Questions and Statements
What are the Epidemiology and Risk Factors for LVT?
Before the introduction of coronary reperfusion therapy for acute coronary syndrome,
the incidence of LVT in patients with ST-elevation myocardial infarction was reported
in a range from 20 to 40% and up to 60% in larger infarction of the anterior wall.[3]
[4]
[5] The incidence decreased after the introduction of early pharmacological and interventional
coronary reperfusion therapy and nowadays the rate is reported to range between 4
and 15%.[6]
[7] The incidence of LVT reported in different Italian cohorts of patients with ischemic
heart disease was similar, ranging from 5% in studies using trans-thoracic echocardiography
to 19% in those using magnetic resonance.[8]
[9] This large difference in LVT incidence may be due to the different time lag from
the onset of myocardial infarction and diagnostic evaluation, and the differences
in included patients in terms of location and severity of myocardial infarction and
type of LVT risk factors.[10] The diagnostic method may also affect incidence value. Cardiac magnetic resonance
represents the gold standard for LVT diagnosis, while trans-thoracic echocardiography
still remains the screening diagnostic tool in patients at risk for LVT development
with its sensitivity improving thanks to the administration of contrast media.[11] However, magnetic resonance should be considered in the case of undiagnostic echocardiography
and a high clinical suspicion of LVT.[12] Trans-esophageal echocardiography does not increase LVT assessment rate as it does
not improve the visualization of the left ventricle apex.[11] Even if no sound data are available, contrast-enhanced coronary computed tomography
showed great potential for LVT detection due to its very high spatial resolution (<1 mm),
excellent evaluation of cardiac morphology, ease of use, and low costs.[13]
LVT can be classified based on the time horizon since the onset of acute myocardial
infarction as “recent” or “non-recent” if the diagnosis is made within 7 days or within 1 to 6 months after the acute myocardial
infarction, respectively. Although LVT was recent in most of the cases, the non-recent
form is quite rare (10% of patients) and may have different pathogenesis, depending
on persistent systolic dysfunction of left ventricle.[14]
[15]
[16]
[17] LVT can also be categorized according to its morphological characteristics as “mural” if its borders are contiguous with the adjacent endocardium, or as “protuberant” if it protrudes into the left ventricle cavity.[14] Mural LVT is often undetected by trans-thoracic echocardiography because a close
approximation of the thrombus to the adjacent akinetic wall can limit its detection.
The risk of LVT is greater when the anterior wall—encompassing the perfusion territory
of the left anterior descending coronary—or a large area of infarct is involved, and
when there are a relevant delay in presentation to reperfusion time, a pre-angioplasty
TIMI flow grade ≤1, and a reduced left ventricular ejection fraction (e.g., <40%)
([Table 2]).[6]
[18]
[19]
[20] Nevertheless, LVT can be found in patients with smaller and inferior myocardial
infarction, in patients with non-ST-elevation myocardial infarction as well as in
patients with preserved or moderately reduced left ventricular ejection fraction.[5]
[21]
[22] The use of balloon angioplasty instead of drug-eluting or bare medical stents appeared
to further increase the risk of LVT.[7] Other risk factors in ischemic heart disease patients include concomitant atrial
fibrillation, left ventricle aneurysm, left heart valvular disease, acute or chronic
deep venous thrombosis/pulmonary embolism, and alcohol abuse.[23] Also cardiac arrest is associated with an increased risk of LVT.[7] An inverse association with female sex has been also reported.[23]
Table 2
Risk factors for LVT development in patients with acute myocardial infarction
|
Clinical conditions
|
High-risk features for LVT development
|
|
Acute myocardial infarction
|
Left ventricle antero-apical wall involvement
|
|
ST-elevation acute myocardial infarction
|
|
Large area of infarct
|
|
Left-ventricle aneurysm
|
|
Left heart valve disease
|
|
Relevant delay in presentation to reperfusion time
|
|
Pre-angioplasty TIMI flow grade ≤1
|
Abbreviation: LVT, left ventricular thrombus.
Patients with acute myocardial infarction-related LVT have an increased risk—up to
5-fold higher—of embolic complications compared with patients without LVT, whereas
anticoagulated patients have a reduced risk of embolic complications compared with
untreated ones.[24] A recent study including 155 patients with LVT diagnosis based on late gadolinium
enhancement cardiovascular magnetic resonance imaging showed a 3.7% annualized rate
of a composite of stroke, transient ischemic attack, and extracranial systemic embolism
during a median follow-up of 3 years compared with the 0.8% of matched controls without
LVT.[25] Most of embolic events, however, are acute ischemic stroke and occur within the
first month after LVT occurrence with incidence values as high as 10%.[26]
[27]
[28]
[29] The embolic risk of LVT appeared to be higher in patients with protruding and mobile
thrombus, in patients with LVT persistence and/or recurrence, and in patients not
receiving anticoagulation.[24]
[26]
[30]
[31]
[32]
[33] An accurate clinical and radiological evaluation as well as a proper anticoagulant
therapy is mandatory to ameliorate patients' prognosis.[34]
Limited data are available about LVT in patients affected by non-ischemic heart diseases.
[Table 3] reports relevant causes and high-risk features for LVT development in patients with
non-ischemic heart disease. Dilated cardiomyopathy represents the second most common
underlying cause of LVT with incidence rates higher than 2%.[35]
[36] A reduced left ventricular ejection fraction, the presence of a scar, and a turbulent
intracardiac flow are risk factors for LVT in dilated cardiomyopathy along with the
presence of inflammation, hypercoagulability, and endocardial involvement of specific
diseases (e.g., amyloidosis, eosinophilic myocarditis).[35] The incidence of LVT in Takotsubo syndrome was reported to be around 2%.[37]
[38] Incidence values were similar in European and Italian cohort of patients.[39]
[40] Patients with LVT and Takotsubo syndrome seem to have a higher prevalence of prior
vascular disease (e.g., transient ischemic attack, stroke, myocardial infarction,
peripheral artery disease, aortic plaques), a higher heart rate, and a lower left
ventricular ejection fraction.[38] The interTAK Thrombus risk score—including apical involvement, prior vascular disease,
left ventricular ejection fraction <30%, and white blood cells >10,000/mL—has been
proposed to identify patients with Takotsubo syndrome at low (<3 points) or high risk
(≥3 points) of LVT development.[38] An increased risk of thromboembolism in patients with left ventricle non-compaction
also exists with history of stroke or transient ischemic attack and/or left ventricle
dysfunction, being related to LVT formation in the deep intertrabecular recesses.[36]
[41]
[42] Several observational studies reported a relevant incidence of LVT (10–17%) in women
with peripartum cardiomyopathy.[43]
[44]
[45] The use of specific intracardiac devices (e.g., edge-to-edge repair of mitral valve
and left ventricular assisted devices) or anti-cancer treatments (e.g., anthracyclines)
have been associated with an increased risk of LVT.[6]
[10]
[46]
[47]
[48]
[49] Finally, a small number of case reports and case series of LVT detection have been
reported in patients with other forms of cardiomyopathy, including hypertrophic cardiomyopathy,
cardiac amyloidosis, cardiomyopathy attributable to Chagas disease, and eosinophilic
myocarditis.[50]
[51]
[52]
[53]
[54]
Table 3
High-risk features for LVT development in patients with non-ischemic cardiomyopathy
|
Clinical conditions
|
High-risk features for LVT development
|
|
Chemotherapy-related cardiomyopathy[48]
|
Left ventricular restrictive filling pattern and/or ejection fraction <30%
|
|
Takotsubo syndrome[37]
[38]
[39]
|
Left ventricle dysfunction (ejection fraction <30%) and/or apical ballooning
|
|
Peripartum cardiomyopathy[44]
[45]
|
Bromocriptine administration and/or ejection fraction <35%
|
|
Dilated cardiomyopathy[35]
[36]
|
Blood stasis in dilated left ventricle, presence of a scar and of a turbulent intracardiac
flow
|
|
Severe functional mitral regurgitation[46]
|
Edge-to-edge Mitra Clip intervention
|
|
Left ventricular assisted devices[47]
|
Device malfunction and embolism
|
|
Hypertrophic cardiomyopathy[50]
|
Apical aneurysm
|
|
Left ventricular non-compaction[36]
[42]
|
History of stroke or transient ischemic attack and/or left ventricle dysfunction
|
|
Cardiac amyloidosis[52]
|
Amyloid light chain type and/or left ventricle restrictive filling pattern
|
|
Cardiomyopathy due to Chagas disease[53]
|
Apical aneurysm
|
|
Eosinophilic myocarditis[54]
|
Prior embolic episode
|
Abbreviation: LVT, left ventricular thrombus.
Statements
-
An evaluation for LVT detection is recommended in patients with acute myocardial infarction
and with high-risk features for LVT development (see [Table 2]).
-
An evaluation for LVT detection is suggested in patients with non-ischemic heart disease
and high-risk features for LVT development (see [Table 3]).
Is Anticoagulation Effective in Preventing LVT?
Identification of patients in whom primary prophylaxis with anticoagulants may have
a favorable risk–benefit profile is not well understood.[55]
Even if limited by the heterogeneity of treatment regimens in terms of type, dose,
and duration of anticoagulation and by the differences in diagnostic methods and treatments
used in the pre-reperfusion era, a meta-analysis of four RCTs showed a reduced probability
of LVT development in patients receiving anticoagulation compared with no treatment
(odds ratio 0.32; 95% confidence interval, 0.20 to 0.52).[24] No data on bleeding events were reported.[24] In the same time period, 776 patients with acute anterior myocardial infarction
were randomized in the FRAMI study to receive dalteparin (150 U/kg q12h for 9 ± 2
days) or placebo on top of thrombolytic therapy with intravenous streptokinase and
aspirin.[56] Dalteparin significantly reduced LVT formation (absolute risk difference, 8.1%;
number needed to treat, 12) at the cost of an increased rate of major bleeding (absolute
risk difference, 2.6%; number needed to harm, 39).[56] No differences have been reported in terms of systemic embolism (1.3% in both groups).[56] The administration of dalteparin in such a short period surely limited the interpretation
of results as a not negligible part of LVT develops after the first days from the
acute myocardial infarction. More recently, a smaller RCT randomized 60 patients with
acute anterior myocardial infarction to receive enoxaparin (1 mg/kg q12h for 1 month)
or warfarin (INR between 2 and 3 for 3 months) on top of antiplatelet therapy.[57] Even if limited by different treatment durations, fewer patients in the warfarin
group than in the enoxaparin group had an LVT at 3.5 months of follow-up (4% versus
15%, respectively).[57] At 1 and 3 months of follow-up, there were no stroke and systemic embolization in
either group.[57] The incidence of any bleeding requiring treatment was similar (7% versus 4%).[57] In the last published RCT, a total of 279 patients with acute anterior myocardial
infarction were randomized to receive low-dose rivaroxaban (2.5 mg q12h) or placebo
on top of dual antithrombotic therapy for 1 month.[58] Patients in the rivaroxaban group had a significantly lower risk of LVT than controls
(0.7% versus 8.6%; hazard ratio, 0.08 ; 95% confidence interval, 0.01 to 0.62) with
a doubled and apparently not significant increase in the risk of bleeding events (3.6%
versus 1.7%; hazard ratio, 2.08; 95% confidence interval, 0.38 to 11.33).[58] Furthermore, patients in the rivaroxaban group had a trend toward a reduced risk
of systemic embolism compared with controls (0.7% versus 2.9%; hazard ratio, 0.51;
95% confidence interval, 0.09 to 2.69).[58] It should be acknowledged that this RCT included only patients from China, most
of the included patients had a preserved or moderately reduced left ventricular ejection
fraction, and that there was a high rate of drop-out (more than 15%) possibly limiting
the generalizability and the robustness of results.[58]
Few data were available on the primary prevention in patients with LVT of non-ischemic
origin. Even though limited by the observational design, a recent observational study
in patients with dilated cardiomyopathy showed similar incidence of LVT detection
in patients receiving warfarin (2.9%) and lower incidence in patients receiving direct
oral anticoagulants (DOACs) (1.3%) for different indications (e.g., atrial fibrillation)
compared with untreated patients (2.7%).[35] In these latter cases, the administration of anticoagulants as primary prophylaxis
must be carefully evaluated on a case-by-case basis taking into account specific patients'
characteristics, thrombotic and bleeding risks, and preferences.
Statements
-
Routine administration of anticoagulants to prevent LVT is not recommended.
-
Administration of anticoagulants for primary prophylaxis is suggested in patients
with acute myocardial infarction and high-risk features for LVT development (see [Table 2]).
-
If primary prophylaxis with anticoagulants is prescribed, the administration of low-dose
rivaroxaban (i.e., 2.5 mg q12h) is suggested for at least 1 month and up to 3 to 6
months after the acute myocardial infarction, on top of dual antithrombotic therapy
and depending on bleeding risk. A careful evaluation of thrombotic and bleeding risks
is recommended on a case-by-case basis to assess the benefits and risks of extending
primary prophylaxis beyond the first month.
-
In patients with non-ischemic cardiomyopathy, a careful evaluation on a case-by-case
basis is recommended to assess the need of a primary prophylaxis of LVT with anticoagulants.
How to Treat Patients with LVT?
Data on the efficacy and safety of heparin treatment are sparse.[59] Unfractionated or low-molecular-weight heparin administration within few days from
LVT diagnosis was associated with an acceptable rate of thrombus resolution and with
no embolic complications.[60]
[61] The role of vitamin K antagonists (VKAs) in LVT has been investigated in several
observational and randomized studies. Even though limited by the small sample size
(60 patients overall), 60% of patients randomized to VKAs (international normalized
ratio [INR] range 1.6 to 2) had a complete thrombus resolution within the first 3
months of follow-up compared with 45% of patients randomized to aspirin (650 mg daily)
and 10% of untreated patients.[62] No patients in the VKAs group developed an embolic event compared with 15% of untreated
patients.[62] Recent observational studies confirmed the effectiveness of VKAs in terms of both
thrombus resolution and embolic events prevention.[63] The most used INR range was between 2.0 and 3.0.[63] However, the time in therapeutic range (TTR)—calculated by Rosendaal interpolation
method or % of INR in range—should be used for the therapeutic management of these
patients as it reflects the quality of VKAs therapy. It has been reported from studies
in other setting (i.e., atrial fibrillation) that patients with TTR <60% have higher
thrombotic, bleeding, and mortality rates than those with higher TTR.[64] Reaching TTR values of at least 70% is therefore advisable.[64] A recent study showed that a TTR <50% (in patients with an INR target between 1.6
and 2.6) was associated with a higher incidence of ischemic events (19.0% versus 2.9%)
and a lower rate of thrombus resolution (78% versus 91%).[65]
DOACs use is increasing over the years.[63] To date, five RCTs have been published comparing standard dose of DOACs (three studies
with apixaban and two studies with rivaroxaban) with warfarin for 3 to 6 months.[63]
[66] Although limited by the small sample size and methodological issues (e.g., open-label
design), no significant differences in terms of efficacy have been found between DOACs
and VKAs.[67] The use of DOACs was also evaluated in several observational studies that showed
a high rate of thrombus resolution and a reduction of embolic events in patients with
dilated cardiomyopathy-related LVT.[63]
[68]
[69]
[70] The largest and up-to-date available meta-analysis reported a trend toward high
risk of thrombus persistence and a trend toward lower risk of embolic events in patients
treated with DOACs compared with patients treated with VKAs.[63]
[71] Although awaiting sound data, the use of DOACs may be a reasonable alternative to
VKAs to be considered in patients who are unsuitable (e.g., difficulties in achieving
therapeutically stable INR, inability to undergo frequent blood sample collection
for INR monitoring) and/or refusing VKAs.
Anticoagulant therapy profile in non-ischemic form of cardiomyopathy is limited to
small case series and case reports and clinical decision must be addressed on a case-by-case
basis.[72] Among others, the case of two children with LVT who received VKAs was reported,
with an uneventful follow-up.[73]
The role of early thrombolysis was evaluated in small case series including patients
with high-risk features (e.g., mobile thrombus and reduced left ventricular ejection
fraction). Even though thrombolysis appeared as an effective and safe procedure in
these small case series further data are necessary to support its administration.[74]
[75] Finally, a tendency toward fewer embolic complications has been reported in patients
treated with surgical LVT removal (8 patients) versus conventional therapy (42 patients).[76] Prophylactic anticoagulation with warfarin for 3 to 6 months after surgical LVT
removal appeared to not reduce the incidence of LVT recurrence and other clinical
outcomes compared with no treatment.[77]
Statements
-
Oral anticoagulant therapy is recommended in patients with newly diagnosed LVT.
-
In case of VKA administration, an INR range between 2.0 and 3.0—with concomitant therapeutic
dose of heparin until the target INR is reached—as well as a TTR ≥70% is recommended
to reach the highest possible rate of thrombus resolution and embolic events prevention.
-
The use of DOACs is mostly suggested in patients who are considered unsuitable and/or
refusing VKAs.
How Long Should Anticoagulant Therapy be Continued in Patients with LVT?
Data from observational studies showed that LVT resolution generally occur within
the first 6 months of therapy with oral anticoagulation.[78]
[79]
[80] Thus, anticoagulant treatment was administered up to 6 months after LVT diagnosis
in most cases.[63] Some resolution may occur beyond the first 6 months of therapy; also some embolic
complications may develop during the long-term follow-up.[68]
[80]
[81]
[82]
[83]
[84]
[85] Similarly, thrombus recurrence after resolution has been reported to develop in
10 to 20% of patients and appeared to be associated with a high embolic risk.[81]
[84]
[86] An anticoagulant treatment duration longer than 3 to 6 months—and beyond 12 months—is
associated with a reduced risk of events development compared with a shorter regimen
of therapy.[87]
[88]
Some variables have been identified to guide treatment duration. Recent thrombi, as
detected by clinical characteristics and specific echocardiographic measures (i.e.,
strain rate analysis), were associated with a higher rate of resolution than non-recent
ones (94% versus 7%) after 6 months of phenprocoumon therapy.[89] However, warfarin treatment appeared to be more effective than no treatment in patients
with a non-recent thrombus also, both in terms of thrombus resolution and embolic
complications.[90] Limited data also suggest that protuberant thrombi may resolve earlier than mural
ones, possibly reducing their long-term thromboembolic potential.[12] Smaller baseline thrombus size was associated with a greater likelihood of LVT regression
(hazard ratio, 0.66; 95% confidence interval, 0.45 to 0.96).[87] Even though anticoagulation withholding may be considered after LVT resolution—especially
in patients without high-risk features and/or high bleeding risk—it should be acknowledged
that a prolonged anticoagulation over 3 months is associated with a reduced risk of
major adverse cardiovascular events (hazard ratio, 0.42 ; 95% confidence interval,
0.20 to 0.88) and with a trend toward lower rate of embolic complications (hazard
ratio 0.46; 95% confidence interval, 0.18 to 1.14).[87] Furthermore, a recent observational study reported the incidence of LVT resolution
was higher at 12 months than at 3 and 6 months of anticoagulation.[91] Although no data are available on optimal anticoagulant therapy duration in patients
with reversible ventricle dysfunction (e.g., Takotsubo syndrome), the cumulative incidence
of LVT resolution progressively increased over a 6-month period in a cohort of patients
with dilated cardiomyopathy.[69]
Among risk factors for LVT persistence, the presence of a reduced left ventricular
ejection fraction and a left ventricle apical aneurysm are the most relevant ones.[84] Conversely, a preserved or a moderately reduced left ventricular ejection fraction
appeared not to be associated with an increased risk of thrombus persistence.[91] Regarding LVT recurrence, left ventricle aneurysm and anticoagulant treatment continuation
were associated, respectively, with an increase and a reduction in the risk of this
outcome in a retrospective cohort of 115 patients including both ischemic and non-ischemic
cardiomyopathy-related LVT.[86] From a clinical point of view, advanced age is a relevant risk factor for a worst
prognosis in patients with LVT, having a lower incidence of thrombus resolution and
a higher incidence of systemic embolism compared with young patients.[91]
[92] Similarly, the presence of heart failure and chronic kidney disease appeared to
be other relevant prognostic risk factors that have been associated with a reduced
rate of thrombus resolution at 6 months and a higher rate of embolic complications.[93]
[94]
[95]
Visual summary reports the suggested antithrombotic regimens in patients with acute
coronary syndrome–related and with non-ischemic cardiomyopathy-related LVT.
Statements
-
Anticoagulant therapy is recommended until LVT resolution and for a minimum of 3 to
6 months.
-
A longer duration of anticoagulant therapy—at least 12 months—is suggested in patients
at high risk of thrombus persistence/recurrence and embolic complications (see [Tables 2] and [3]).
Can Anticoagulant Therapy be Safely Administered Along with Antiplatelets?
Overall, the incidence of major bleedings in patients with LVT receiving anticoagulation
ranges between 2 and 3% and appears to be similar to the incidence reported in other
clinical setting (e.g., atrial fibrillation with or without acute coronary syndrome).[63]
[96]
[97] Concomitant antiplatelet therapy may be needed in specific subgroups of patients,
and this may increase the bleeding risk.[98] Short-term triple therapy—i.e., less than 1 month—with dual antiplatelets and warfarin
appeared to confer low rates of major bleeding (1.1%) in 180 patients undergoing interventional
procedure for acute myocardial infarction, half of whom had LVT as an indication for
oral anticoagulation.[99] Data from small RCTs comparing DOACs with warfarin in patients with LVT showed a
comparable safety profile during triple therapy. No patient receiving DOACs (apixaban)
and 4.7% of those receiving warfarin developed a major bleeding during follow-up,
all beyond the first month and after triple antithrombotic therapy was stopped.[100]
[101] Results were similar in a small observational study that indirectly compared triple
therapy with rivaroxaban (0%) or warfarin (3.2%) for a median duration of 8.5 months
in patients with acute myocardial infarction.[102] A larger study on 159 patients with confirmed LVT, of whom nearly 70% were receiving
concomitant single or dual antiplatelets, showed a bleeding incidence as high as 13.2%
during a follow-up of 632 days.[87] No further data were reported on specific subgroups of patients or on the timing
of bleeding in relation to antithrombotic treatment.[87]
Concerning the duration of concomitant triple antithrombotic therapy and type and
dosage of concomitant antiplatelet therapy, data may be extrapolated from available
RCTs on LVT management and from previous RCTs and guidelines recommendation regarding
different clinical settings (e.g., atrial fibrillation in patients needing coronary
reperfusion therapy).[98]
[103] Triple therapy with an oral anticoagulant (DOACs or warfarin) and dual antiplatelets
(aspirin and a P2Y12 inhibitor, preferably clopidogrel) was administered for at least
of 7 days and up to a maximum of 1 month and followed by dual therapy with oral anticoagulant
and a P2Y12 inhibitor.[98]
[103] In very high bleeding risk patients—and in medically managed acute coronary syndrome—it
may be useful to consider treating patients with anticoagulants and a single antiplatelet
agent instead of triple therapy.[104]
[105] At LVT resolution, aspirin was resumed instead of anticoagulant therapy and dual
antiplatelet was continued up to 12 months after the acute myocardial infarction.
Thus, the P2Y12 inhibitor was continued indefinitely. A summary of these treatment
strategies is reported in Visual Summary.
Statements
-
In patients with LVT needing coronary reperfusion therapy, triple therapy with anticoagulants
and dual antiplatelets is recommended for at least of 7 days and up to a maximum of
1 month, followed by dual therapy with anticoagulant and single antiplatelet.
-
At LVT resolution, resuming a second antiplatelet instead of anticoagulant therapy
up to 12 months after the acute myocardial infarction is suggested. A single antiplatelet
is recommended lifelong after the first 12 months of therapy.
-
A different duration of concomitant anticoagulant and antiplatelet therapy is suggested
on a case-by-case basis weighing bleeding and thrombotic risks.
