Author + information
- Received February 11, 2016
- Revision received June 2, 2016
- Accepted June 30, 2016
- Published online October 10, 2016.
- Takumi Higuma, MD, PhDa,b,
- Tsunenari Soeda, MD, PhDb,
- Masahiro Yamada, MD, PhDa,
- Takashi Yokota, MD, PhDa,
- Hiroaki Yokoyama, MD, PhDa,
- Kei Izumiyama, MD, PhDa,
- Fumie Nishizaki, MD, PhDa,
- Yoshiyasu Minami, MD, PhDb,
- Lei Xing, MD, PhDb,
- Erika Yamamoto, MD, PhDb,
- Hang Lee, PhDc,
- Ken Okumura, MD, PhDa and
- Ik-Kyung Jang, MD, PhDb,d,∗ ()
- aDepartment of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- bCardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- cBiostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- dDivision of Cardiology, Kyung Hee University, Seoul, Republic of Korea
- ↵∗Reprint requests and correspondence:
Dr. Ik-Kyung Jang, Cardiology Division, Massachusetts General Hospital, GRB 800, 55 Fruit Street, Boston, Massachusetts.
Objectives The aim of this study was to evaluate if residual thrombus burden after aspiration thrombectomy affects the outcomes of primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI).
Background Recent studies failed to show clinical benefit of aspiration thrombectomy in STEMI patients. This might be due to insufficient removal of thrombus at the culprit lesion.
Methods A total of 109 STEMI patients who underwent aspiration thrombectomy followed by stenting within 24 h from symptom onset were included. Optical coherence tomography was performed after thrombectomy to measure residual thrombus burden. Patients were divided into tertiles based on the amount of residual thrombus and the outcomes were compared.
Results Myocardial no reflow, defined as TIMI (Thrombolysis In Myocardial Infarction) flow grade of ≤2 and/or myocardial blush grade of ≤1 after stenting, was more observed frequently in patients in the highest tertile compared with those in the lowest tertile (44.4% vs. 16.7%; p = 0.001). Patients in the highest tertile also had greater myocardial damage measured by creatine kinase MB compared with those in the lowest tertile (p = 0.002).
Conclusions STEMI patients with greater residual thrombus burden after aspiration thrombectomy had worse microvascular dysfunction and greater myocardial damage compared with those with smaller residual thrombus burden.
- intracoronary thrombus
- optical coherence tomography
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
Routine aspiration thrombectomy before balloon angioplasty or stenting failed to show clinical benefit in patients with ST-segment elevation myocardial infarction (STEMI) (1,2). The TOTAL (ThrOmbecTomy versus PCI Alone) trial demonstrated that routine aspiration thrombectomy before percutaneous coronary intervention (PCI) compared with PCI alone did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association functional class IV heart failure within 180 days (2). Proposed explanations for the lack of clinical benefit include the presence of a large amount of residual thrombus even after thrombectomy, a small amount of thrombus at the culprit lesion before thrombectomy, or a limited role of culprit lesion thrombus on infarct size.
Intracoronary optical coherence tomography (OCT) is an emerging diagnostic modality that enables us to accurately evaluate plaque morphologies, such as thin-cap fibroatheroma, macrophages, and intracoronary thrombus (3,4). It has been shown that evaluation of prestent thrombus burden using OCT in patients with STEMI is feasible and reliable (5). Surprisingly, a substudy of TOTAL using OCT revealed that manual aspiration thrombectomy did not reduce prestent thrombus burden at the culprit lesion compared with PCI alone (6). Lack of clinical benefit of aspiration thrombectomy was thought to be due to low thrombus burden at the culprit site.
The aim of this study was to test if residual thrombus burden after thrombectomy affects the outcomes of primary PCI in patients with STEMI.
Study population and PCI procedures
This retrospective analysis of a previously published study (7) included 111 patients admitted to Hirosaki University Hospital (Hirosaki, Japan) with STEMI between January 2013 and June 2014. STEMI was defined as typical chest pain lasting >20 min, electrocardiogram showing new ST-segment elevation ≥0.2 mV in ≥2 contiguous precordial leads, ≥0.1 mV in ≥2 contiguous limb leads, or new left bundle branch block, and cardiac markers (creatine kinase-MB fraction or cardiac troponin T) increased to greater than the upper reference limit. Exclusion criteria included cardiogenic shock, unsuccessful reperfusion to achieve antegrade flow despite aspiration thrombectomy, acute stent thrombosis, inability to advance an intravascular imaging catheter to the culprit lesion, poor image quality, massive thrombus, coronary embolism, and STEMI caused by spontaneous coronary dissection. All patients underwent primary PCI within 24 h after the onset of symptoms. All images were deidentified, digitally stored, and sent to Massachusetts General Hospital (Boston). This collaboration study was approved by the Institutional Review Boards at Massachusetts General Hospital and Hirosaki University Hospital. All patients provided written informed consent for the primary intervention procedure.
Acquisition of OCT image
A frequency-domain OCT system (ILUMIEN OCT Intravascular Imaging System, St. Jude Medical, St. Paul, Minnesota) was used in this study. Aspirin 200 mg, clopidogrel 300 mg, and heparin 100 IU/kg were administrated before the procedure. None of the patients were pretreated with a thrombolytic agent and a glycoprotein IIb/IIIa inhibitor. The primary PCI was performed using a 7-F or 6-F guiding catheter. Manual aspiration thrombectomy using Rebirth (Goodman Co. Ltd., Nagoya, Japan) or Eliminate 3 (Terumo, Tokyo, Japan) was performed to restore antegrade coronary flow. The number of passes with the aspiration catheter was at the operator’s discretion. The OCT imaging catheter was then advanced distal to the lesion, and automated pullback was performed during injection of contrast media or Dextran through the guiding catheter to clear blood from the imaging field. Manual aspiration thrombectomy was repeated when image quality was suboptimal due to large amount of residual thrombus. Pre-dilation with balloon angioplasty was not allowed before OCT imaging.
Plaques were categorized into plaque rupture, plaque erosion, calcified nodule, and others (8). Tissue characterization of the underlying plaque was defined using the previously established criteria (4,9). A lipid plaque was defined as a plaque with lipid arc of >90°. For each lipid plaque, the thinnest fibrous cap thickness, the maximal arc of lipid, and lipid length were measured. Thin-cap fibroatheroma was defined as a lipid plaque with the thinnest fibrous cap thickness of <65 μm.
For the thrombus measurement, OCT images were analyzed at 0.2-mm intervals for the entire analyzable segment, including the culprit site by 2 independent investigators blinded to clinical and angiographic data. Thrombus was defined as an irregular mass floated from the vessel wall or attached to surface of the vessel wall with a dimension of ≥250 μm. Thrombus was categorized as either erythrocyte-rich (red) thrombus, defined by high backscattering and high attenuation, or platelet-rich (white) thrombus, defined by homogeneous backscattering with low attenuation. Thrombus area was measured by planimetry in each frame, and thrombus volume was calculated by multiplying the thrombus areas in each frame times the number of frames (0.2 mm). Lumen area was measured by planimetry in each frame, and lumen volume was calculated by multiplying the lumen areas in each frame times the number of frames (0.2 mm). Lumen and thrombus areas were traced as previously described (5). In imaging frames where the luminal border was visible in at least 3 of the 4 quadrants, the lumen area was traced using the ‘area - multiple points’ tool of the proprietary analysis software (St. Jude Medical) (Figure 1). In frames with difficulties in luminal border detection in >1 quadrant, the lumen area was extrapolated from the nearest proximal or distal frame with visible lumen contour. The copy–paste function of the proprietary software was used, supplemented by manual corrections to adjust the copied area to the visible parts of vessel lumen in the frame to which it was copied. If necessary, additional manual corrections were made with the assistance of the longitudinal view (5). Thrombus length was estimated by multiplying the number of frames time thrombus. Thrombus burden was calculated as thrombus volume divided by lumen volume multiplied by 100.
Coronary angiograms before intervention, after aspiration thrombectomy, and at the end of the procedure were analyzed. We evaluated baseline, post-thrombectomy, and final antegrade coronary flow according to the TIMI (Thrombolysis In Myocardial Infarction) criteria (10), and final myocardial blush grades (11). No reflow was defined as TIMI flow grade ≤2 or TIMI flow grade 3 with myocardial blush grade ≤1 at the final angiogram (12). Reference diameter, minimal lumen diameter, percentage of diameter stenosis, and lesion length were also measured. Coronary angiograms were analyzed using an off-line quantitative coronary angiography program (CAAS version 5.10.1, Pie Medical Imaging BV, Maastricht, the Netherlands).
Categorical outcomes were presented as counts and percentages, and the Fisher exact test or chi-square test was used as appropriate. The distributions of continuous variables were tested for normality with the Kolgormonov-Smirnov test. The mean ± SD was reported when data were normally distributed, and the median (25th, 75th percentiles) were reported when data were not normally distributed. For between-group comparisons, 1-way analysis of variance or the Kruskal-Wallis test for continuous outcomes and chi-square or Fisher exact test for categorical outcomes was applied for testing overall differences, and then post hoc tests for controlling type 1 error by using Bonferroni correction were performed if the overall test was significant. A p value of <0.05 was considered significant for an overall comparison. If the p value of the overall test was <0.05, then a 2-group post hoc comparison was performed using the Mann-Whitney U test or the independent samples Student t test for continuous outcomes, and chi-square or Fisher exact test for categorical outcomes. The test result was considered significant if the p value was <0.017 (i.e., 0.05 of 3.00). Intraobserver and interobserver reliability of thrombus volume and burden was assessed by intraclass correlation and a value of >0.9 was defined as excellent correlation. All statistical analyses were performed with SPSS version 17.0 (SPSS Inc., Chicago, Illinois).
Thrombus volume and thrombus burden
The baseline characteristics of all study patients are shown in Table 1. OCT was performed after aspiration thrombectomy (average of 1.4 ± 0.6 runs). The mean analyzable segment length was 49.2 ± 6.7 mm (range 30.2 to 54.0). Total number of analyzable cross-sectional images was 27,318. The mean (95% confidence interval [CI]) thrombus volume and burden after aspiration thrombectomy were 4.95 mm3 (95% CI: 3.11 to 6.76) and 1.62% (95% CI: 1.11 to 2.13), respectively. Intraobserver and interobserver reliabilities were high for both thrombus volume (interobserver: 0.998; intraobserver: 0.999) and thrombus burden (interobserver: 0.995; intraobserver: 0.997).
Two patients without stent implantation were excluded and 109 patients were included for final analysis. The 109 patients were divided into tertiles according to the thrombus burden within a 30-mm segment including the culprit lesion (first tertile [T1]: <0.56%; second tertile [T2]: 0.56% to 2.38%; third tertile [T3]: >2.38%).
Comparison of clinical, angiographic, and procedural characteristics among the 3 groups
The comparisons of baseline characteristics among the 3 groups are shown in Table 2. There were no differences, including time delay to reperfusion among the 3 groups. Baseline angiographic characteristics are shown in Table 3. The location of the culprit lesion and the angiographic parameters were similar among the 3 groups except that initial TIMI flow grade ≤1 was significantly more frequent in T3 than in T1 (p = 0.004). There were no differences in the number of stents, stent diameter, total stent length, and maximal balloon pressure among the 3 groups.
OCT findings after aspiration thrombectomy are shown in Table 4. The prevalence of plaque rupture, plaque erosion, and calcified nodule as a culprit lesion morphology was not different across the 3 groups. The prevalence of lipid plaque was also not different among the 3 groups. Thrombus volume was significantly greater in T3 compared with T1 (6.57 vs. 0.27 mm3). After thrombectomy, white thrombus (platelets) was the predominant component of residual thrombus.
Outcomes after PCI
The post-thrombectomy and post-stent final angiographic findings are shown in Table 5 and Figure 2. The post-thrombectomy angiogram shows significantly larger minimal lumen diameter in T3 and T2 than in T1 (p = 0.004 and p = 0.012, respectively). Post-stent TIMI flow grade ≤2 was >3 times more frequent in T3 compared with T1, although the difference did not reach a significant level. The incidence of myocardial blush grade ≤1 was significantly higher in T3 than in T1 (36.1% vs. 8.3%; p = 0.009). The incidence of no reflow was significantly greater in T3 than in T1 (44.4% vs. 16.7%; p = 0.001). The peak creatine kinase and creatine kinase MB fraction were significantly higher in T3 than in T1 (3,621 [25th, 75th percentiles: 1,583 to 6,340] vs. 1,838 [25th, 75th percentiles: 968 to 3,330], p = 0.004 and 391 [25th, 75th percentiles: 207 to 728] vs. 90 [25th, 75th percentiles: 186 to 414], p = 0.002, respectively) (Figure 3). To evaluate the influence of initial TIMI flow grade on no reflow after stenting, we performed a logistic regression analysis using both parameters. Multivariate analysis adjusted for initial TIMI flow grade ≤1 revealed that T3 was significantly associated with no reflow (odds ratio of 3.119 compared with T1 as a reference; 95% CI: 1.006 to 9.663; p = 0.049).
To the best of our knowledge, this is the first study to investigate the impact of residual thrombus burden after aspiration thrombectomy on post PCI outcome in patients with STEMI. The main findings of this study were: 1) residual thrombus was present after aspiration thrombectomy irrespective of underlying mechanism of plaque disruption or plaque morphology; and 2) STEMI patients with greater residual thrombus burden after aspiration thrombectomy had more severe microvascular dysfunction and greater myocardial damage after stenting, compared with those with smaller thrombus burden. Therefore, aggressive removal of the thrombus at the culprit lesion may be important to improving outcome of primary PCI in patients with STEMI.
Thrombus at the culprit lesion
Rapid recanalization of an infarct-related coronary artery has become a main target in patients with STEMI. However, despite successful restoration of epicardial blood flow, abnormal myocardial perfusion has been associated with an increased infarct size and mortality in patients with STEMI (13,14). Embolization of thrombus and/or plaque debris downstream in the infarct-related artery is one of the mechanisms affecting the microvasculature at the time of reperfusion (15). In the setting of STEMI, large thrombus burden on angiogram was associated independently with no reflow phenomenon (16). Therefore, retrieving thrombi from the culprit lesion was thought to prevent distal embolization and to reduce no reflow phenomenon. Several clinical trials demonstrated that routine aspiration thrombectomy at the time of primary PCI resulted in improved myocardial perfusion grade (17,18), reduced infarct size (18), and reduced mortality (17,19). However, the recent clinical trial involving the large cohort of patients with STEMI, TOTAL (ThrOmbecTomy versus PCI Alone), failed to show an additional benefit of routine thrombus aspiration before stenting compared with PCI alone (2). A recent large national cohort study provided further evidence against aspiration thrombectomy as a routine use during primary PCI in patients with STEMI (20). Potential explanations for the lack of clinical benefit include the presence of a large amount of residual thrombus burden even after aspiration thrombectomy, a small amount of thrombus burden at the culprit lesion before intervention, or less influence of thrombus burden on infarct size. Additionally, most aspiration thrombectomy devices are relatively bulky; therefore, it is possible that their introduction might dislodge thrombus and/or plaque debris, with subsequent embolization into the microcirculation.
The clinical outcome of the main study was supported by the OCT substudy, which revealed no significant difference in pre-stent thrombus burden at the culprit lesion between the 2 groups (6). The prestent thrombus burden was 2.36% after aspiration in the thrombectomy group and 2.88% after wire insertion or balloon angioplasty in the PCI alone group (p = 0.373). They concluded that thrombectomy did not reduce prestent thrombus burden at the culprit lesion compared with PCI alone. However, enrollment in this study was at operator’s discretion (6). Therefore, it is possible that some patients with large thrombus burden or poor epicardial coronary flow might have been excluded and as a consequence, the potential benefit of thrombectomy might have been mitigated.
Influence of residual thrombus burden after aspiration thrombectomy on myocardial reperfusion grade and myocardial damage
In patients with STEMI treated with primary PCI, the no reflow phenomenon is a strong predictor for both short-term and long-term mortality (21). The etiology of the no reflow phenomenon has not been understood fully. Previous studies have identified several factors associated with the no reflow phenomenon, including delayed reperfusion, plasma glucose, baseline TIMI flow grade, advanced age, and pre-PCI thrombus burden (16,22,23). A longer time to reperfusion is associated with a higher incidence of no reflow, as prolonged ischemia and delayed reperfusion can impair endothelial function and cause myocardial edema of distal capillary beds and swelling of myocardial cells (12). However, in our study there was no significant difference among the 3 groups in onset to reperfusion time. This discrepancy may relate to the multifactorial mechanism underlying no reflow in STEMI, including distal embolization, ischemic injury, reperfusion injury, and individual sensitivity (12).
Large intracoronary thrombus burden was known to be associated with a higher incidence of the no reflow phenomenon. Previous angiography and intravascular ultrasound studies showed that intracoronary thrombus was associated with adverse procedural outcomes such as persistent or transient no reflow (16,24–26) and greater myocardial damage (26). Kirma et al. (16) reported that angiographic high thrombus burden was an independent predictor for no reflow phenomenon. A study using contrast-enhanced cardiac magnetic resonance showed that patients with angiographic large thrombus burden had a larger infarct size index and more frequent transmural necrosis (26). In our study, we quantified the intracoronary thrombus after aspiration thrombectomy using multiple cross-sectional images of OCT. Our OCT findings showed that aspiration thrombectomy often results in incomplete retrieval of the thrombus. We assessed the influence of residual thrombus burden after aspiration thrombectomy on the outcomes of primary PCI. There was a trend toward worse outcomes in patients with large residual thrombus burden. Patients in the highest tertile of residual thrombus burden had a higher incidence of myocardial blush grade ≤1 and no reflow compared with those in the lowest tertile of residual thrombus burden. Additionally, patients in the highest tertile had greater enzymatic myocardial damage compared with those in the lowest tertile. A potential explanation for the lack of clinical benefit of aspiration thrombectomy in the TOTAL trial may be related to an inadequate retrieval of thrombus using the current aspiration thrombectomy device.
We found that initial TIMI flow grade ≤1 was significantly more frequent in the highest tertile of residual thrombus burden. Previous studies reported that a reduced TIMI flow grade at baseline was associated with worse clinical outcomes, including a worse final reperfusion grade in patients with STEMI undergoing primary PCI (23). To rule out possible influence of baseline TIMI flow on the final outcome, we performed multivariate analysis adjusting for baseline TIMI flow ≤1. The result showed that the highest tertile of thrombus burden still remained significantly associated with no reflow, indicating the significance of residual thrombus burden on clinical outcomes.
Our study did not aim to examine the effect of routine aspiration thrombectomy on PCI outcomes, but rather to investigate the significance of residual thrombus. Indeed, a smaller amount of thrombus was associated with improved outcomes both at the microvascular and myocardial levels. Aspiration thrombectomy can no longer be recommended as a routine strategy in patients with STEMI. However, our results strongly indicate that a more thorough removal of thrombus is beneficial to patients with large thrombus burden, which can be achieved by more effective aspiration thrombectomy devices with effective antithrombotic therapy.
First, this was a single-center study, and analysis was done retrospectively. Second, the number of subjects included in this study was small. One-quarter of the patients with STEMI admitted during the study period were excluded. It should be noted that 8 cases were excluded due to poor image quality (4 were due to poor blood removal, and 4 due to residual massive thrombus). Third, accurate tracing of the lumen border is sometimes challenging, especially when the thrombus burden is large. Fourth, patients were not pretreated with a glycoprotein IIb/IIIa inhibitor. Fifth, although the reperfusion time was relatively longer in our study than in a previous study (6), the reperfusion time did not vary among the 3 groups. Finally, because OCT was not performed before aspiration thrombectomy, initial thrombus burden could not be assessed.
Residual thrombus persists after aspiration thrombectomy irrespective of underlying mechanism of plaque disruption or plaque morphology in patients with STEMI. STEMI patients with larger residual thrombus burden after thrombectomy had more severe microvascular dysfunction, and greater myocardial damage compared with those with smaller residual thrombus burden.
WHAT IS KNOWN? Routine aspiration thrombectomy before balloon angioplasty or stenting failed to show clinical benefit in patients with STEMI. It is unclear if residual thrombus burden after aspiration thrombectomy affects the outcomes of primary PCI in patients with STEMI.
WHAT IS NEW? STEMI patients with a greater residual thrombus burden after aspiration thrombectomy had worse microvascular dysfunction and greater myocardial damage, compared with those with a lesser residual thrombus burden.
WHAT IS NEXT? A more thorough removal of thrombus is beneficial to patients with large thrombus burden, which can be achieved by more effective aspiration thrombectomy devices with effective antithrombotic therapy.
The authors thank all the investigators and all supporting staff. Ik-Kyung Jang’s research was also supported by “Mr. and Mrs. Michael and Kathryn Park” and by “Mr. and Mrs. Allan and Gillian Gray.” They also thank Shankha Mukhopadhyay, MS, for his editorial assistance.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The first two authors contributed equally to this work.
- Abbreviations and Acronyms
- optical coherence tomography
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Received February 11, 2016.
- Revision received June 2, 2016.
- Accepted June 30, 2016.
- American College of Cardiology Foundation
- Jang I.K.,
- Bouma B.E.,
- Kang D.H.,
- et al.
- Yabushita H.,
- Bouma B.E.,
- Houser S.L.,
- et al.
- Kajander O.A.,
- Koistinen L.S.,
- Eskola M.,
- et al.
- Bhindi R.,
- Kajander O.A.,
- Jolly S.S.,
- et al.
- Higuma T.,
- Soeda T.,
- Abe N.,
- et al.
- Jia H.,
- Abtahian F.,
- Aguirre A.D.,
- et al.
- Chesebro J.H.,
- Knatterud G.,
- Roberts R.,
- et al.
- van 't Hof A.W.,
- Liem A.,
- Suryapranata H.,
- Hoorntje J.C.,
- de Boer M.J.,
- Zijlstra F.
- Niccoli G.,
- Burzotta F.,
- Galiuto L.,
- Crea F.
- Stone G.W.,
- Peterson M.A.,
- Lansky A.J.,
- Dangas G.,
- Mehran R.,
- Leon M.B.
- Henriques J.P.,
- Zijlstra F.,
- van 't Hof A.W.,
- et al.
- Topol E.J.,
- Yadav J.S.
- Sardella G.,
- Mancone M.,
- Bucciarelli-Ducci C.,
- et al.
- Sirker A.,
- Mamas M.,
- Kwok C.S.,
- Kontopantelis E.,
- Ludman P.,
- Hildick-Smith D.
- Iwakura K.,
- Ito H.,
- Ikushima M.,
- et al.
- De Luca G.,
- Ernst N.,
- Zijlstra F.,
- et al.