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Incidence and clinical consequences of distal embolization on the coronary angiogram after percutaneous coronary intervention for ST-elevation myocardial infarction

Marieke L. Fokkema , Pieter J. Vlaar , Tone Svilaas , Mathijs Vogelzang , Diny Amo , Gilles F.H. Diercks , Albert J.H. Suurmeijer , Felix Zijlstra
DOI: http://dx.doi.org/10.1093/eurheartj/ehp033 908-915 First published online: 18 February 2009

Abstract

Aims We investigated the incidence and sequelae of angiographically visible distal embolization (AVDE) after primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction patients treated with aspirin, heparin, clopidogrel, and glycoprotein-IIb/IIIa inhibitors.

Methods and results As part of TAPAS, AVDE was a predefined secondary endpoint. We compared angiographic and clinical characteristics, and outcomes of patients with and without AVDE after PCI. AVDE was present on 6.3% of 883 post-procedural angiograms. Angiographically visible distal embolization was associated with significantly worse outcomes, as expressed by lower myocardial blush grade, impaired ST-segment resolution, and higher enzyme levels (all P ≤ 0.001). Mortality 1 year after PCI was 4 of 56 (7.1%) in patients with AVDE and 43 of 827 (5.2%) in patients without AVDE (P= ns), re-infarction occurred in 5 of 56 (8.9%), and 25 of 827 (3.0%) patients (P = 0.018). The thrombus aspirate more often contained erythrocytes in patients with AVDE than in patients without AVDE (50.0% vs. 15.7%, P < 0.001), and the size of the aspirated thrombus was larger in patients with AVDE (P = 0.002).

Conclusion In patients with triple anti-platelet therapy, the incidence of AVDE after PCI is low, compared with previous reports. Nevertheless, AVDE is associated with impaired myocardial reperfusion and poor outcome. Thrombus composition and size are related to AVDE after PCI.

Keywords
  • ST-elevation myocardial infarction
  • Reperfusion
  • Angioplasty
  • Distal embolization

Introduction

Primary percutaneous coronary intervention (PCI) is the preferred treatment to achieve reperfusion in ST-elevation myocardial infarction (STEMI) patients. However, a significant proportion of patients treated with PCI shows inadequate perfusion of the infarcted myocardium after restoration of epicardial coronary blood flow.14 This results in a larger infarct size, worse left ventricular ejection fraction, and increased mortality.1 Myocardial perfusion can be evaluated angiographically by Myocardial Blush Grade (MBG), which is a strong predictor of major adverse cardiac events.46

Suboptimal myocardial reperfusion can be caused by microvascular dysfunction, reperfusion injury, myocardial oedema, or embolization of thrombotic or atherosclerotic particles.7 In some patients, embolization of atherothrombotic material can be visible on the coronary angiogram as a filling defect with abrupt cut-off distal from the culprit lesion. Angiographic visible distal embolization (AVDE) is associated with poor clinical outcome.8 AVDE may be reduced by the glycoprotein-IIb/IIIa inhibitor abciximab, as administration during primary PCI results in better clinical outcomes than after PCI alone.911

Currently, no data are available about the incidence and clinical consequences of AVDE after primary PCI in patients receiving pre-treatment with aspirin, heparin, and clopidogrel, and with the systematic use of periprocedural glycoprotein-IIb/IIIa inhibitors. The aim of this study was to investigate the incidence and clinical relevance of AVDE after PCI for acute STEMI in a contemporary cohort of patients.

Methods

The design, methods, and primary results of the Thrombus Aspiration during PCI in Acute myocardial infarction Study (TAPAS) have been reported previously and are summarized here.5,6,12

Patient population

In TAPAS, it was investigated whether thrombus aspiration was superior to conventional treatment during PCI in patients with acute myocardial infarction. The trial was a single-centre, prospective, randomized, open trial involving the blinded evaluation of endpoints. Between January 2005 and December 2006, patients with acute STEMI and candidates for primary PCI presenting in the University Medical Center of Groningen were included in TAPAS. The inclusion criteria were chest pain suggestive for myocardial ischaemia between 30 min and 12 h before presentation and an electrocardiogram (ECG) showing ST-elevation of >0.1 mV in ≥2 leads. The exclusion criteria were rescue PCI after thrombolytic therapy, the presence of a life-threatening disease with prognosis of <6 months or the absence of informed consent.12 The study was conducted according to the Declaration of Helsinki. The Medical Ethics Committee of our institution has approved the research protocol.

Randomization and treatment

In TAPAS, patients were randomized to manual thrombus aspiration (6F Export aspiration Catheter, Medtronic) before stenting or to balloon dilatation before stenting. Randomization was performed before initial angiography. All patients were treated with aspirin (500 mg followed by 80–100 mg/24 h), heparin (5000 IU), and clopidogrel (600 mg followed by 75 mg/24 h) directly following the electrocardiographic confirmation of STEMI. Additional doses of heparin were given during PCI procedure guided by activated clotting time measurements. In addition, patients were treated with the glycoprotein-IIb/IIIa inhibitor abciximab immediately at the start of the PCI procedure, if not contra-indicated.12,13 The bolus dosage of abciximab was 0.25 mg/kg.

Inclusion and definition of angiographically visible distal embolization

As part of TAPAS, the presence of AVDE on the final angiogram after completion of PCI was analysed as a predefined secondary endpoint.12 For analysis of AVDE, we included all patients undergoing primary PCI who presented with epicardial coronary blood flow through the infarct-related lesion [Thrombolysis In Myocardial Infarction (TIMI) flow 2 or 3] on the angiogram during and/or after PCI procedure. The angiogram after PCI procedure could be evaluated for AVDE when epicardial coronary flow was present through the infarct-related lesion and the distal vessels were visualized. AVDE was defined as a distal-filling defect with abrupt cut-off in the vessel located distally of the culprit lesion.8 Patients presenting with no reflow after PCI (TIMI 2 or 3 during PCI and TIMI 0 or 1 after PCI in the absence of a flow limiting dissection) were also classified as AVDE.

Angiographic data

Coronary angiograms were obtained before, during, and after PCI procedure. In addition to AVDE, the MBG4 was evaluated on the final angiogram after PCI. TIMI flow14 was evaluated on the initial angiogram and on the final angiogram after PCI. In addition, the presence of an intraluminal thrombus in the culprit lesion on the initial angiogram was assessed.15 All angiographic endpoints were assessed by an independent core laboratory.

Furthermore, we evaluated all angiograms of patients with AVDE to investigate the moment that AVDE was visible for the first time during the procedure. The first moment of AVDE was categorized as on the initial angiogram, after wire passage, after thrombus aspiration or balloon dilatation, or after completion of PCI procedure.

To obtain information about the size of the embolic particles, we measured lumen vessel diameter at the site of AVDE by quantitative coronary analysis (MEDIS, Leiden). Vessel diameter was measured before the abrupt cut-off point in the coronary artery. The diastolic frame was selected that showed AVDE most clearly, with minimal branch overlap. Vessel diameter was automatically calculated and categorized into five size groups: ≤1.00, 1.00–1.25, 1.25–1.50, 1.50–1.75, and >1.75 mm.

Electrocardiography

ST-segment elevation was measured on the first ECG at presentation and on the ECG made 30–60 min after intervention. ST-segment elevation resolution was calculated by comparing the sum of ST-segment elevation on the post-intervention ECG with those on the ECG at presentation. The percentage ST-segment elevation resolution was estimated as complete ST-segment resolution (>70%), partial resolution (30–70%), or no resolution (<30%).12,16 In addition, the presence of new Q-waves was assessed on the post-intervention ECG.

Enzymatic infarct size

Serum creatine kinase (CK) and myocardial band of creatine kinase (CK-MB) measurements were collected for all patients during their stay at our hospital. A minimum of two measurements, with one measurement after 12 h, were required to allow calculation of area under the curve for enzymatic infarct size. The area under the curve was calculated from the PCI procedure to 24 h later, with the curve being linearly interpolated between measurements.

Clinical outcome at 1 year follow-up

Follow-up data were collected from hospital records and telephone interviews at 30 days and 1 year after primary PCI as a secondary outcome measure of TAPAS. Death was regarded as cardiac unless a non-cardiac cause of death was assessed.5,6 Re-infarction was defined as the onset of recurrent symptoms of ischaemia combined with new ST-elevations and a second increase of serum CK or CK-MB to at least twice the upper limit of the normal range.

Histopathological analysis of thrombus aspirate

If thrombus aspiration was performed during primary PCI, the aspirate samples were collected for assessment of atherothrombotic characteristics of the aspirated material. Thrombus aspiration was defined as effective if atherothrombotic material was present at histological analysis. The aspirated material was analysed for plaque fragments and thrombus type. Thrombus material was classified as thrombus with an erythrocyte component when it contained layers of coagulated erythrocytes, or as thrombus containing only aggregated platelets. In addition, the thrombus size was measured and categorized into three size groups: <0.5, 0.5–2.0, or >2.0 mm.

Statistical analysis

Categorical variables are presented as frequency values and proportions and were compared by chi-square test, Fisher-exact test, or Mann–Whitney U-test, when appropriate. Continuous normal distributed variables are presented as mean values ± standard deviation (SD), and were compared by two-tailed Student's t-test. For skewed variables, median values with inter-quartile range are presented, and comparisons are performed by Mann–Whitney U-test. Statistical significance was defined as a P-value <0.05 for all analyses. Statistical analysis was performed using Statistical Package for the Social Sciences (version 16.0; SPSS Inc., Chicago, IL, USA).

Results

A total of 1071 patients were included in the TAPAS trial between January 2005 and December 2006. Primary PCI was performed in 1005 patients. In 974 of 1005 patients, TIMI 2 or 3 flow was present during and/or after procedure. Angiograms of 883 patients could be evaluated for the presence of AVDE after PCI (Figure 1). A total of 122 angiograms of patients undergoing PCI could not be evaluated for AVDE, 52 (42.6%) of these patients were randomized to thrombus aspiration.

Figure 1

Flow diagram. Evaluation of angiograms for the presence of distal embolization. In 91 cases, angiograms after PCI could not be evaluated because the distal vessels were not recorded. AVDE, angiographic visible distal embolization; CABG, coronary artery bypass graft; CAG, coronary angiogram; PCI, percutaneous coronary intervention.

Angiographically visible distal embolization after percutaneous coronary intervention

Angiographically visible distal embolization was observed in 6.3% (56 of 883) of angiograms after PCI. Baseline characteristics did not differ between patients with and without AVDE, except for gender (Table 1). In patients with AVDE, the culprit lesion was located in the RCA in 46.4% and in the LAD in 32.1% compared with 38.5% and 42.9% in patients without AVDE (P= ns). Clinical and angiographic outcome measures are shown in Table 2, and the timing of angiographic evidence of distal embolization in Table 3.

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Table 1

Clinical and angiographic baseline characteristics

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Table 2

Clinical and angiographic outcome measures

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Table 3

Timing of angiographic evidence of distal embolization

Angiographic data

Thrombus was visible on the initial angiogram in 66.7% of patients with AVDE and in 46.0% of patients without AVDE (P = 0.003). Angiographically visible distal embolization was seen on 10 of 56 (17.9%) initial angiograms of patients with AVDE after PCI (Table 3). On the angiogram after thrombus aspiration or balloon dilatation, AVDE was observed in 27 of 56 (48.2%) cases. After PCI, the MBG was significantly lower in patients with AVDE than in patients without AVDE (Table 2). MBG 0 or 1 was present in 50.9% of patients with AVDE and in 17.0% of patients without AVDE (P < 0.001). In addition, TIMI flow 3 was achieved in 58.9% in the AVDE group vs. 87.9% in the non-AVDE group (P < 0.001) after PCI. The luminal diameters of the vessels with AVDE as measured by quantitative coronary analysis in the 49 patients with epicardial coronary flow ranged from 0.70 to 2.00 mm, median 1.3 (inter-quartile range 1.0–1.6) (Figure 2).

Figure 2

Vessel diameter at the site of angiographic visible distal embolization after PCI procedure, as measured by quantitative coronary analysis. Vessel diameter at the location of distal embolization after PCI, divided in five size groups. PCI, percutaneous coronary intervention.

Electrocardiographic outcomes

ST-segment resolution >70% was achieved in 22.0% of patients with AVDE compared with 54.2% of patients without AVDE (P < 0.001) (Table 2). In addition, significantly more patients in the AVDE group showed new Q-waves (94.0% vs. 78.6%, P = 0.002).

Enzymatic outcomes

In total, 640 of 883 (72.5%) patients met criteria for analysis of enzymatic infarct size. These patients had a median number of seven measurements (inter-quartile range 6–8). In 96 patients, less than two measurements were available. Patients with AVDE had higher enzyme levels of CK area under the curve (P = 0.001) and CK-MB area under the curve (P = 0.001) compared with patients without AVDE (Table 2).

Clinical outcome at 1 year follow-up

Follow-up data were available in all 883 patients. At 1 year after PCI, 4 of 56 (7.1%) patients with AVDE had died from any cause compared with 43 of 827 (5.2%) patients without AVDE (P= ns) (Table 2). The number of cardiac deaths was 3 of 56 (5.4%) in patients with AVDE and 34 of 827 (4.1%) in patients without AVDE. Re-infarction occurred in 5 of 56 (8.9%) patients with AVDE and in 25 of 827 (3.0%) patients without AVDE (P = 0.018).

Thrombus aspiration

Angiographically visible distal embolization was present in 30 of 450 (6.7%) patients randomized to thrombus aspiration, compared with 26 of 433 (6.0%) patients randomized to conventional PCI (Table 3). During intervention, thrombus was effectively aspirated in 69.0% (20 of 29) of patients with AVDE and in 72.5% (280 of 386) of patients without AVDE (Table 4). The aspirated thrombus contained erythrocytes in 50.0% of patients with AVDE and in 15.7% of patients without AVDE (P < 0.001). The size of aspirated thrombus particles was significantly larger in patients with AVDE than in patients without AVDE (P = 0.002).

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Table 4

Histopathological analysis of thrombus aspirate in patients with and without angiographic visible distal embolization

Discussion

This prospective study demonstrated that AVDE had an incidence of 6.3% after PCI in an unselected contemporary population with STEMI. Early administration of aspirin, heparin, and clopidogrel before PCI, and systematic use of abciximab at the start of the PCI procedure may have contributed to the low incidence of AVDE compared with previous reports.8,1719 The presence of AVDE after PCI was associated with worse MBG and TIMI flow, less ST-segment resolution, higher incidence of new Q-waves, higher enzyme levels, and a higher incidence of re-infarction at 1 year after PCI. Thrombus composition and size were important determinants of the occurrence of AVDE.

Embolization of atherothrombotic particles can occur during intervention due to crushing or fragmentation of material in the culprit lesion.20,21 The incidence and clinical impact of embolization after PCI have been investigated before by Henriques et al.8 This retrospective study found a more than two times higher incidence of embolization (15.2%) as compared with our study. Other recent trials investigating the effect of adjunctive mechanical devices on myocardial reperfusion report an incidence of embolization ranging between 2% and 8% in the intervention group and between 10% and 19% in the control group.1719 However, in the study of Henriques et al. aspirin and heparin were not administered before admission to the hospital and none of the patients received high-dose clopidogrel in combination with periprocedural glycoprotein-IIb/IIIa inhibitors. In addition, in studies investigating the effect of adjunctive mechanical devices on embolization, clopidogrel was not administered before the initial angiogram and abciximab was not or less often used.17,18 The lower incidence of AVDE after PCI in our study suggests that early pre-treatment with aspirin, heparin, and clopidogrel, and treatment with periprocedural abciximab may have contributed in reducing AVDE. In addition, randomized trials comparing abciximab treatment during primary PCI with standard PCI have documented a reduction in major adverse cardiac events after PCI procedure.911 It has been described that early treatment with abciximab improves myocardial reperfusion.2224 This supports the concept that treatment with abciximab results in less microvascular obstruction and distal embolization.

In previous reports, it has been observed that patients with angiographic visible thrombus had significantly more AVDE25 and less often TIMI flow 326 after PCI procedure than patients without visible thrombus. In the current study, we observed a higher incidence of angiographic visible thrombus in the culprit lesion in patients with AVDE. This suggests that visible thrombus on the angiogram before PCI is associated with an increased risk for AVDE. In addition, although not significant, AVDE was more often visible in the RCA and less often in the LAD. This may be due to the structure of the RCA with only a few side branches located proximally, resulting in stasis and significant thrombus formation during coronary occlusion.

In the TAPAS trial, patients were randomly assigned to manual thrombus aspiration before stenting or to balloon dilatation before stenting. Better myocardial reperfusion and clinical outcomes were found in the thrombus aspiration group than in the conventional group.5,6 However, we did not find an effect of thrombus aspiration on the incidence of AVDE, probably at least in part due to the low incidence of AVDE. In addition, thrombus aspiration could have no protective effect in some patients as AVDE was already visible on the initial angiogram. In a majority of thrombus aspiration patients, atherothrombotic material was aspirated. Thrombus aspirated in patients with AVDE contained an erythrocyte component more often than thrombus aspirated in patients without AVDE. Aspirated particles in patients with AVDE were larger. The composition and size of the thrombus, therefore, are an important determinant of AVDE after PCI.

Patients who had AVDE after PCI had worse MBG and TIMI flow, less ST-segment elevation resolution and higher enzyme levels. This suggests that embolization of thrombus and plaque material is an important mechanism in patients with suboptimal reperfusion, associated with worse clinical outcomes at follow-up. We observed a higher incidence of re-infarction in patients with AVDE than in patients without AVDE at 1 year after PCI. However, the mortality rate in patients with and without AVDE was not significantly different.

We observed a higher proportion of male gender in patients with AVDE compared with patients without AVDE. There is no pathophysiologic rationale for this observation. We presume that this difference is a chance finding as a consequence of the low incidence of AVDE.

Despite triple anti-platelet therapy and the performance of thrombus aspiration, AVDE is still visible on the angiogram in some patients and impairs myocardial reperfusion. Novel anti-thrombotic treatment strategies may result in further reduction of AVDE and microvascular obstruction by suppression of platelet activity and lysis of embolized thrombus particles. A promising approach is the administration of the thienopyridine prasugrel instead of clopidogrel during PCI.27 Furthermore, the intracoronary administration of abciximab has been suggested to be more effective in improving myocardial reperfusion compared with intravenous administration, as a high local concentration of glyocoprotein-IIb/IIIa inhibitors may increase platelet inhibition and induce lysis of fresh platelet thrombus.28 New developments in anti-thrombin treatment may also provide a more optimal balance between the risks of thrombosis and bleeding.29

Limitations

Several limitations of our study should be taken into consideration. The incidence of AVDE in this study may be underestimated, as not all coronary angiograms could be evaluated for the presence of AVDE after primary PCI. In addition, it is not known if poor myocardial reperfusion in AVDE patients is caused by AVDE itself or by an increased microvascular dysfunction, because they cannot be assessed independent from each other. It should be taken into consideration that we evaluated AVDE after PCI, and that from these observations it cannot be concluded that AVDE occurred during PCI procedure, as AVDE could already have been present in a total occluded coronary artery. The inability of angiography to evaluate AVDE in a total coronary occlusion limited the evaluation of initial AVDE in our population with STEMI, as the majority of STEMI patients present with a total coronary occlusion on the initial angiogram. In addition, the evaluation of the presence of an intraluminal thrombus is limited on angiography. Optical coherence tomography allows the evaluation of intraluminal thrombi on high-resolution in vivo images and will be a more sensitive technique to analyse the presence of intraluminal thrombi in future studies. Finally, ECG outcomes, cardiac enzyme measurements, and thrombus aspirates were not available in all patients and this may attenuate our findings. Unfortunately, enzymatic infarct size could only be assessed in 72.5% of patients. As a proportion of STEMI patients go to a regional hospital within 24 h after PCI procedure, insufficient cardiac enzyme measurements could be collected in some patients.

Conclusion

The incidence of AVDE on the coronary angiogram after PCI is low in this contemporary cohort of STEMI patients treated with triple anti-platelet therapy. Nevertheless, AVDE remains associated with reduced myocardial reperfusion and poor outcome. The composition and size of the thrombus are important determinants of AVDE after PCI.

Funding

Supported by a grant from Medtronic (for angiographic analyses by the core laboratory). All other costs were covered by the Thorax Center of the University Medical Center Groningen. There were no other relationships between the investigators and companies that make the products studied or discussed in this article or related products.

Conflict of interest: none declared.

References

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