ARTICLE IN PRESS CLINICAL RESEARCH STUDY
Left Ventricular Thrombus After Primary PCI for ST-Elevation Myocardial Infarction: 1-Year Clinical Outcomes ,
Alastair J. Moss, MD a , Anoop S.V. Shah, MD, PhD a, Eunice T. Zuling b, Michael Freeman, MD b, David E. Newby, MD, PhD a, Philip D. Adamson, MD, PhD a,c, Nicholas L. Cruden, MD, PhD b a
British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; b Edinburgh Heart Centre, Royal Inﬁrmary of Edinburgh, Edinburgh, UK; c Christchurch Heart Institute, University of Otago, Christchurch, New Zealand.
ABSTRACT BACKGROUND: Left ventricular thrombus formation is a complication of acute myocardial infarction. However, the incidence and risk of systemic thromboembolism in the era of primary angioplasty for ST elevation myocardial infarction (STEMI) is unclear. This study aims to determine clinical outcomes in patients with STEMI treated with primary angioplasty and left ventricular thrombus at 1 year. METHODS: Patients who underwent primary angioplasty for STEMI and had a transthoracic echocardiogram were recruited. The primary endpoint was a composite of all-cause mortality, stroke, and systemic thromboembolism at 1 year. For the primary endpoint, the difference between the presence and absence of left ventricular thrombus was compared using a logistic regression, adjusting for minimization variables including age, diabetes mellitus, hypertension, and previous stroke. RESULTS: Of 2608 patients who underwent primary angioplasty for STEMI, 1645 (63%) patients had a transthoracic echocardiogram performed during the index hospital admission. Forty patients (2.4%) had evidence of left ventricular thrombus on transthoracic echocardiography. Patients with left ventricular thrombus were more likely to develop atrial ﬁbrillation in the immediate postinfarction period (6 [15%] vs 87 [5.4%], P = 0.025). At 1 year, the primary endpoint occurred in 4 (10%) patients with left ventricular thrombus and 146 (9.1%) who did not (logistic regression hazard ratio 0.79, 95% conﬁdence interval 0.23-2.70). CONCLUSIONS: In the contemporary era of mechanical reperfusion for STEMI, echocardiographic detection of left ventricular thrombus was observed in b 3% patients. The presence of left ventricular thrombus was not associated with an increased risk of systemic thromboembolism. Crown Copyright © 2019 Published by Elsevier Inc. All rights reserved. All rights reserved. • The American Journal of Medicine (2019) xxx:xxx-xxx KEYWORDS: Anticoagulation; Clinical outcomes; Left ventricular thrombus; ST elevation myocardial infarction (STEMI)
BACKGROUND Acute myocardial infarction is a pro-thrombotic state associated with left ventricular thrombus formation.1 In the era of primary percutaneous coronary intervention (PCI), improved Funding: None. Conﬂicts of Interest: AJM is supported by the Chief Scientiﬁc Ofﬁce of the Scottish Government (CGA/17/53). DEN is supported by the British Heart Foundation (CH/09/002, RE/13/3/30183) and is a recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). Authorship: All authors had access to the data and a role in writing this manuscript. Requests for reprints should be addressed to Dr Alastair J Moss, BHF Centre for Cardiovascular Science, Chancellor’s Building, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB. E-mail address: [email protected]
myocardial salvage and smaller infarct size has reduced the incidence of early left ventricular thrombi following STelevation myocardial infarction (STEMI) to between 4% and 15%.2,3 However, clinical outcome measures regarding the prognostic signiﬁcance of left ventricular thrombi in the primary PCI era remain unclear.4 Importantly, the identiﬁcation of left ventricular thrombus following myocardial infarction is associated with a 4-fold increased risk of systemic thromboembolism.5 The heightened risk of thromboembolic stroke with left ventricular thrombus has resulted in international guidelines mandating the use of oral anticoagulation, predominantly with coumarin-derived anticoagulants.6 Coumarin-derived anticoagulants have been considered to provide insufﬁcient protection against the risk of stent
0002-9343/Crown Copyright © 2019 Published by Elsevier Inc. All rights reserved. All rights reserved. https://doi.org/10.1016/j.amjmed.2019.02.033
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thrombosis or target vessel revascularisation following myoor heterogeneous echogenic mass with central lucency that cardial infarction; therefore recommendations on the choice protruded into the left ventricular cavity and was adjacent to of antithrombotic therapy following myocardial infarction an abnormally contracting, akinetic, or aneurysmal myocardial support triple therapy (ie, dual-antiplatelet therapy and oral segment. anticoagulation) in the ﬁrst instance.7 Of note, triple therapy is recognized to increase bleeding events, and indeed, this Study Outcomes risk may outweigh the beneﬁts with The primary outcome was a composite regard to reduced thrombotic of 1 year all-cause mortality, stroke, CLINICAL SIGNIFICANCE complications.8 Consequently, esand systemic thromboembolism. The tablishing the frequency of thromsecondary outcomes included the inciLeft ventricular thrombus occurs in botic and bleeding complications dence of individual measures of the b 3% following percutaneous coronary associated with left ventricular composite outcome at 30 days and 1 intervention for ST elevation myocarthrombus following myocardial inyear and bleeding events at 30 days dial infarction (STEMI). farction is a necessary step to inform and 1 year. Bleeding events were deThe identification and treatment of left future therapeutic trials in this ﬁeld. ﬁned according to thrombolysis in ventricular thrombus following STEMI is This study aims to evaluate the fremyocardial infarction (TIMI) as either not associated with a significant increase quency of left ventricular thrombus major (ie, any intracranial bleeding, in all-cause mortality and systemic thromin patients presenting with acute clinically overt fall in hemoglobin of STEMI and 1 year thromboembolic boembolism at 1 year. ≥ 50 g/L or a ≥ 15% absolute decrease and bleeding outcomes. Future studies are required to assess the in hematocrit or fatal bleeding) or use of direct oral anticoagulants in this minor (ie, clinically overt fall in hemoglobin of 30 to b 50 g/L or a ≥ 10% setting. absolute decrease in hematocrit, any METHODS hemorrhage requiring intervention, prolonging hospital admission, or prompting an unscheduled health care Study Population assessment).10 Clinical outcomes were obtained from data Consecutive patients who underwent primary PCI between linkage with the Information Services Division of NHS ScotJanuary 2009 and December 2014 with diagnosis of land as previously described.11 Follow-up was obtained in STEMI were included in this single-center (Edinburgh all patients who remained resident in Scotland. Heart Centre, Royal Inﬁrmary of Edinburgh, UK) retrospec-
tive analysis. Patients were included if they fulﬁlled the diagnostic criteria for STEMI: characteristic symptoms of myocardial ischemia in association with persistent electrocardiographic ST elevation and subsequent release of biomarkers of myocardial necrosis or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Primary PCI (including the use of drug-eluting stents, aspiration thrombectomy, and use of glycoprotein IIb/IIIa inhibitors) was at the discretion of the interventional cardiologist. Following attempted revascularisation, patients were transferred to the coronary care unit where an in-hospital noncontrast transthoracic echocardiogram was performed before discharge. Baseline demographic, procedural, and echocardiographic data were obtained from case record review. Patients in whom echocardiographic data was not obtainable (n = 963) were excluded.
Statistical Analysis All data were displayed as a mean and standard deviation for continuous variables and as numbers and percentages of patient for categorical variables. Continuous variables were compared using the Student t test and categorical variables were compared with the chi-square test. For the primary endpoint, the difference between the 2 groups (presence or absence of left ventricular thrombus) was compared using a logistic regression, adjusting for minimization variables including age, diabetes mellitus, hypertension, and previous stroke. Cumulative incidence of the primary endpoint was estimated using the Kaplan-Meier method over 3 years of follow-up and the differences were assessed using a Cox regression model adjusted for minimization variables including age, diabetes mellitus, hypertension, and previous stroke.
Echocardiographic Assessment of Left Ventricular Thrombus
The presence of left ventricular thrombus was assessed using transthoracic echocardiography, which was undertaken within 48 hours of admission using either iE33 (Philips Medical Systems, Andover, Mass.) or Vivid 7 (GE Healthcare, Waukesha, Wis.) consoles and analyzed using dedicated image-viewing software. Each study was performed and reported in accordance the European Society of Cardiology guidelines.9 Left ventricular thrombus was deﬁned as either a homogeneous
In total, 2608 patients underwent primary percutaneous coronary angiography for STEMI during the study period, of whom 1645 (63%) underwent transthoracic echocardiography during their index admission. Left ventricular thrombus was identiﬁed in 40 (2.4%) patients. There were no signiﬁcant differences in age, sex, or risk factors for coronary artery disease between those with and those without left ventricular thrombus (Table 1).
ARTICLE IN PRESS Moss et al LV Thrombus Post STEMI
Left anterior descending artery plaque rupture was found in 92.5% (n = 37/40) of patients with left ventricular thrombus. Culprit lesions in the proximal left anterior descending artery had a 2-fold increased risk for early thrombus formation (57.5%, 23/40 vs 28.0%, 449/1605, P b 0.001; Table 1). In the immediate postinfarction period, patients with left ventricular thrombus were more likely to develop atrial ﬁbrillation (15%, 6/40 vs 5.4%, 87/1605, P = 0.025) compared with those without left ventricular thrombus (Table 1). The proportion of patients with left ventricular thrombus discharged on triple antithrombotic therapy (ie, aspirin, clopidogrel, and coumarin), dual therapy (ie, clopidogrel and coumarin), and dualantiplatelet therapy only was 60% (n = 24/40), 17.5% (n = 7/ 40) and 22.5% (n = 9/40), respectively.
Primary Outcome There was no difference in the composite 1-year outcome of all-cause mortality, stroke, and systemic thromboembolism between patients with and without left ventricular thrombus
(10.0%, 4/40 vs 9.1%, 146/1605, logistic regression hazard ratio [HR] 0.79, 95% conﬁdence interval [CI] 0.23-2.70; Table 2). Furthermore, there was no difference in all-cause mortality, stroke, and systemic thromboembolism between patients with and without left ventricular thrombus out to 3 years follow-up (Cox proportional HR 1.00, 95% CI 0.14-7.16; Figure 1). There was no difference in the incidence of stroke at 30 days (5.0%, 2/40 vs 1.1%, 18/1605, P = 0.139) or later at 1 year (5.0%, 2/40 vs 1.8%, 29/1605, P = 0.38) following acute myocardial infarction in patients with left ventricular thrombus (Table 2). The safety endpoint of TIMI major bleeding showed no difference between patients with left ventricular thrombus group compared with those without thrombus at 30 days (2.5%, 1/40 vs 1.9%, 30/1605, p = 1.0) and 1 year (2.5%, 1/40 vs 2.7%, 43/1605, p = 1.0).
Outcomes Stratified by Antithrombotic Therapy Exploratory analysis of different antithrombotic strategies (ie, dual-antiplatelet therapy, dual therapy, triple therapy) revealed
Table 1 Baseline demographics All Patients (n = 1645)
No Left Ventricular Thrombus (n = 1605)
Left Ventricular Thrombus (n = 40)
Age Male sex
62.0 (12.5) 1179 (71.7)
62.0 (12.5) 1148 (71.5)
58.7 (12.8) 31 (77.5)
Cardiovascular Risk Factors Hypertension Hyperlipidaemia Smoker Diabetes mellitus Previous stroke Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary artery bypass grafting Preadmission atrial fibrillation Postdischarge atrial fibrillation
535 (32.5) 660 (40.1) 965 (58.7) 213 (12.9) 66 (4.0) 161 (9.8) 116 (7.1) 29 (1.8) 64 (3.9) 93 (5.7)
525 (32.7) 650 (40.5) 939 (58.5) 207 (12.9) 63 (3.9) 159 (9.9) 113 (7.0) 29 (1.8) 64 (4.0) 87 (5.4)
10 (25.0) 10 (25.0) 26 (65.0) 5 (12.5) 3 (7.5) 2 (5.0) 3 (7.5) 0 0 6 (15.0)
Periprocedural Factors Symptom to Balloon Time Glycoprotein IIb/IIIa Administered TIMI Flow, 3 TIMI Flow, 0-2 TIMI Flow, unknown Cardiogenic shock
1381 (84.0) 1259 (76.5) 275 (16.7) 111 (6.7) 130 (7.9)
156.0 (126.0- 285.5) 1345 (83.8) 1228 (76.5) 269 (16.8) 108 (6.7) 128 (8.0)
218.0 (130.5- 329.5) 36 (90.0) 31 (77.5) 6 (15.0) 3 (7.5) 2 (5.0)
Treated coronary vessel Left main stem Proximal left anterior descending artery Mid/distal left anterior descending artery Left circumflex Right coronary artery Posterior descending artery Multiple segments Unknown
18 (1.1) 472 (28.7) 248 (15.1) 206 (12.5) 589 (35.8) 13 (0.8) 77 (4.7) 22 (1.3)
18 (1.1) 449 (28.0) 234 (14.6) 206 (12.8) 586 (36.5) 13 (0.8) 77 (4.8) 22 (1.4)
0 23 (57.5) 14 (35.0) 0 3 (7.5) 0 0 0
Variables presented as number and percentages. Mean and standard deviation Median and interquartile range
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Table 2 Clinical Outcomes at 30 d and 1 Year Following Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction All (n = 1645)
No Left Ventricular Thrombus (n = 1605)
Left Ventricular Thrombus (n = 40)
Hazard Ratio (95% Confidence Interval)
Primary Outcome 1-year all-cause mortality, stroke, systemic embolism
Individual 1-Year Outcomes All-cause mortality Stroke Systemic embolism TIMI major bleeding
120 (7.3) 31 (1.9) 10 (0.6) 44 (2.7)
116 (7.2) 29 (1.8) 10 (0.6) 43 (2.7)
4 (10.0) 2 (5.0) 0 1 (2.5)
30-d Outcomes 30-d all-cause mortality, stroke, systemic embolism All-cause mortality Stroke Systemic embolism TIMI major bleeding
91 (5.5) 69 (4.2) 20 (1.2) 7 (0.4) 31 (1.9)
88 (5.5) 67 (4.2) 18 (1.1) 7 (0.4) 30 (1.9)
3 (7.5) 2 (5.0) 2 (5.0) 0 1 (2.5)
— — — — —
Variables presented as number and percentage Logistic regression model adjusted for age, diabetes mellitus, hypertension, and previous stroke.
no difference at 12 months in the rates of all-cause mortality, in-stent thrombosis, stroke, and bleeding events (Table 3).
DISCUSSION In this real-world retrospective analysis of STEMI presentations, the frequency of early left ventricular thrombus was 2.4%. Importantly, the clinical prognosis following the detection of left ventricular thrombus is not associated with an increased risk of all-cause mortality and thromboembolic events at 1 year. Although thromboembolic complications occur in 10% of patients with left ventricular thrombi, further trials are required to explore whether novel antithrombotic strategies can be applied in this population. Our study has a number of strengths. First, it is the largest single-center retrospective analysis to address the frequency of left ventricular thrombi in the modern era of primary PCI. During the prethrombolytic era, cohorts were of limited size (40 to 198 patients) and hence may have lacked accuracy in reporting the prevalence of left ventricular thrombi and the risk of systemic embolization.12,13 Additionally, the introduction of PCI in the management of STEMI has resulted in greater myocardial salvage, a decrease in adverse left ventricular remodeling, and smaller sized infarcts, which have all contributed to a decline of left ventricular thrombi in patients with STEMI to 1.6%-4% of cases.2,14,15 Our study’s low frequency of 2.4% is consistent with large-volume primary PCI centers in the United Kingdom and reﬂects the temporal trend in the improved guideline-directed delivery of care.2,16 Second, by using data linkage of national registries to obtain clinical outcomes, this ensures 100% follow-up in all patients who reside within Scotland. Using this resource ensures independent coding of deaths, systemic thromboembolic events,
and bleeding events with no ascertainment bias from study investigators. The overlapping cumulative thromboembolic event curves out to 3 years follow-up supports the 1-year observation that there is no difference between patients with and without left ventricular thrombus. Indeed, while the duration of anticoagulation required following the detection of left ventricular thrombus remains unclear, there is no lag in thromboembolic events over a period of 3 years. Nearly all (92.5%, 37/40) left ventricular thrombi occurred following an anterior STEMI. This is keeping with previous studies that have shown that an anterior site of myocardial infarction: a key determinant of thrombus formation.2,17 When the proximal left coronary artery is occluded, there is an extensive region of subendocardial injury that may in itself promote thrombus formation by the upregulation of protective remodeling pathways (αvβ3 integrin).18,19 The increased frequency of thrombi with anterior wall myocardial infarctions (5.0%, 37/738 anterior vs 0.3%, 3/907 non-anterior) suggests that subendocardial injury and ﬂow of blood in close proximity to the apical anterior wall is different from other regions. Novel noninvasive cardiac positron emission tomography magnetic resonance imaging studies may inform why thrombi are more predilected to this region of the myocardial-blood interface.20,21 If thromboembolic complications occur in 10% of patients with left ventricular thrombi, is it worth exploring whether different antithrombotic regimens are beneﬁcial in this group of patients? To date, vitamin K antagonists have been the only therapy advocated in the management of mural thrombi. However, the challenge posed in achieving adequate time in the therapeutic range was highlighted in a recent publication by Maniwa et al.5 Although suboptimal treatment (ie, time in the therapeutic range b 50%) had similar rates of major bleeding events, there was a 6-fold increase in the risk of
ARTICLE IN PRESS Moss et al LV Thrombus Post STEMI
Figure 1 Cumulative event plot of all-cause mortality, stroke, and systemic thromboembolism. Cumulative incidence of primary outcome (all-cause mortality, stroke, and systemic thromboembolism) stratiﬁed by presence of left ventricular thrombus (blue) and no left ventricular thrombus during index admission with ST elevation myocardial infarction more than 3 years follow-up. Cox regression model adjusted for age, diabetes mellitus, hypertension, and previous stroke (hazard ratio 1.00, 95% conﬁdence interval 0.14-7.16).
thromboembolic events (2.9% vs 19%, P = 0.036).5 Direct oral anticoagulants against factor Xa and thrombin have an improved pharmacodynamic proﬁle that does not require serum
blood testing and small-scale clinical studies are now investigating whether apixaban (NCT02982590) and dabigatran (NCT03415386) can be used in this setting.
Table 3 Clinical Outcomes at 1 Year in Patients with Left Ventricular Thrombus Stratified by Antithrombotic Therapy
All-cause mortality TIMI major or minor bleeding In-stent thrombosis Stroke
Dual Antiplatelet Therapy: Aspirin + Clopidogrel (n = 9)
Dual Therapy: Clopidogrel + Coumarin (n = 7)
Triple therapy: Aspirin + Clopidogrel + Coumarin (n = 24)
2 (22.2) 0 1 (11.1) 0
0 1 (14.3) 0 1 (14.3)
2 (8.3) 2 (8.3) 0 1 (4.2)
Variables presented as number and percentages.
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Limitations There are some limitations that we should acknowledge. First, this is a single tertiary center study with a 24-hour primary PCI service that performs more than 2000 PCIs per annum and thus, ﬁndings may differ in other cardiac centers. As some patients from remote hospitals centers were repatriated to their local center before routine echocardiography, there may be selection bias. In this regard, the identiﬁcation of left ventricular thrombus used routinely performed transthoracic echocardiography. Diagnostic performance for the detection of thrombi can be improved by using echo contrast and late gadoliniumenhanced cardiac magnetic resonance; however, this mainly increases the yield of small mural thrombi rather than large protuberant thrombi with the potential for systemic thromboembolism.22 As this is a retrospective analysis, cardiac magnetic resonance was not routinely undertaken but was performed in selected cases with a high index of suspicion for thrombus, such as those with reduced apical wall motion.23
CONCLUSIONS In the contemporary era of mechanical reperfusion for STEMI, echocardiographic detection of left ventricular thrombus was observed in b 3% patients. The presence of left ventricular thrombus was not associated with an increased risk of systemic thromboembolism. However, the majority of patients with evidence of left ventricular thrombus were discharged on an oral anticoagulant in addition to antiplatelet therapy.
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