020) USA	Retrospective multicenter (2012-2019)	99	19 (apixaban [n = 15], rivaroxaban [n = 2], dabigatran [n = 2])	1 year	Stroke occurred in 2 patients in the warfarin group and none in the DOACs group (P = .49). Bleeding events were observed in 4 in the warfarin group and 1 in the DOACs group (P = .96). No difference between patients in the DOACs group compared to the VKAs group (80% vs 81%; P = .9) for thrombus resolution.
Jones et al (2020) UK	Prospective observational single-center (tertiary referral center) (2015-2018)	101	41 (rivaroxaban [n = 24], apixaban [n = 15], edoxaban [n = 2])	Median: 2.2 years	29 patients in the DOAC group and 29 in the VKA had resolution of thrombus noted on their first follow-up imaging (P = .04), at 151 days (IQ 63-352) and 175 days (98-340), respectively. Greater and earlier LV thrombus resolution in the DOAC group (82% vs 64.4%, P = .0018, at 1 year), which persisted after adjusting for baseline variables (OR 1.8 95% CI 1.2-2.9). Major bleeding events were lower in the DOAC group, compared with VKA group (0% vs 6.7%, P = .030). No difference in rates of systemic thromboembolism (5% vs 2.4%, P = .388).
RED VELVT Robinson et al (2020) USA	Retrospective multicenter (tertiary referral centers) (2013-2019)	514	185 (64 switched between groups) (apixaban [n = 141], rivaroxaban [n = 46], dabigatran [n = 9])	Median: 351 days (IQ 51-866 days)	Oral anticoagulation use was not associated with thrombus resolution (HR of DOACs vs warfarin, 1.08; 95% CI, 0.78-1.50; P = .64). DOACs treatment is associated with stroke or SE (HR, 2.64; 95% CI, 1.28-5.43; P = .01). Anticoagulation type was not associated with death (HR 1.19; 95% CI,0.72-1.96; P = .50). Treatment with DOACs significantly associated with death or stroke or SE (HR, 1.55; 95% CI, 1.05-2.30; P = .03).

DOAC, direct oral anticoagulants; VKA, vitamin-K antagonists; SE, systemic embolism; USA, United States of America; UK, United Kingdom; OR, odds ratio; IQ, interquartile range; HR, hazard ratio; RED VELVT, Retrospective Evaluation of DOACs and Vascular Endpoints of Left Ventricular Thrombi.

Risk of Bias

The quality assessment for each study is presented in the Newcastle-Ottawa Scale summary (Figure 2). The study by Robinson et al was judged to have the highest risk of bias (7 points). Therefore, sensitivity analysis for all outcomes was conducted excluding that study from the analysis.

Figure 2.

Newcastle-Ottawa scale summary. *Represents one point for each topic.

Thrombus Resolution

All studies reported the LVT resolution, although the timing of echocardiographic evaluation varied, and follow-up echocardiography was not performed for every patient. The pooled analysis comprised 819 patients with a similar proportion of thrombus resolution for patients taking DOACs versus those with VKA treatment (pooled OR, 0.91, 95% CI, 0.47-1.75; I ²= 63%; P = .78; Figure 3). In a sensitivity analysis, including the 3 studies that reported the total number of patients with follow-up echocardiography (n = 235),^19,21,22 there was also no inter-group difference in thrombus resolution (pooled OR, 1.20, 95% CI, 0.47-3.10; I ² = 59%; P = .70; Figure 4).

Figure 3.

Pooled analysis of thrombus resolution comparing patients receiving DOACs with patients receiving VKAs. Numbers displayed represent ORs with 95% CIs. DOAC, direct oral anticoagulant; OR, odds ratio; VKA, vitamin K antagonist. * Please note that for easy of understanding, VKA is represented “left” and DOAC is presented “right” in the forest plot.

Figure 4.

Sensitivity analysis of thrombus resolution comparing patients receiving DOACs with patients receiving VKAs. Numbers displayed represent ORs with 95% CIs. DOAC, direct oral anticoagulant; OR, odds ratio; VKA, vitamin K antagonist. * Please note that for easy of understanding, VKA is represented “left” and DOAC is presented “right” in the forest plot.

Systemic Embolism

All included studies reported SE or stroke; 828 patients and 45 pooled events. There was a similar incidence of SE or stroke during follow-up (pooled OR, 1.59; 95% CI, 0.85-2.97; I ² = 0%; P = .14; Figure 5). Sensitivity analysis (removal of data from Robinson et al) showed similar results (pooled OR, 0.80; 95% CI, 0.24-2.63; I ² = 0%; P = .72). A subgroup analysis that focused only on stroke (284 patients and 7 pooled events), also revealed no difference between groups (pooled OR, 0.64; 95% CI, 0.13-3.18; I ² = 0%; P = .59; Figure 6).

Figure 5.

Pooled analysis of systemic embolism or stroke comparing patients receiving DOACs with patients receiving VKAs. Numbers represent ORs with 95% CIs. DOAC, direct oral anticoagulant; OR, odds ratio; VKA, vitamin K antagonist.

Figure 6.

Pooled analysis of stroke comparing patients receiving DOACs with patients receiving VKAs. Numbers represent ORs with 95% CIs. DOAC, direct oral anticoagulant; OR, odds ratio; VKA, vitamin K antagonist.

Bleeding Events

Bleeding events were reported in 4 studies, involving a total of 769 patients (with 267 [35%] treated with DOACs) and 66 pooled events. In an analysis for clinically relevant bleedings (36 pooled events), the anticoagulation strategy did not differ in the odds for bleeding (pooled OR, 0.66; 95% CI, 0.31-1.40; I ² = 0%; P = .28; Figure 7). Sensitivity analysis showed similar results (pooled OR, 0.64; 95% CI, 0.13-3.09; I ² = 0%; P = .58). The risk of all bleeding events was halved in the DOAC group compared with the VKA group (pooled OR, 0.49; 95% CI, 0.26-0.90; I ² = 0%; P = .02; Figure 8). Sensitivity analysis showed similar results (pooled OR, 0.35; 95% CI, 0.14-0.83; I ² = 0%; P = .02).

Figure 7.

Pooled analysis of relevant bleeding events comparing patients receiving DOACs with patients receiving VKAs. Numbers displayed represent ORs with 95% CIs. DOAC, direct oral anticoagulant; OR, odds ratio; VKA, vitamin K antagonist.

Figure 8.

Pooled analysis of all bleeding events comparing patients receiving DOACs with patients receiving VKAs. Numbers displayed represent ORs with 95% CIs. DOAC, direct oral anticoagulant; OR, odds ratio; VKA, vitamin K antagonist.

Discussion

Our systematic review and meta-analysis suggest a similar proportion of complete LVT resolution in patients treated with DOACs and those treated with VKAs. The ischemic risk was also similar for both treatments. Clinically relevant bleeding events were similar between the 2 groups of patients; however, the risk for all bleeding events was lower with DOAC treatment.

The clinical prognosis of patients with LVT is considered poor with a high risk of major cardiovascular events and mortality.²³ Thrombus resolution with anticoagulation is a predictor of a good prognosis. Nevertheless, a large proportion of patients, as assessed by our pooled analysis, failed to achieve total thrombus resolution and hence remained at high risk of adverse events.

Although evidence is limited, the standard of care for LVT treatment has been VKAs. However, 3 important factors may significantly influence the success of VKA treatment. The first is treatment duration. A recent study reported a lower occurrence of major adverse cardiovascular events in patients receiving anticoagulants for at least 3 months versus patients receiving anticoagulants for a shorter time. The second factor is the intensification of the antithrombotic treatment.²³ In a subgroup of patients initially treated with DOACs without thrombus resolution at 3 months, treatment was changed to VKA anticoagulation with a target INR of 3-4; these patients subsequently obtained resolution of their thrombus. This intensification of treatment may nevertheless be compromised by more frequent bleeding complications. The third, and perhaps most important factor in VKA therapy, is the time in therapeutic range (TTR). Clinical benefit is associated with high TTR³³ and, conversely, risk of bleeding is increased when TTR is low.³⁴ It is, therefore, clear that there is scope for improvement in VKA anticoagulation management of LVT.

The efficacy of DOACs for LVT resolution was initially described in case reports with varying regimens and durations of treatment. A recent case-report meta-analysis reported successful LVT resolution after 6 months of DOAC therapy varying from 81% to 100%, with different DOACs.³⁵ Other series reported a success of 83%, 83% and 100%, respectively.^29
-31 The incidence of SE or stroke was 2%, 0%, 0%, and 2% respectively.^29
-31,35 The reported proportion of bleeding events were 8%, 13%, 10% and 2%, respectively.^29
-31,35 However, it is possible that publication bias occurred because negative results might not have been reported.

Each individual study (except for Jones et al) included in our pooled analysis found no differences between the incidence of thrombus resolution for DOACs vs VKAs.^18

-22 Jones and colleagues reported greater and earlier LVT resolution in the DOAC group.²¹ Two studies not included in the analysis showed divergent results.^5,23 Although it was not powered for direct comparison of anticoagulant strategies, one of these studies suggested a similar incidence of thrombus resolution, major adverse cardiovascular events, and bleeding events.²³ The other study showed thrombus resolution in all patients treated with DOACs versus 75% resolution in VKA-treated patients.⁵ In acute MI, LVTs can be caused by blood stasis and endocardial changes, or both.³⁶ DOACs were first approved for prevention of embolism in AF, where thrombosis is primarily the result of stasis. Thus, the presence of endocardial damage may be less amenable to DOAC therapy. The same argument applies to VKAs.

Most studies used a target international normalized ratio (INR) of 2 to 3 in patients treated with VKAs.^19,21,22 TTR was reported only by Jones et al,²¹ which revealed almost half (47%) of the patients in the VKA group had suboptimal INR control (TTR < 65%). As mentioned earlier, TTR is crucial in determining clinical efficacy and bleeding risk. Another issue that could influence anticoagulation response is the concomitant use of antiplatelet therapy. However, this was similar in both treatment groups and therefore probably not responsible for any difference in efficacy.

In AF, studies have consistently shown that not only was there a similar or even reduced bleeding incidence with DOACs versus VKAs. Furthermore, patients experiencing major bleeding with DOACs were also shown to have a more favorable outcome than those receiving VKA treatment.^37

-40 Most patients with an LVT present to their clinician after an acute MI. The recent evidence of DOAC use after percutaneous coronary intervention in combination with a P2Y12 inhibitor has also revealed a noninferior or even superior safety profile compared with VKA-based regimens in patients with AF, and this is without increasing the risk of ischemic or embolic events.^41

-44 For LVT management in patients with concomitant acute MI, there is certainly a need for an individualized approach that considers anticoagulation duration, intensification regimes, the need for antiplatelet therapy, and bleeding risk.

Although DOACs confer several advantages over VKAs, the off-label use of DOACs may be problematic. There is evidence that DOACs may not be equivalent to VKAs; for example, for the thromboprophylaxis of mechanical heart valves⁴⁵ or for patients with antiphospholipid syndrome.⁴⁶ In contrast, encouraging evidence has emerged for the use of DOACs in conditions where they were previously contraindicated, such as rheumatic mitral stenosis and late-stage chronic renal failure.^47,48

Limitations

All the studies included in this analysis had a nonrandomized observational design and are thereby prone to bias. For example, the off-label use of DOAC may result in selection bias; i.e. the selection of a specific type of patient—one with less probability for adverse outcomes. Follow-up time for thrombus resolution and embolic events varied considerably between studies. Therefore, comparison is compromised. Only one study reported TTR. Consequently, we have no idea of TTR in the majority of patients; the greater the TTR, the greater the likelihood of clinical success. Not all the patients included had a follow-up echocardiogram. Patients without imaging re-evaluation in the studies by Robinson et al and Guddeti et al were included as if the thrombus had not resolved. Therefore, the real proportion of thrombus resolution might have been higher than the values used in our analysis. Because we were unable to determine how many patients had undergone re-evaluation echocardiography within each treatment group, we decided that our designation was the best way to conduct the analysis. However, the results might lead to bias in the follow-up, because patients receiving off-label DOACs would not be denied a follow-up echocardiogram. This possibly accounts for the high heterogeneity for this outcome. The criteria for reporting bleeding events varied (see Table 1). Finally, the included studies employed different DOACs and so the results should be interpreted with caution because efficacy may be agent dependent.

Future Directions

Clearly, randomized controlled trials (RCTs) are needed to remove potential bias that may have been present in the observational studies. In fact, several RCTs are underway. A multicenter randomized trial (EARLY-MYO-LVT) is currently underway to investigate the efficacy and safety of rivaroxaban (15 mg daily) vs warfarin (INR, 2-2.5) plus antiplatelet therapy for the prevention of LVT after ST-segment elevation acute MI.⁴⁹ Similarly, 2 single-center randomized trials comparing apixaban (5 or 2.5 mg twice a day) with warfarin (INR, 2-3) regarding the size reduction or resolution of LVTs are also under way.^50,51 These RCTs should have well-defined follow-up times with appropriate echocardiography imagine and should report TTR for warfarin-treated patients. Furthermore, cost-effectiveness should also be determined if DOACs are to become standard therapy for LVT.

Conclusion

The results of this systematic review and meta-analysis suggest that DOAC use was as effective as VKA use for the treatment of patients with LVT, with a similar risk of systemic embolism/stroke and clinically relevant bleeding. Nonetheless, the limitations of the observational studies revealed by our meta-analysis emphasize the need for RCTs designed to determine the best anticoagulant strategy for LVT treatment.

Footnotes

Authors’ Note

All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Author Contributions

CS and RT designed the work, made the acquisition, analysis, and interpretation of the data and draft of the work. JL, DC, and LP designed the work and revised it. MC and LN revised the work. All authors read and approved the final manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Carolina Saleiro

References

McCarthy

Vaduganathan

McCarthy

Januzzi

Bhatt

McEvoy

. Left ventricular thrombus after acute myocardial infarction: screening, prevention, and treatment. JAMA Cardiol. 2018;3(7):642–649.

Gottdiener

Gay

VanVoorhees

DiBianco

Fletcher

. Frequency and embolic potential of left ventricular thrombus in dilated cardiomyopathy: assessment by 2-dimensional echocardiography. Am J Cardiol. 1983;52(10):1281–1285.

Ezekowitz

Wilson

Smith

, et al. Comparison of indium-111 platelet scintigraphy and two-dimensional echocardiography in the diagnosis of left ventricular thrombi. N Engl J Med. 1982;306(25):1509–1513.

Maniwa

Fujino

Nakai

, et al. Anticoagulation combined with antiplatelet therapy in patients with left ventricular thrombus after first acute myocardial infarction. Eur Heart J. 2018;39(3):201–208.

McCarthy

Murphy

Venkateswaran

, et al. Left ventricular thrombus: contemporary etiologies, treatment strategies, and outcomes. J Am Coll Cardiol. 2019;73(15):2007–2009.

Kernan

Ovbiagele

Black

, et al. American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160–2236.

Ibanez

James

Agewall

, et al. ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–177.

Connolly

Ezekowitz

Yusuf

, et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151.

Patel

Mahaffey

Garg

, et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891.

10.

Granger

Alexander

McMurray

, et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992.

11.

Giugliano

Ruff

Braunwald

, et al.; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104.

12.

Schulman

Kearon

Kakkar

, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–2352.

13.

Schulman

Kakkar

Goldhaber

, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764–772.

14.

Bauersachs

Berkowitz

Brenner

, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–2510.

15.

Agnelli

Buller

Cohen

, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.

16.

Ozaki

Choi

, et al. Real-world adherence and persistence to direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2020;13(3):e005969.

17.

Ruff

Giugliano

Braunwald

, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):P955–P962.

18.

Robinson

Trankle

Eubanks

, et al. Off-label use of direct oral anticoagulants compared with warfarin for left ventricular thrombi. JAMA Cardiol. 2020;5(6):685–692.

19.

Iqbal

Straw

Craven

Stirling

Wheatcroft

Witte

. Direct oral anticoagulants compared to vitamin K antagonist for the management of left ventricular thrombus. ESC Heart Failure. 2020;7(5):2032–2041.

20.

Guddeti

Anwar

Walters

, et al. Treatment of left ventricular thrombus with direct oral anticoagulants: a retrospective observational study [published online ahead of print June 27, 2020]. Am J Med. 2020;S0002-9343(20): 30523–4. doi:10.1016/j.amjmed.2020.05.025

21.

Jones

Wright

Alizadeh

, et al. The use of novel oral anti-coagulant’s (NOAC) compared to Vitamin K Antagonists (Warfarin) in patients with left ventricular thrombus after acute myocardial infarction (AMI) [published online ahead of print Jul 30, 2020]. Eur Heart J Cardiovasc Pharmacother. 2020;pvaa096. doi:10.1093/ehjcvp/pvaa096

22.

Daher

Costa

Hilaire

, et al. Management of left ventricular thrombi with direct oral anticoagulants: retrospective comparative study with vitamin K antagonists. Clin Drug Investig. 2020;40(4):343–353.

23.

Lattuca

Bouziri

Kerneis

, et al. Antithrombotic therapy for patients with left ventricular mural thrombus. J Am Coll Cardiol. 2020;75(14):1676–1685.

24.

Seecheran

Persad

Seecheran

. Rivaroxaban as an antithrombotic agent in a patient with ST-segment elevation myocardial and left ventricular thrombus: a case report. J Investig Med High Impact Case Rep. 2017;5(1):2324709617697991.

25.

Elikowski

Małek-Elikowska

Słomczyński

Ganowicz-Kaatz

Bolewski

Skrzywanek

. Rivaroxaban-resistant right ventricular thrombus, successfully treated with vitamin K antagonist in a patient with dilated cardiomyopathy. Pol Merkur Lekarski. 2016;41(245):238–242.

26.

Makrides

. Resolution of left ventricular postinfarction thrombi in patients undergoing percutaneous coronary intervention using rivaroxaban in addition to dual antiplatelet therapy. BMJ Case Rep. 2016;2016:bcr2016217843.

27.

Kaya

Hayıroğlu

Mİ

Keskin

Tekkeşin

Aİ

Alper

. Resolution of left ventricular thrombus with apixaban in a patient with hypertrophic cardiomyopathy. Turk Kardiyol Dern Ars.2016;44(4):335.

28.

DeCampos

Lopes

Saleiro

, et al. Successful resolution of a large left ventricular thrombus with rivaroxaban. CASE (Phila). 2020;4(4):270–273.

29.

Fleddermann

Hayes

Magalski

Main

. Efficacy of direct acting oral anticoagulants in treatment of left ventricular thrombus. Am J Cardiol. 2019;124(3):367–372.

30.

Smetana

Dunne

Parrott

Davis

Schmelzer Collier

Covell

Smyth

. Oral factor Xa inhibitors for the treatment of left ventricular thrombus: a case series. J Thromb Thrombolysis. 2017;44(4):519–524.

31.

Shokr

Ahmed

Abubakar

, et al. Use of direct oral anticoagulants in the treatment of left ventricular thrombi: a tertiary center experience and review of the literature. Clin Case Rep. 2019;7(1):135–142.

32.

Luchini

Stubbs

Solmi

Veronese

Assessing the quality of studies in meta-analyses: advantages and limitations of the Newcastle Ottawa Scale. World J Meta-Anal. 2017;5(4):80–84.

33.

Alnsasra

Haim

Senderey

, et al. Net clinical benefit of anticoagulant treatments in elderly patients with nonvalvular atrial fibrillation: experience from the real world. Heart Rhythm. 2019;16(1):31–37.

34.

Tiili

Putaala

Mehtälä

, et al. Poor quality of warfarin treatment increases the risk of all types of intracranial hemorrhage in atrial fibrillation. Circ J. 2019;83(3):540–547.

35.

Kajy

Shokr

Ramappa

. Use of direct oral anticoagulants in the treatment of left ventricular thrombus: systematic review of current literature. Am J Ther. 2020;27(6):e584–e590.

36.

Delewi

Zijlstra

Piek

. Left ventricular thrombus formation after acute myocardial infarction. Heart. 2012;98(23):1743–1749.

37.

Hylek

Held

Alexander

, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes. J Am Coll Cardiol. 2014;63(20):2141–2147.

38.

Piccini

Garg

Patel

, et al. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J. 2014;35(28):1873–1880.

39.

Majeed

Hwang

Connolly

, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013;128(21):2325–2332.

40.

Giugliano

Ruff

Wiviott

, et al. Mortality in patients with atrial fibrillation randomized to edoxaban or warfarin: insights from the ENGAGE AF-TIMI 48 Trial. Am J Med. 2016;129(8):850–857. e2.

41.

Vranckx

Valgimigli

Eckardt

, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet. 2019;394(10206):1335–1343. doi:10.1016/S0140-6736(19)31872-0

42.

Gibson

Mehran

Bode

, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423–2434. doi:10.1056/NEJMoa1611594

43.

Cannon

Bhatt

Oldgren

, et al. RE-DUAL PCI Steering Committee and Investigators. Dual antithrombotic therapy with dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017;377(16):1513–1524. doi:10.1056/NEJMoa1708454

44.

Windecker

Lopes

Massaro

, et al. AUGUSTUS Investigators. Antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome treated medically or with percutaneous coronary intervention or undergoing elective percutaneous coronary intervention: insights from the AUGUSTUS trial. Circulation. 2019;140(23):1921–1932. doi:10.1161/CIRCULATIONAHA.119.043308

45.

Eikelboom

Connolly

Brueckmann

, et al. RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206–1214.

46.

Dufrost

Risse

Reshetnyak

, et al. Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants: results from an international patient-level data meta-analysis. Autoimmun Rev. 2018;17(10):1011–1021.

47.

Kim

S-H

Myong

, et al. Outcomes of direct oral anticoagulants in patients with mitral stenosis. J Am Coll Cardiol. 2019;73(10):1123–1131.

48.

Siontis

Zhang

Eckard

, et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation. 2018;138(15):1519–1529. Erratum in: Circulation. 2018;138(15):e425.

49.

Dong

, et al. Rationale and design of a prospective multi-center randomized trial of EARLY treatment by rivaroxaban versus warfarin in ST-segment elevation MYOcardial infarction with Left Ventricular Thrombus (EARLY-MYO-LVT trial). Ann Transl Med. 2020;8(6):392.

50.

Alcalai

; Hadassah Medical Organization. Apixaban versus warfarin in patients with left ventricular (LV) thrombus. Published 2018. Accessed May 19, 2020. https://clinicaltrials.gov/ct2/show/study/NCT03232398

51.

Isa

YHW

. Apixaban versus warfarin in patients with left ventricular thrombus. Published 2018. Accessed May 19, 2020. https://clinicaltrials.gov/ct2/show/NCT02982590