Angiographic Thrombus Burden Classification in Patients With ST-Segment Elevation Myocardial Infarction Treated With Percutaneous Coronary Intervention

Primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) has been proven to be more effective and safe compared to fibrinolytic therapy.^1–3 Stenting has improved the short- and long-term outcome of patients presenting with STEMI in comparison to balloon alone angioplasty both in randomized trials and in real-world practice,^4,5 while the introduction of drug-eluting stents (DES) has also demonstrated promising results in the primary PCI setting.^6,7 The administration of glycoprotein IIb/IIIa antagonists during primary PCI is also associated with improved outcomes.⁸

Despite the improvement in treatment strategies for PCI in recent years, patients with acute coronary syndromes and angiographic presence of thrombus suffer from increased incidence of in-hospital major adverse cardiac events (MACEs).^9,10 Intracoronary thrombus has also been associated with adverse procedural outcomes such as persistent or transient no reflow,^11,12 distal embolization and abrupt closure.^13,14

Mechanical treatment of thrombotic lesions by means of manual aspiration, thrombectomy and distal or proximal protection devices has been proposed to prevent the complications caused by thrombus and improve the outcome after primary PCI, but the results of available studies are not conclusive regarding usefulness.^15–18 A common major limitation in these trials is the absence of thrombus burden, as baseline parameter, to assess clinical outcomes.

Various angiographic thrombus classifications have been proposed but have never been clinically validated. In an unselected cohort of patients with STEMI we applied the most frequently used thrombus classification¹⁹ and, based on clinical outcomes, we propose a new simplified classification for PCI during STEMI.

Methods

Patients and Procedure We retrospectively studied 900 consecutive patients who presented with STEMI from April 2002, when DES were introduced, until December 2004. All patients underwent PCI (primary or rescue) within 12 hours after the onset of chest pain. All patients were pre-treated with 250 mg aspirin and 300 mg clopidogrel. PCI was performed according to standard clinical practice. The choice of stenting technique, the use of the AngioJet Rheolytic Thrombectomy System (RT; Medrad Interventional/Possis, Minneapolis, Minnesota), the only thrombectomy or aspiration system used, and the peri-procedural pharmacological treatment were at the operator’s discretion. All patients received dual antiplatelet therapy; aspirin 325 mg/day indefinitely and clopidogrel 75 mg/day for 1 month after balloon angioplasty or bare-metal stent implantation and for 3 and 6 months after sirolimus- and paclitaxel-eluting stent implantation, respectively.

Clinical Follow-up Information regarding baseline clinical characteristics, procedural details and in-hospital events was obtained from electronic databases maintained at our institution. Post-discharge survival status was obtained from the Municipal Civil Registry. A questionnaire was mailed to all living patients focusing on re-hospitalization and MACEs. Referring cardiologists, general practitioners and patients were contacted when additional information was necessary. Written informed consent was obtained from all living patients.

Angiographic Analysis and Definitions Intracoronary thrombus was angiographically identified and scored in five grades as previously described.¹⁹ According to this classification, in thrombus Grade 0 (G0), no cineangiographic characteristics of thrombus are present; in thrombus Grade 1 (G1), possible thrombus is present, with such angiography characteristics as reduced contrast density, haziness, irregular lesion contour, or a smooth convex “meniscus” at the site of total occlusion suggestive but not diagnostic of thrombus; in thrombus Grade 2 (G2), there is definite thrombus, with greatest dimensions ≤ 1/2 the vessel diameter; in thrombus Grade 3 (G3), there is definite thrombus, but with greatest linear dimension > 1/2 but

Since G5 is essentially a classification of flow and not of thrombus, patients initially presenting with G5 were reclassified into one of the other categories after flow achievement either with wire crossing or a small (1.5 mm diameter) balloon passage or dilatation. After reclassification of thrombus and based on clinical data, thrombus burden was also stratified in two categories, scored as small (STB) for thrombus

Thrombosis in myocardial infarction (TIMI) flow and myocardial blush were assessed as previously reported.^20,21 No reflow was defined as reduced antegrade flow (TIMI flow grade

Two experienced interventional cardiologists reviewing the angiographies together assessed all procedural parameters including thrombus classification. Both reviewers were blinded to clinical outcomes and consensus was achieved in all patients. Half of the films were randomly selected and reanalyzed by the same analysts for intraobserver variability, and by a third experienced interventional cardiologist for interobserver variability of the proposed LTB-STB classification.

MACEs were defined as any death, repeat non-fatal myocardial infarction (MI) and infarct-related artery (IRA) revascularization. Repeat MI was defined as new clinical symptoms or ECG changes associated with a rise in the creatine kinase level to more than twice the upper normal limit with an increased creatine kinase-MB. In cases in which the creatine kinase had not returned to normal values after the index event, a second peak was defined as repeat MI.

Statistical Analysis Baseline characteristics were compared using the c2 test or Fisher’s exact test when appropriate for categorical variables (presented as counts and percentages) and the unpaired t-test for continuous variables (presented as the mean ± standard deviation). Cumulative event rates were estimated using the Kaplan-Meier method and differences between groups were assessed by the log-rank test of significance. Variables associated with event rates on univariate analysis at p level ≤ 0.2 were entered in a multivariate Cox model with a stepping algorithm, then the variables referring to thrombus burden and AngioJet were forced into the model in order to estimate their independent effect.

In-hospital events were included in the survival analysis. All tests were two-tailed and p value

Results

Follow-up information was obtained in 886 (98.4%) patients (Table 1). Median duration was 18.5 months (range: 0–34 months) and minimum follow-up for patients who survived the index hospitalization was 12 months. Drug-eluting stents were used in 90.1% of the patients.

Thrombus Burden Grading More than half of the patients (n = 511, 57.7%) presented with an occluded vessel (G5; Table 2). Reclassification into a thrombus category (G0–G4) was achieved in 495 (96.9%) patients; in 335 (65.6%) after some flow achievement with guide-wire crossing and in 160 (31.3%) after small balloon (1.5 mm) passage or dilatation (mean dilatation pressure was 6.8 atm and mean duration of dilatation was 16.7 sec). In 12 patients thrombus G5 was sustained (no flow achievement at any stage of the procedure) and in 4 patients reclassification was not possible due to inadequate angiographic documentation. Finally, thrombus burden was estimated in 870 (98.2%) patients.

Clinical Outcomes Total population. The overall 2-year cumulative survival and MACE-free survival were 88.2% and 80.9%, respectively. Procedural mortality was 1.8% and in-hospital mortality was 6.8%. At 2 years, the cumulative repeat MI, IRA revascularization and any repeat revascularization rates were 6%, 6.1% and 17.2%, respectively. The results of the univariate analysis for 2-year mortality and MACE rate are presented in Figure 1. The independent predictors of 2-year mortality and MACE rate are reported in Table 3.

Reference thrombus burden classification (G0–G5). Patients with reference (i.e., initially classified) thrombus burden G0, G4 and G5 had lower survival and MACE-free survival compared to G1–3 patients (Figures 2A and 2B). In patients presenting with occluded IRA (G5), the 2-year cumulative survival was significantly lower compared to patients with open IRA (G0–4; 85.9% versus 91.3%, p = 0.024 respectively; Figure 2C), but MACE-free survival was similar (79.8% versus 82.2%, p = 0.27; Figure 2D).

G5 reclassification. In the group with open IRA (375 patients), G0 and G4 patients had lower survival and MACE-free survival compared to G1–3 patients (Figures 3A and 3B). Similarly, in the reclassified G5 group, G0 and G4 patients had lower survival and MACE-free survival compared to G1–3 patients (Figures 3C and D). In the reclassified G5 group, there were more G4 patients compared to the group with open IRA (34.9% versus 23.1%, p

Reclassified thrombus burden (G0–G4). Patients with reclassified (including both the open IRA and the reclassified G5 group) thrombus G0, G1, G2 and G3 had comparable procedural (1.4%, 0%, 0.9% and 0.7% respectively, p = 0.59) and in-hospital (8.3%, 3%, 5.1% and 5.4% respectively, p = 0.36) mortality. Figures 4A and 4B depict the overall 2-year cumulative survival and MACE-free survival according to thrombus score after having reclassified the G5 group. Patient groups G1, G2 and G3 had similar 2-year cumulative survival (92% versus 90.3% versus 91.8% respectively, p = 0.95) and MACE-free survival rates (84.5% versus 85.9% versus 87% respectively, p = 0.83), while groups G0 and G4 had significantly lower rates (survival: 84.4% and 85.3% respectively, p = 0.046; MACE-free survival: 75.8% and 75% respectively, p = 0.001) compared to the former groups.

The 12 patients with no flow achieved at any stage of the procedure had the worst outcome (procedural mortality: 33.3%, in-hospital mortality: 58.3%, 2-year cumulative survival and MACE-free survival: 41.7% and 22.2% respectively).

New classification. Based on the aforementioned results, we stratified thrombus burden in two groups of small (STB), combining the G0 to G3 groups, and large (LTB), same as G4, thrombus burden. The LTB group had higher procedural (3% versus 0.7%, p = 0.01) and in-hospital mortality (8.6% versus 5%, p = 0.045). At 2 years, LTB patients had a higher incidence of cumulative repeat MI (4.8% versus 9%, p = 0.009) and IRA revascularization (4.8% versus 9.5%, p = 0.008) and significantly lower cumulative survival and MACE-free survival compared to the STB group (Figures 4C and 4D). LTB was an independent predictor (Table 3) of both 2-year mortality (HR: 1.66, 95% CI: 1.04–2.68, p = 0.035) and MACE rate (HR: 2.04, 95% CI: 1.44–2.88, p

Procedural Data Total population. Pre- and post-procedural TIMI flow, and post-procedural myocardial blush results are reported in Figure 5. No reflow occurred in 21 (2.4%) patients and there was no distal embolization in 76 (8.6%) patients.

Reference thrombus burden classification (G0–G5). Post-procedural TIMI flow (TIMI-3 flow: 88.5% versus 90.1%, p = 0.43), no reflow (2.5% versus 2.1%, p = 0.82) and distal embolization (9% versus 8%, p = 0.63) were similar in patients with reference thrombus G5 compared to patients with thrombus

Reclassified thrombus burden (G0–G4). There were no differences in procedural outcome (TIMI-3 flow, G0: 93.1%, G1: 94.6%, G2: 94%, G3: 95.2%, p = 0.92; myocardial blush grade 3, G0: 62%, G1: 48.6%, G2: 54%, G3: 52.2%, p = 0.46) except for distal embolization (G0: 2.8%, G1: 1.2%, G2: 2.8%, G3: 7.5%, p = 0.02) between patients with thrombus G0, G1, G2 and G3 after reclassification.

New classification. The STB group had better procedural angiographic outcome compared to the LTB group with more complete thrombus removal (97.7% versus 85.7%, p

AngioJet rheolytic thrombectomy. AngioJet rheolytic thrombectomy was mainly used in patients with LTB (75/80, 94%); in 28.2% of LTB and only 0.8% of STB patients (Table 1).

There was no difference in final TIMI-3 flow (87.5% versus 89.3%, p = 0.62), myocardial blush grade 3 (46.3% versus 46.6%, p =0.96), complete thrombus removal (6.3% versus 7.2%, p = 0.75) between the AngioJet and non-AngioJet groups, respectively. Distal embolization was significantly more frequent in the AngioJet group (16.3% versus 7.8%, p = 0.02), but there was no difference in the incidence of no reflow (AngioJet: 5% versus 2.1%, p = 0.11), perforation (AngioJet: 0% versus 0.9%, p = 1), dissection (AngioJet: 2.5% versus 4.1%, p = 0.76) or bleeding complications (AngioJet: 3.8% versus 2.7%, p = 0.49) compared to the non-AngioJet group.

There were no significant differences in procedural (AngioJet: 1.3% versus 1.9%, p = 0.7) and in-hospital (AngioJet: 3.8% versus 7.1%, p = 0.35) mortality between the AngioJet and non-AngioJet group. Thrombus removal with AngioJet in patients with TBL reduced IRV stent-thrombosis rates (AngioJet: 0% versus 11.3 precent, p = 0.011). The 2-year cumulative survival (91.2% for AngioJet versus 88.5%, p = 0.42) and MACE-free survival (86% for AngioJet versus 80.3%, p = 0.3) were also similar in the total population. However, LTB subgroup analysis revealed that LTB patients treated with AngioJet had significantly better 2-year outcomes compared to LTB patients without AngioJet and similar to those of STB patients (Figures 4E and 4F).

Discussion

The current study presents the impact of thrombus burden on the procedural and two-year clinical outcome of patients who underwent PCI for STEMI. Based on the clinical outcome, we applied a pre-existing thrombus burden classification and we propose a new, simplified one that allows thrombus burden estimation in patients with angiographically occluded IRA and categorizes thrombus ≥ 2 vessel diameters as large and having clinical importance.

The majority, almost 60%, of the patients with STEMI presented with an occluded IRA (G5). This is essentially a flow classification (TIMI-0) and, consequently, excludes these patients from any analysis focusing on thrombus burden. We proposed a method that allowed thrombus burden estimation in almost 97% of these patients after minimal intervention with either angioplasty guidewire crossing or a small (1.5 mm) balloon passage or pre-dilatation. Minimal antegrade flow (even TIMI-1) and contrast penetration are adequate to allow thrombus estimation. The clinical outcome of the reclassified G5 group was proportional to the non-G5 group; in both these groups, G0 and G4 always had the worse outcome. This finding, in combination with the similar incidence of distal embolization between G5 and non-G5 patients, indicates that this minimal intervention does not modify the thrombus burden and allows its reliable estimation in patients presenting with occluded IRA.

In our study, patients presenting with occluded IRA had worse survival and tended to have worse MACE compared to patients presenting with open IRA. This is in accordance with previous observations22 and might be explained by the longer ischemia and the higher incidence of large thrombus in patients with occluded IRA as shown in Table 2.

Patients with thrombus G1–3 had similar procedural and clinical outcomes and therefore, there is no value in separating them. Additionally, they had better procedural and clinical outcomes compared to G4 patients. This is the rationale of grouping these patients in the new classification as STB, while G4 patients are classified separately as LTB patients.

Patients with no thrombus (G0) at presentation also exhibited worse outcomes compared with G1–3 patients and similar outcomes to G4. However, they had more multi-vessel PCI (19.4% versus 10.7%, p = 0.031), more left main stem and less right coronary artery involvement (4.2% versus 1.3% and 23.6% versus 36.7% respectively, p = 0.044), were more often treated with plain balloon angioplasty (6.9% versus 1.5%, p = 0.013) and tended to receive direct stenting less often (45.8% versus 56.4%, p = 0.091). Despite their increased risk these patients were included in the STB group, since it is obvious that therapeutic strategies to improve their clinical outcome should not target thrombus.

This study is limited by its retrospective nature including no randomization with respect to the use of AngioJet, but our results are based on a series of consecutive patients representing a real-world clinical setting. Established parameters related to clinical outcomes such as infarct duration and myocardial blush were not available for all patients and were not included in the multivariate analysis model. Potential thrombus burden modification related to pre-procedural pharmacotherapy cannot be excluded. Angiography has inherent limitations for assessing thrombus burden and there is no gold standard method to be compared with. However, it is the imaging modality used for decision making during PCI for STEMI and in that respect this classification is clinically relevant.

Conclusions

In patients with STEMI, minimal intervention with either guidewire crossing or pre-dilatation with a 1.5 mm balloon does not modify the thrombotic burden and restores flow enough to allow its reliable estimation in angiographically occluded vessels. Large thrombus (≥ 2 vessel diameters) is a significant independent predictor of mortality and MACE. Thrombus

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