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J Am Coll Cardiol, 2006; 48:1355-1360, doi:10.1016/j.jacc.2006.05.059 (Published online 12 September 2006).
© 2006 by the American College of Cardiology Foundation
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FOCUS ISSUE: CARDIAC INTERVENTION: INTERVENTION IN ACUTE CORONARY SYNDROME

Thrombus Aspiration Reduces Microvascular Obstruction After Primary Coronary Intervention

A Myocardial Contrast Echocardiography Substudy of the REMEDIA Trial

Leonarda Galiuto, MD, PhD*, Barbara Garramone, MD, Francesco Burzotta, MD, PhD, Antonella Lombardo, MD, Sabrina Barchetta, MD, Antonio G. Rebuzzi, MD, Filippo Crea, MD, FACC on behalf of the REMEDIA Investigators

Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy.

Manuscript received March 24, 2006; revised manuscript received May 8, 2006, accepted May 8, 2006.

* Reprint requests and correspondence: Dr. Leonarda Galiuto, Institute of Cardiology, Catholic University of the Sacred Heart, Policlinico A. Gemelli, Largo A. Gemelli 8, 00168 Rome, Italy. (Email: lgaliuto{at}rm.unicatt.it).


   Abstract
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 Abstract
Materials and methods
 Results
 Discussion
 References
 
OBJECTIVES: The aim of this study was to clarify the role of microembolization in the genesis of microvascular obstruction (MO) after percutaneous coronary intervention (PCI).

BACKGROUND: Fifty consecutive patients entered the myocardial contrast echocardiography (MCE) substudy of the REMEDIA (Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus Aspiration in Primary and Rescue Angioplasty) trial, which defined the role of a new thrombus-aspirating device in preventing distal microembolization after PCI.

METHODS: A total of 25 patients were randomized to be pretreated with thrombus aspiration before PCI of the culprit lesion and 25 received standard PCI. At 24 h, 1 week, and 6 months after PCI, MCE was performed by Sonovue, and real-time imaging was performed by contrast pulse sequencing technology. Regional wall motion score index (WMSI), contrast score index (CSI), endocardial length of wall motion abnormality (WML) and contrast defect (CDL), end-diastolic and end-systolic left ventricular (LV) volumes, and ejection fraction were calculated.

RESULTS: At each time point, in patients treated with a thrombus-aspiration filter device, WMSI, CSI, WML, and CDL were significantly lower and ejection fraction higher (p < 0.05 vs. control patients), whereas LV volumes were slightly but not significantly smaller compared with control patients. In the overall study population, the extent of MO significantly correlated with temporal changes in LV volumes.

CONCLUSIONS: Thrombus aspiration used at the time of PCI significantly reduces the extent of MO and myocardial dysfunction, although it does not have a significant favorable effect in preventing LV remodeling. Thus, the beneficial effect of thrombus aspiration occurs at the microvascular level, but additional mechanisms may play a role in influencing the final extent of MO, which strictly correlates with post-infarct LV remodeling.

Abbreviations and Acronyms
  CDL = contrast defect
  CSI = contrast score index
  LV = left ventricular
  MCE = myocardial contrast echocardiography
  MO = microvascular obstruction
  PCI = percutaneous coronary intervention
  REMEDIA = Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus Aspiration in Primary and Rescue Angioplasty
  STEMI = ST-segment elevation myocardial infarction
  WM = wall motion
  WML = (endocardial length of) wall motion abnormality
  WMSI = (regional) wall motion score index

Despite optimal recanalization of the infarct-related coronary artery by percutaneous coronary intervention (PCI), microvascular perfusion may be largely impaired in a substantial number of ST-segment elevation myocardial infarction (STEMI) patients. Distal embolization is one of the mechanisms responsible for post-PCI microvascular obstruction (MO) (1).

We and others have recently shown (2,3) that use of a thrombus-aspirating device during PCI significantly improves the angiographic and electrocardiographic evidence of myocardial reperfusion. To demonstrate the potential benefit of thrombus aspiration at the microvascular level, a subgroup of patients enrolled in the REMEDIA (Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus Aspiration in Primary and Rescue Angioplasty) trial underwent myocardial contrast echocardiography (MCE) evaluation.


   Materials and methods
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 Abstract
 Materials and methods
Results
 Discussion
 References
 
Study population.   Consecutive patients referred to our institution between January and November 2004 for primary or rescue PCI within 12 h of onset of STEMI entered the REMEDIA trial. After enrollment and before coronary angiography, patients were randomly assigned 1:1 to undergo either standard PCI or PCI with thrombus aspiration according to a computer-generated random series of numbers. The first 50 consecutively randomized patients entered the MCE-REMEDIA substudy. The ethical committee of the Catholic University of the Sacred Heart approved the study, and all patients gave informed consent to participate in the study.

Angiographic methods have been previously described (2). Briefly, in patients randomized to standard PCI, after crossing the target lesion with the guidewire, direct stent implantation was attempted if judged possible by the operator, whereas in the remaining cases, predilation with an undersized balloon was used before stent implantation. In patients randomized to manual thrombus aspiration, after placement of the guidewire, stenting was preceded by thrombus aspiration by Diver CE (Invatec, Brescia, Italy). All patients were treated with heparin, aspirin, clopidogrel, or abciximab according to conventional protocols (2).

MCE.   Conventional echocardiogram and MCE were performed in all patients within 24 h (19.9 ± 12.3 h) of coronary recanalization, at 1 week, and at 6 months.

Myocardial contrast echocardiography studies were performed using real-time contrast pulse sequencing operating on a Sequoia ultrasound system (Siemens, Malvern, Pennsylvania). Contrast pulse sequencing is a novel real-time MCE method that, thanks to the analysis of non-linear response of contrast bubbles in fundamental and higher harmonics, is able to provide an image with excellent signal-to-noise ratio and with particularly high sensitivity and penetration using a very low mechanical index (Fig. 1). A second-generation ultrasound contrast agent Sonovue (Bracco, Milan, Italy) was administered intravenously (5 ml at 1 ml/min).


Figure 1
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  		Figure 1 Example of myocardial contrast echocardiography images in 4-chamber view. Microvascular network reached by microbubbles is colored in orange, whereas the area of microvascular obstruction (MO) is shown in both images as a black area at the apex (within arrows). The MO area is larger in A (control group patient) compared with that in B (thrombus-aspiration group patient).

 
Data analysis.   Coronary angiograms were reviewed offline by 2 expert interventional cardiologists as previously described (2). Regional wall motion (WM) was semiquantitatively scored by 2 experienced blinded observers according to the recommendations of the American Society of Echocardiography (1 = normal, 2 = hypokinesia, 3 = akinesia, 4 = dyskinesia) and a wall motion score index (WMSI) was calculated by the sum of the score of all segments divided by the total number of segments. Functional improvement at 6 months was calculated as percentage change of WMSI at 6 months compared to 24 h. Left ventricular (LV) volumes were calculated by the modified Simpson biplane method. Temporal changes in LV volumes were calculated as the percentage changes at 6 months compared to baseline. Left ventricular remodeling was considered as an increase in LV end-diastolic volume >20% at 6 months compared to baseline. Ejection fraction was calculated from the formula: (end-diastolic volume – end-systolic volume)/end-diastolic volume.

Myocardial opacification at MCE was visually assessed in each of the 16 myocardial segments and semiquantitatively scored. Single perfusion score was assigned on the basis of both the change in myocardial signal intensity throughout the replenishment curve and the degree of opacification at the peak contrast effect (4). Scores were graded as 1 = normal, 2 = reduced, or 3 = absent opacification. A contrast score index (CSI) was calculated by the sum of MCE score in each segment divided by the total number of segments. Endocardial length of severe WM abnormality (WM score = 3) (WML) and of transmural contrast defect (CD score = 3) (CDL) were calculated in each apical view, averaged, and expressed as a percentage of LV length.

Statistical analysis.   Continuous variables (presented as mean ± SD) were compared by Student t test for normally distributed variables and by Wilcoxon test for non-normally distributed variables. Categorical variables were expressed as number of subjects and percentages and were analyzed by the chi-square or Fisher exact test, as appropriate. Changes over time of continuous variables and comparison among groups were carried out using 2-way analysis of variance for repeated measures and Scheffe’s F test. A linear regression analysis was carried out to correlate continuous variables with the percentage change of LV volumes at follow-up. Cohen’s kappa statistical analysis was performed to measure intra- and interobserver agreement of MCE score and LV volume analysis. Statistical analysis was performed with the use of the SPSS software package for Windows 11.0 (SPSS Inc., Chicago, Illinois). Differences were considered significant at p < 0.05.

Reproducibility.   To assess intraobserver variability of MCE analysis, 16 MCE studies obtained in the first 8 patients were independently reviewed by the same observer (L.G.), 40 ± 10 days after initial scoring. Segments with signal attenuation and artifacts were excluded from analysis. Interobserver variability was assessed by comparing the reading of 2 observers (L.G., A.L.). Intraobserver and interobserver variability of CSI analysis was 3.2 ± 2% and 4.2 ± 2% (absolute difference), with a K value for agreement of 0.91 and 0.95, respectively. For LV volume analysis, intra- and interobserver variability was 3.4 ± 1% and 5.1 ± 2%, with a K value for agreement of 0.89 and 0.93, respectively.


   Results
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 Abstract
 Materials and methods
 Results
Discussion
 References
 
The study population comprised 50 patients with first STEMI, treated by primary or rescue PCI within 12 h of symptom onset. Clinical characteristics of the study population divided into thrombus aspiration and control patients are summarized in Table 1.


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  		Table 1. Clinical and Angiographic Characteristics of the Study Population
 
Extent of microvascular obstruction and myocardial dysfunction.   At 24 h, 1 week, and 6 months, severity and extent of MO were consistently reduced in thrombus-aspirated patients as compared with control patients (Figs. 2A and 2B). In both groups, a significant reduction of CSI over time was observed at 1 week and 6 months, whereas CDL/LV length was reduced only in Group B (Fig. 3).


Figure 2
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  		Figure 2 Contrast score index (CSI) (upper panel), contrast defect length (CDL)/left ventricular (LV) length (%) (lower panel) at 24 h, 1 week, and 6 months in control patients (white bars) and thrombus aspiration (black bars). At each time point, both MO parameters are significantly reduced by thrombus-aspiration device (upper panel: *p < 0.01 vs. controls, {dagger}p < 0.0005 vs. control patients; lower panel: *p < 0.05 vs. control patients). In both groups, a significant reduction of myocardial contrast echocardiography (MCE) score over time has been observed at 1 week (upper panel: {ddagger}p = 0.01 vs. 24 h and $p < 0.0001 vs. 24 h), whereas myocardial contrast echocardiography /LV length was reduced only in thrombus aspiration (lower panel: {dagger}p < 0.001 vs. 24 h).

 

Figure 3
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  		Figure 3 Example of reduction of the extent of microvascular obstruction (MO) at 1 week compared to 24-h myocardial contrast echocardiographic imaging performed in 2-chamber view. The area of MO between arrows is larger at 24 h compared to 1 week.

 
Similarly, at 24 h, 1 week, and 6 months, regional extent of myocardial dysfunction, expressed as WMSI (Fig. 4, upper panel) or as WML/LV length % (Fig. 4, lower panel), was significantly reduced in thrombus-aspirated patients as compared with control patients. In both groups, a significant reduction of WMSI and WM/LV length over time was observed at 1 week and 6 months.


Figure 4
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  		Figure 4 Wall motion (WM) score index (WMSI) (upper panel) and left ventricular (LV) length WML/LV length (%) (lower panel) at 24 h, 1 week, and 6 months in control patients (white bars) and thrombus aspiration patients (black bars). At each time point, both WM parameters are significantly reduced by thrombus-aspiration device (upper panel: *p < 0.005 vs. control patients, lower panel: *p < 0.05 vs. control patients). In both groups, a significant reduction of WM score over time has been observed at 1 week and 6 months ({dagger}p = 0.0001 vs. 24 h). At 1 week and 6 months, WM/LV length was also reduced in controls ({dagger}p < 0.005 vs. 24 h) and in thrombus aspiration ({ddagger}p < 0.0005 vs. 24 h).

 
LV volumes and ejection fraction.   Left ventricular volumes were smaller in thrombus aspiration as compared with control patients, but this difference did not reach statistical significance (Figs. 5A and 5B). Ejection fraction was significantly better in thrombus aspiration as compared with control patients at each time point, and it further improved at 1 week and 6 months (Fig. 5C).


Figure 5
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  		Figure 5 End-diastolic volume (A) and end-systolic volume (B) at 24 h, 1 week, and 6 months in controls (white bars) and thrombus aspiration (black bars). Although a slight reduction in both volumes could be observed at each time point in thrombus aspiration compared with control patients, such differences did not reach statistical significance. (C) Ejection fraction at 24 h, 1 week, and 6 months in control patients (white bars) and thrombus aspiration (black bars). In thrombus-aspiration patients, at each time point, ejection fraction was significantly better compared with control patients (*p < 0.05 vs. control patients), and it further improved at 1 week and 6 months ({dagger}p < 0.05 compared to 24 h).

 
In both the thrombus-aspiration and control groups tested separately, CSI at 24 h was linearly related to temporal changes in LV volumes at 6 months (r = 0.3, p = 0.04) and to functional improvement at 6 months (r = 0.4, p = 0.01).


   Discussion
Top
 Abstract
 Materials and methods
 Results
 Discussion
References
 
Manual thrombus aspiration significantly reduces the severity and extent of MO 24 h after primary or rescue PCI. Accordingly, regional WM and ejection fraction are better in treated patients. However, both end-diastolic and end-systolic LV volumes were only slightly smaller in thrombus-aspiration patients compared with control patients. On the other hand, in the overall population, the severity and extent of MO are linearly related with temporal changes in LV volumes, and the reduction in MO over time is inversely related to increase in LV volumes.

Assessment of post-PCI perfusion at microvascular level.   Mechanical reopening of thrombotic coronary occlusion by balloon angioplasty and stent placement is the most effective way to re-establish flow within the infarct area, thus limiting necrosis extent. However, this invasive maneuver is responsible for displacement of plaque and thrombus fragments that embolize distally. When the amount of displaced material is consistent, an abrupt obliteration of coronary branches may be recognized at coronary angiogram performed soon after successful PCI (1). However, coronary angiography is able to detect only microembolization responsible for the plugging of vessels with a diameter >100 microns, thus underestimating the phenomenon. Surrogate markers of microvascular perfusion, such as resolution of electrocardiographic elevation and myocardial blush grade, have been used to assess the efficacy of PCI at tissue level. In this study, we elected to assess post-PCI MO by MCE because this technique is readily available in our institution at patient’s bedside in the coronary care unit, effective in the evaluation of MO, well tolerated by the patients, and easily repeatable to perform serial assessment (5).

The results of this study demonstrate that post-PCI microembolization plays a significant role in the pathogenesis of MO, because aspiration of thrombotic material significantly reduces the severity and extent of MO.

Temporal changes of microvascular obstruction and myocardial dysfunction.   A collateral finding of this study is that, in both treated and control patients, MO progressively improves over time at 1 week and 6 months follow-up. This temporal change in MO extent is paralleled by similar temporal improvement of regional WM. These findings are in close agreement with the demonstration of dynamic changes of post-infarct microvascular damage characterized by a progressive reduction of MO at serial MCE evaluation (5,6). It is conceivable that temporal changes of MO are the result of progressive resolution of mechanisms that concur in the pathogenesis of post-PCI MO, such as microvascular spasm or reduction of tissue edema and microvessel compression or resolution of leukocyte plugging. Temporal reduction of myocardial dysfunction may be interpreted as the resolution of myocardial stunning, and such temporal resolution may be enhanced by the parallel reduction of MO extent.

Prevention of distal embolization and LV remodeling.   End-diastolic and -systolic LV volumes are the best predictors of patient survival after acute myocardial infarction, and the extent of MO has already been demonstrated to be closely linked to post-infarct LV dilation and remodeling (7). So it is reasonable to expect that a thrombus-aspiration-related reduction in MO is associated with limited LV remodeling. Yet, in this study, end-diastolic and end-systolic LV volumes were slightly but not significantly smaller in treated patients compared with control patients. Because the study sample was powered to demonstrate a possible effect of thrombus aspiration on MO, a larger study population probably is needed to demonstrate prevention of LV remodeling. Regardless, a possible reason for the limited effect of thrombus aspiration on LV volumes may be the multiple pathogenic causes of MO, so that the reduction of only 1 factor, such as microembolization, is sufficient to reduce MO, but to an extent insufficient to prevent LV remodeling. In a randomized trial with a design similar to our REMEDIA study, de Luca et al. (3) were able to demonstrate a significant reduction in both end-diastolic and end-systolic LV volumes by the same thrombus-aspiration device. However, all 75 patients included in their study exhibited anterior wall acute myocardial infarction, which might have highlighted potential beneficial effects of thrombus aspiration, although information on the extent of MO was not provided.


   References
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 Abstract
 Materials and methods
 Results
 Discussion
 References
 

  1. Henriques JPS, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction Eur Heart J 2002;23:1112-1117.[Abstract/Free Full Text]
  2. Burzotta F, Trani C, Romagnoli E, et al. Manual thrombus-aspiration improves myocardial reperfusionThe Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus-Aspiration in Primary and Rescue Angioplasty (REMEDIA) trial. J Am Coll Cardiol 2005;46:371-376.[Abstract/Free Full Text]
  3. De Luca L, Sardella G, Davidson CJ, et al. Impact of intracoronary aspiration thrombectomy during primary angioplasty on left ventricular remodelling in patients with anterior ST-elevation myocardial infarction Heart 2006;92:951-957.[Abstract/Free Full Text]
  4. Balcells E, Powers ER, Lepper W, et al. Detection of myocardial viability by contrast echocardiography in acute infarction predicts recovery of resting function and of contractile reserve J Am Coll Cardiol 2003;41827–3.
  5. Galiuto L, Lombardo A, Maseri A, et al. Temporal evolution and functional outcome of no-reflow: sustained and spontaneously reversible patterns following successful coronary recanalization Heart 2003;89:731-737.[Abstract/Free Full Text]
  6. Galiuto L, DeMaria AN, May-Newman K, et al. Evaluation of dynamic changes in microvascular flow during ischemia-reperfusion by myocardial contrast echocardiography J Am Coll Cardiol 1998;32:1096-1101.[Abstract/Free Full Text]
  7. Bolognese L, Carrabba N, Parodi G, et al. Impact of microvascular dysfunction on left ventricular remodeling and long term clinical outcome after primary coronary angioplasty for acute myocardial infarction Circulation 2004;109:1121-1126.[Abstract/Free Full Text]



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This Article
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