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J Am Coll Cardiol, 2006; 48:1552-1559, doi:10.1016/j.jacc.2006.03.068
(Published online 25 September 2006). © 2006 by the American College of Cardiology Foundation |
* Interventional Cardiology, A. De Gasperis Department, Niguarda Hospital, Milan, Italy
Cardiology, Department of Medicine and Surgery, University School of Medicine, Milan, Italy
Department of Public Health and Microbiology, University of Turin, Turin, Italy
Manuscript received December 2, 2005; revised manuscript received March 7, 2006, accepted March 7, 2006.
* Reprint requests and correspondence: Dr. Pedro Silva-Orrego, Interventional Cardiology, A. De Gasperis Department, Niguarda Hospital, piazza Ospedale Maggiore 3, 20162 Milan, Italy (Email: pedrosilva{at}tiscali.it).
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Abstract |
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BACKGROUND: In STEMI patients, PPCI may cause thrombus dislodgment and impaired microcirculatory reperfusion. Controversial results have been reported with different systems of distal protection or thrombus removal.
METHODS: One-hundred forty-eight consecutive STEMI patients, admitted within 12 h of symptom onset and scheduled for PPCI, were randomly assigned to PPCI (group 1) or manual thrombus aspiration before standard PPCI (group 2). Patients with cardiogenic shock, previous infarction, or thrombolytic therapy were excluded. Primary end points were complete (>70%) ST-segment resolution (STR) and myocardial blush grade (MBG) 3.
RESULTS: Baseline clinical and angiographic characteristics were similar in the 2 groups. Comparing groups 1 and 2: complete STR 50% versus 68% (p < 0.05); MBG-3 44% versus 88% (p < 0.0001); coronary Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 78% versus 89% (p = NS); corrected TIMI frame count 21.5 ± 12 versus 17.3 ± 6 (p < 0.01); no reflow 15% versus 3% (p < 0.05); angiographic embolization 19% versus 5% (p < 0.05); direct stenting 24% versus 70% (p < 0.0001); and peak creatine kinase-mass band fraction 910 ± 128 µg/l versus 790 ± 132 µg/l (p < 0001). In-hospital clinical events were similar in the 2 groups. After adjusting for confounding factors, multivariate analysis showed thrombus aspiration to be an independent predictor of complete STR and MBG-3.
CONCLUSIONS: Manual thrombus aspiration before PPCI leads to better myocardial reperfusion and is associated with lower creatine kinase mass band fraction release, lower risk of distal embolization, and no reflow compared with standard PPCI. (Thrombus Aspiration Before Standard Primary Angioplasty Improves Myocardial Reperfusion in Acute Myocardial Infarction; http://clinicaltrials.gov/ct/show/NCT00257153).
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Restoration of normal flow in the epicardial infarct-related artery (IRA) is not always indicative of myocardial salvage (13,14). Even in the presence of normal epicardial flow, impaired myocardial perfusion assessed with contrast echocardiography (15,16) or angiographic myocardial blush grade (MBG) (14,17) after PPCI is associated with poor recovery of ventricular function and is an independent predictor of long-term mortality. On the other hand, although the resolution of ST-segment elevation (STR) correlates with IRA patency (18), its absence does not predict an occluded artery (19). However, several studies suggest that STR failure indicates inadequate myocardial reperfusion and is associated with poor recovery of left ventricular function and increased mortality, even in the presence of patent IRA (18,20–24). In recent years, controversial results on myocardial reperfusion have been reported with different strategies of mechanical distal protection or thrombus removal (25–30). This study was designed to test the hypothesis that thrombus aspiration before standard PPCI may improve myocardial reperfusion as compared with the standard procedure.
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Methods |
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30 min, ST-segment elevation >0.1 mV (0.2 mV in case of anterior leads) in 3 contiguous leads on a 12-lead electrocardiogram (ECG), and technical feasibility for primary angioplasty independently of initial Thrombolysis In Myocardial Infarction (TIMI) flow or angiographic evidence of intraluminal thrombus in the culprit artery. Exclusion criteria were cardiogenic shock, previous myocardial infarction or coronary bypass surgery, bundle branch block or pacemaker-induced rhythm on admission ECG, and contraindication to glycoprotein IIb/IIIa inhibitors. The study protocol was approved by the local ethics committee, and informed consent was obtained from all patients.
Procedure and device description. After enrollment, patients were 1:1 randomly assigned to standard angioplasty with stenting and abciximab (group 1) or thrombus aspiration plus standard angioplasty (group 2).
Thrombus aspiration was performed using the Pronto extraction catheter (Vasc.solutions, Minneapolis, Minnesota). The device (Fig. 1) is a simple, dual-lumen, monorail design, 6-F compatible catheter. The smaller lumen is to accommodate a standard 0.014-inch guidewire. The larger extraction lumen allows the removal of thrombus, which is aspirated with a 30-ml locking vacuum syringe. The catheter has a rounded distal tip designed to maximize thrombus aspiration and to protect the vessel wall while advancing and during aspiration.
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Angiographic analysis. Coronary angiograms were performed using a digital technique (Integris 3000, Philips Medical Systems, Best, the Netherlands). At least 2 orthogonal projections of the coronary segment scheduled for coronary intervention were filmed before and after the intervention. Each angiogram was preceded by intracoronary injection of nitrates (Nitroglycerin 100 to 200 µg). Quantitative coronary analysis was performed using the Coronary Quantification Package (Philips Medical Systems, Eindhoven, the Netherlands). At least 1 film after complete treatment included the myocardial territory of contrast distribution to allow estimation of TIMI flow (23-inch field) and MBG (23-inch field). Views were chosen to minimize superimposition of noninfarcted territories in the assessment of the MBG: laterolateral view for the left anterior descending coronary, right anterior oblique 45° view for the right coronary artery, and laterolateral or right anterior oblique 45° (in the presence of big marginal branch) views for the circumflex artery were used in most cases. The duration of cine filming was long enough to see some filling of the venous system to evaluate the washout phase of contrast dye. To facilitate the subjective grading of MBG, angiograms were digitized and a logarithmic nonmagnified mask-mode background substraction was applied to the image subset to eliminate noncontrast medium densities. Final analysis of TIMI flow grade, corrected TIMI frame count, and MBG was carried out by 2 experienced cardiologists (P.C. and P.S.) who were blinded to the study database, according to standard methods (14,31,32).
Coronary TIMI flow and MBG of 50 qualifying angiograms were analyzed, and both observers categorized the TIMI flow grade into TIMI 3, 2, and 0/1 and the MBG into 3, 2, and 0/1. The interobserver agreement was calculated with weighted k statistics, which resulted in a k value of 0.91 (95% confidence interval [CI] 0.78 to 1.03) for TIMI flow and 0.85 (95% CI 0.70 to 0.99) for MBG. Disagreement was resolved by consensus.
Electrocardiographic analysis. A 12-lead ECG was recorded at admission, at the end of the procedure, and at 90 min and 24 h after the procedure. Two observers blinded to randomization and angiographic results analyzed ECG recordings. The ST score, defined as the sum of ST-segment elevation measured at 20 ms from the J-point in the leads V1 to V6, I, and aVL for anterior and D2, D3, aVF, and V5 to V6 for nonanterior infarctions, as well as maximal ST-segment (STmax) elevation in the worst single lead were calculated in all patients. Reciprocal changes of ST-segment depression were not considered. Percent ST score and STmax resolution was calculated from admission and post-PPCI ECG and categorized as complete (>70%), partial (30% to 70%) and no reperfusion (<30%), as previously suggested (18). Interobserver agreement in ECG reading was evaluated by k statistics in 50 admission and post-PPCI ECGs: k value was 0.90 (95% CI 0.77 to 1.03). Disagreement was resolved by consensus.
Enzymatic infarct size. Infarct size was estimated by measurement of enzyme activity by using creatine kinase mass band fraction (CK-MB) as a reference. The enzymatic activity was reported as µg/l, and was assessed every 6 h in the first 48 h after admission. Peak release value from 8 serial measurements up to 48 h after admission is reported.
Study end points. The primary end point of this study was the achievement of myocardial reperfusion, defined by postprocedural complete (>70%) ST-segment resolution and post-PPCI MBG-3. Prespecified secondary end points were the comparison between the incidence of angiographic distal embolization and no reflow, peak of CK-MB release, and direct stenting in the 2 groups. Information on the in-hospital and 30-day occurrence of adverse events including death, nonfatal reinfarction, new hospitalization for heart failure, target vessel revascularization, stroke, and major bleedings was also collected.
Definitions. Cardiogenic shock was defined as hypotension with systolic blood pressure <90 mm Hg and tachycardia >100 beats/min, not caused by hypovolemia and requiring inotropic support or balloon counterpulsation.
Technical success of thrombectomy (device success) was defined as the ability of the device to cross the target lesion and to increase TIMI flow by >1.
Procedural success of the intervention was defined by the achievement of a final TIMI flow grade 2 and a residual stenosis <20%.
The diagnosis of reinfarction was supported by either ECG changes (new onset, significant Q waves in at least 2 ECG leads, recurrent or increased ST-segment elevation in the previous infarct leads, or new-onset ST-segment elevation in different ECG leads) accompanied by 30 min chest pain or cardiac enzyme release (CK-MB >50% above the prior level) occurring >24 h after coronary revascularization.
Distal embolization was defined as the migration of a filling defect or the distal occlusion of the target vessel or one of its branches at the end of or during the procedure.
No reflow was defined as a TIMI flow grade <2 not attributable to dissection, occlusive thrombosis, or epicardial spasm.
Statistical analysis. The target sample size was calculated on an assumption of a 30% improvement in the ST reduction in the study arm considering a 50% complete ST-segment resolution in the control arm (13,24,33). We estimated that 75 patients would be required in each group to have a power of 90% to detect an absolute difference in the occurrence of complete ST-segment resolution with a 2-sided alpha value of 0.05. Considering a 10% drop-out or lose to lecture, we planned to enroll a total of 160 patients. All analyses were performed according to the intention-to-treat principle. Categorical variables are presented as frequency values and were compared by chi-square test. Continuous variables are expressed as mean values ± SD, and were compared with Student t test or analysis of variance as appropriate. Stepwise logistic regression analysis was performed to identify the independent predictors of MBG-3 and complete ST-segment resolution after the procedure. The following variables were entered into model: age >65 years, hypertension, diabetes, infarct location, Killip class >2, ischemic time (from symptom onset to wire crossing), procedure duration (from arrival to the angiographic room to last angiogram), heart rate at admission, multivessel disease, occluded IRA at baseline (TIMI 0/1), angiographic evidence of thrombus, presence of collaterals, direct stenting, and use of aspiration catheter.
A value of p < 0.05 was interpreted as statistically significant. Statistical analysis was performed using SPSS 11.0 (SPSS Inc., Chicago, Illinois) and S-plus (release 2000) statistical package (Insightful Corporation, Seattle, Washington) and the Harrell’s Design and Hmisc libraries were used for analysis.
The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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After aspiration, TIMI flow grade increased from 0.5 ± 0.86 to 2.87 ± 0.36 (p < 0.01). Final TIMI flow and corrected TIMI frame count significantly improved in patients with thrombus removal in comparison with standard PCI: 2.87 ± 0.36 frames versus 2.68 ± 0.5 frames (p < 0.01); and 17.3 ± 6 frames versus 21.5 ± 12 frames (p < 0.01), respectively. In particular, TIMI flow increased by 1 grade in 17.6% versus 20.2% (p = NS), by 2 grades in 21.6% versus 28.4% (p = NS), and by 3 grades in 58.1% versus 39.2% (p < 0.05) of patients. One patient from each treatment group showed persistent TIMI flow grade 1 after the procedure, whereas no patient showed persistent TIMI flow grade 0. In 20% of patients, after thrombus removal, the culprit lesion was located distal to the initial occlusion site, in some cases more than 20 mm, changing the technical approach to the procedure (Fig. 2). Macroscopic aspirated material was observed in 70 of 74 (95%) patients. Angiographic transient no reflow and distal embolization were significantly less frequent in group 2 than in group 1: 3% versus 15% (p < 0.05) and 5% versus 19% (p < 0.05), respectively. Coronary perforation or intimal dissection were not observed.
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After adjusting for potentially confounding covariates, multivariate analysis showed thrombus aspiration (odds ratio 15.37, 95% CI 5.49 to 43) and the duration of the procedure (odds ratio 0.31, 95% CI 0.16 to 0.60) to be the only independent predictors of MBG-3.
The peak CK-MB release was significantly lower in patients with thrombus removal compared with the control group: 790 ± 132 µg/l vs. 910 ± 128 µg/l (p < 0.0001).
Clinical outcomes. In-hospital occurrence of death, reinfarction, left ventricular failure, and new revascularization were similar in the 2 groups. No death or reinfarction was observed during the hospital stay. In the thrombus aspiration group, 1 patient needed a new PCI of the target vessel. In the control group, 1 patient had left ventricular failure.
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Discussion |
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The present randomized study included all consecutive patients with STEMI presenting within 12 h from symptom onset independently of the angiographic evidence of thrombus, assuming that thrombus is always present in a recent myocardial infarction. Cardiogenic shock, previous infarction, and bypass surgery were regarded as exclusion criteria to minimize the risk of misinterpretation in the assessment of angiographic reperfusion. The main finding was that thrombus aspiration was associated with a better epicardial flow, significant improvement of myocardial reperfusion, and reduction of peak CK-MB release. In addition, it conveyed a significantly lower risk of distal embolization and no reflow. Thus, it seems that effective thrombus removal by manual aspiration at the lesion site improves myocardial reperfusion by reducing distal embolization occurring during mechanical revascularization. We previously found (37) severe and diffuse coronary flow impairment after stenting in patients treated with PPCI despite the use of distal protection with a filter. This may suggest a role of humoral mediators released from the thrombus during stenting.
Technical changes during angioplasty. In keeping with previous reports (25–27), the present study shows that thrombus removal allows direct stenting in a significantly higher proportion of patients. The higher rate of direct stenting could have played a role in the reperfusion benefit observed in the aspirated group. However, the multivariate analysis showed thrombus aspiration, but not direct stenting, to be independently associated with reperfusion. Direct stenting avoids unnecessary manipulation of the lesion and diminishes the use of balloons. In addition, the culprit lesion was located distally to the initial occlusion site in 20% of patients treated with thrombus removal. When the initial occlusion is at an important bifurcation site (Fig. 2), thrombus removal may avoid acute complications and improve the long-term result.
Although the aspirated thrombus was very proximal to the lesion and direct stenting should result in shorter stent coverage in many cases, we did not observe a significant difference in stent length between the 2 groups. This likely could be explained by the common approach to the procedure, which included a full coverage of the lesion starting from the occlusion site.
Differently from other studies with distal protection using the GuardWire (Medtronic Corp., Santa Rosa, California) (28) or thrombus removal with X-Sizer (ev-3, White Bear Lake, Minnesota) (26), which included an additional procedural time of 10 to 20 minutes, the duration of the procedure was similar in the 2 groups of our study.
Comparison with other studies. In the present study, the rate of MBG-3 (88%) and complete ST-segment resolution (68%) after thrombus removal was higher compared with previous reports on conventional angioplasty (14,24). A large multicenter randomized trial with a distal balloon occlusion and aspiration system (28) showed that distal protection and retrieval of embolic debris did not result in improvement of myocardial reperfusion or infarct size. Other recent randomized trials comparing thrombectomy with the X-Sizer device and conventional angioplasty have shown a higher rate of MBG-3 and >50% ST-segment resolution in patients treated with thrombus removal (25,26). Two randomized studies using AngioJet (POSSIS Medical Inc., Minneapolis, Minnesota) have shown controversial results in myocardial reperfusion and infarct size reduction (29,30). Differences in patient selection (inclusion of patients with previous infarction, bypass surgery, or treatment with fibrinolytic agents), procedural duration, and type of device could explain in part these discrepancies. More recently, Burzotta et al. (27) reported the results of a randomized trial on thrombus removal versus conventional angioplasty with a different manual aspiration system in patients with STEMI. They found a significant improvement in complete (>70%) ST-segment resolution (58% vs. 36%) and MBG >2 (68% vs. 45%). The evidence of better reperfusion observed in the present study could be explained, at least in part, by differences in patient selection. In fact, although the angiographic evidence of thrombus was not an inclusion/exclusion criteria in both studies, patients with previous infarction, cardiogenic shock, and previous thrombolysis were not included in our study, although they account for >30% of patients in the REMEDIA (Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus Aspiration in Primary and Rescue Angioplasty) trial (27).
Study limitations. The study reflects a single-center experience and was not designed to test differences in clinical outcome. In fact, it dealt with a low-risk population with a short follow-up period and no in-hospital mortality. Another limitation is that the study did not include the entire STEMI population, particularly patients with shock, previous infarction, bypass surgery, or previous treatment with fibrinolytic agents.
Conclusions. In selected patients, thrombus aspiration with the Pronto catheter in the setting of primary angioplasty is a simple and safe procedure. It improves myocardial reperfusion as assessed by myocardial blush and ST-segment resolution. It is associated with a lower CK-MB release and a lower rate of distal embolization and no reflow. Larger randomized trials are warranted to address the impact of thrombus removal on clinical outcome.
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