American Heart Journal
Volume 151, Issue 3 , Pages 597.e1-597.e7, March 2006

Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS)—Study design

  • Tone Svilaas, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Tone Svilaas, MD, Department of Cardiology, Thorax center, University Medical Center Groningen, University of Groningen, Postbus 30.001, 9700 RB Groningen, The Netherlands.
    • ,
  • Iwan C.C. van der Horst, MD, PhD
    • ,
  • Felix Zijlstra, MD, PhD

Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands

Received 12 July 2005; accepted 24 November 2005.

Article Outline

Background and Objective

Embolization of atherothrombotic material is common during percutaneous coronary intervention (PCI) in acute myocardial infarction (MI). This may lead to distal vessel occlusion resulting in impaired myocardial perfusion, which is associated with larger infarct size and increased mortality. Adjunctive devices for PCI to protect the microcirculation have been developed. We intend to determine whether aspiration of thrombotic material before stent implantation of the infarct-related coronary artery results in improved myocardial perfusion compared with conventional primary PCI.

Study Design

TAPAS is a single-center, prospective, randomized trial with a planned inclusion of 1080 patients with ST-elevation MI. Patients are assigned to treatment with thrombus aspiration with the 6F Export Aspiration Catheter (Medtronic Corporation, Santa Rosa, Calif) or to balloon angioplasty before stent implantation in the infarct-related artery. All patients will be treated medically according to current international guidelines including glycoprotein IIb/IIIa inhibitors before PCI. Randomization will be performed before coronary angiography. The primary end point is angiographic myocardial blush grade of <2. Secondary end points are enzymatic infarct size, ST-segment elevation resolution and persistent ST-segment elevation, postprocedural distal embolization, and Major Adverse Cardiac Events at 30 days and 1 year.

Implications

If thrombus aspiration significantly improves myocardial perfusion, it will lend support to the use of this treatment as part of the standard approach in patients with acute MI.

 

Acute myocardial infarction (MI) is considered to be related primarily to the rupture or erosion of a coronary atherosclerotic plaque, initiating intraluminal thrombus superimposed on the ruptured plaque, which leads to total or subtotal occlusion of an epicardial vessel.1, 2, 3 Following coronary angiographic studies showing that thrombotic occlusion of the epicardial artery causes MI,4 reperfusion therapy has been focusing on dissolving, compressing, or surgically bypassing thrombi, aiming at normalization of flow in the epicardial infarct-related artery. Optimal outcome of reperfusion treatment has in recent years been redefined to include not only sustained epicardial patency, but also reperfusion of the myocardium subtended by the affected coronary artery.5, 6, 7, 8, 9, 10, 11 Primary percutaneous coronary intervention (PCI) has emerged as the preferred treatment of acute MI if logistically feasible and has been proven to be a very effective method to obtain patency of the infarct-related artery.12, 13, 14 However, microvascular dysfunction with diminished myocardial perfusion is seen in a significant proportion of patients with a patent epicardial vessel after primary PCI and has been associated with larger infarct size, less recovery of left ventricular ejection fraction, and increased mortality.8, 10

Two major impediments to normalization of microvascular function are considered to be reperfusion injury and microvascular obstruction. Reperfusion injury refers to the inability to reperfuse myocardium that is already necrotic through ischemic cell death.15 Microvascular obstruction is believed to be caused by the embolization of soft plaque gruel (atheroembolization) and/or thrombotic material (thromboembolization) in the downstream bed of the infarct-related artery.16, 17 The embolization may occur spontaneously after plaque rupture, but recent studies emphasize mechanical crushing and fragmentation of the culprit lesion during PCI as the major cause.8, 18, 19 Distal embolization induced by PCI therefore potentially results in further myonecrosis.

Several diagnostic testing strategies have evolved to evaluate the adequacy of reperfusion in the treatment of acute MI. The coronary angiogram can be used to obtain diagnostic information of epicardial as well as myocardial perfusion. Epicardial flow can be described according to the angiographic TIMI grading system20 and quantitatively assessed by the corrected TIMI frame count.21 Coronary angiographic techniques for the assessment of microvascular function and myocardial tissue perfusion include the visualization of distal embolization8 and the evaluation of myocardial blush grade (MBG).7 These angiographic methods are valuable in risk stratification after reperfusion therapy as they have been shown to correlate directly with mortality.7, 22 The angiographic characterization of reperfusion may be complemented by other surrogate markers of tissue level perfusion.6, 23, 24, 25, 26, 27, 28, 29, 30 Of these, the most applicable for routine assessment of perfusion include the electrocardiographic (ECG) analysis of ST-segment resolution for evaluation of the efficacy of myocardial tissue reperfusion6, 23, 24 and cardiac marker release patterns for determination of the amount of myocardial damage as measure of infarct size.25, 26

The frequent suboptimal myocardial reperfusion after primary PCI has resulted in the development of adjunctive devices for PCI to protect the microcirculation, which include devices for use distal as well as proximal to the lesion. Distal embolic protection devices consist of occlusion balloons or filters in combination with aspiration devices. Occlusion balloons serve to obstruct the target vessel distal from the site of revascularization, thereby blocking the outflow of debris. The debris is then aspirated out of the vessel by an export catheter before the balloon is deflated. Filtering devices are attached to guidewires and serve as a basket to trap embolic material downstream from the lesion. Aspiration has been attempted with devices such as over the wire balloons or the angiography catheter itself. These techniques have some limitations. The lumen of an over the wire balloon system is just large enough to allow passage of 0.014-in wire, which may not allow rapid aspiration. Use of the angiography catheter as an aspiration tool is limited by the inability to manipulate it deeply enough into the infarct-related artery to approach the culprit lesion, with the risk of damage. In two published randomized trials, the PROMISE trial (filterwire, FilterWire-Ex)31 and the EMERALD trial (distal balloon and aspiration system, GuardWire),32 the distal protection system did not result in improved reperfusion, reduced infarct size, or improved clinical outcome, despite a high procedural success rate in both trials (Table I).

Table I. Randomized trials in protection of distal embolization in ACS
Year of publicationFirst authorProcedureDeviceCategoryNo. of ptsCDSuccessful, n (%)TIMI 3 C/D (%)cTFC C/D (mean)MBG C/D (%)ST resolution C/D (%)
2002Beran 34ThrombectomyX-sizerACS66313031 (91)84/9025/18⁎1.6/1.8†52/83⁎
2003Napadano 35ThrombectomyX-sizerACS92464640 (87)96/94NA37/72⁎52/83⁎
2005Lefèvre 38ThrombectomyX-sizerSTEMI20110110087 (87)89/9625/2330/3153/68⁎
2004Antoniucci 37ThrombectomyAngioJetSTEMI100505048 (96)NA23/18⁎NA72/90⁎
2005Ali 39ThrombectomyAngioJetSTEMI480240240228 (95)97/9229/3237/3168/60
2004Dudek 36ThrombectomyRESCUESTEMI72324035 (87)86/8519/2138/5425/68
2005Burzotta 42ThrombectomyDiverCESTEMI100504944 (88)NA26/2368/45‡58/37
2005Stone 32Distal ProtectionGuardWireSTEMI501249252193 (79)89/9220/1853/6162/63
2005Gick 31Distal ProtectionFilterWireExAMI20010010095 (95)93/93NA67/64⁎, ‡NA

Category, Patients included in study, that is, patients with ST elevation myocardial infarction (STEMI), acute coronary syndrome (ACS), and acute myocardial infarction (AMI); C, control group; D, device group; No. of pts, number of patients included in study; Successful, number of interventions in the treatment group that were successful according to definition in respective trials; TIMI 3, Thrombolysis in Myocardial Infarction flow 3 after the procedure; cTFC, corrected TIMI frame count at the end of the procedure; MBG, myocardial blush grade 3 after the procedure; ST resolution, percentage of patients with ST-segment elevation resolution after the procedure according to definition in respective trials; NA, not available.

⁎P < .05.

†Mean MBG.

‡MBG 2/3.

Embolic protection with intracoronary thrombectomy devices without a distal protection component may be useful in the setting of acute MI.33 A few randomized trials have shown some advantage of these devices in acute coronary syndromes (Table I).34, 35, 36, 37, 38 In one large randomized trial, the AIMI trial, the patients treated with the AngioJet showed larger infarct sizes as compared with control patients.39 The use of an aspiration catheter may be beneficial for embolic protection.36, 40, 41 In the REMEDIA trial, manual thrombus aspiration with the Diver CE in patients with acute ST elevation MI resulted in improved angiographic and ECG myocardial reperfusion rates (Table I).42 The 6F Export Aspiration Catheter (Medtronic Corporation, Santa Rosa, Calif) may be practical in the setting of primary PCI because its size allows access to the lesion over a routine wire and maneuvering into tortuous and distal coronary arteries. In this trial, we intend to evaluate the usefulness of this aspiration catheter in the improvement of myocardial perfusion during primary PCI in patients with acute ST-elevation MI. If thrombus aspiration significantly improves myocardial perfusion, it will lend support to the use of this treatment as part of the standard approach in patients with acute MI.

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Study objectives 

The primary objective is to evaluate whether thrombus aspiration compared with balloon inflation before stent implantation of the infarct-related artery results in improved myocardial perfusion in the treatment of patients with acute MI. We hypothesize that aspiration will reduce the occurrence of MBG of <2 by a quarter (from 30% in the control group to 22.5% in the intervention group). Secondary objectives include investigating whether thrombus aspiration improves enzymatic infarct size, ST-segment elevation resolution and the incidence of persistent ST-segment elevation, postprocedural distal embolization, and Major Adverse Cardiac Events at 30 days and 1 year.

We will examine our primary and secondary objectives for the total population and according to two main prespecified subgroups defined by angiographic evidence of thrombus on the initial angiogram and successful thrombus aspiration.

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Study design 

This is a single-center, prospective, randomized, open trial with blinded evaluation of end points. Patient recruitment will start in 2005 and inclusion continues until 1080 patients with an acute MI have been randomized. Patients will be randomly assigned to one of two arms: treatment with intracoronary thrombus aspiration device followed by stenting, or balloon angioplasty followed by stenting. The study has been approved by the institutional review board. The study will take place at the University Medical Center of Groningen, a center with experience in primary PCI of patients with acute MI and with access to emergency cardiac surgery.

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Patient selection and randomization 

All patients with acute MI and candidates for primary PCI admitted to a single university center are considered for participation in the study.

Inclusion and exclusion criteria 

The inclusion criterion is a diagnosis of acute MI defined by chest pain suggestive for myocardial ischemia for at least 30 minutes, with a time from onset of symptoms of <12 hours before hospital admission, and an ECG with ST-segment elevation of >0.1 mV in ≥2 leads. Exclusion criteria are rescue PCI after thrombolytic therapy, inability to obtain informed consent, and known existence of a life-threatening disease with a life expectancy of <6 months.

Randomization 

After informed consent, eligible patients are randomized 1:1 to a strategy of thrombus aspiration followed by stenting of the infarct-related artery or to balloon angioplasty followed by stenting of the infarct-related artery. Randomization will be performed at the catheterization laboratory before coronary angiography, by means of a computerized voice response system. The invasive cardiologist contacts the randomization center and states his or her own code and the date of birth of the patient. The computer program is operating in blocks of 3 to 6 patients and is stratified by the invasive cardiologist to achieve a balanced allocation for therapy as well as for the cardiologist performing the procedure. The randomization computer discloses the treatment assignment of the patient and records the date and time of randomization. The cardiologist records the randomization outcome on the dedicated Case Report Form.

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Treatment 

Medication 

Before PCI, the patient is treated with the following medical therapy:

˙aspirin (a bolus of 300 mg if not already being taken, followed by 80-100 mg/24 hours);

˙intravenous heparin/low-molecular-weight heparin;

˙clopidogrel (600 mg followed by 75 mg/24 hours);

˙glycoprotein IIb/IIIa inhibitor: abciximab, unless contraindicated.

Additional standard treatment consists of nitroglycerin intravenously. During PCI, 5000 to 10000 IU heparin is administered guided by ACT measurements. In patients with atrial fibrillation, a large dyskinetic area of the left ventricle, and in immobile patients, low-molecular-weight heparin is given for 1 to 3 days after sheath removal. Standard therapies after PCI include aspirin 80 mg, clopidogrel 75 mg, β-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, according to current international guidelines.14

Study device 

The Export Aspiration Catheter (Medtronic Corporation) is a 6F thrombus aspiration catheter. The total usable length is 145 cm. The catheter has an oblique aspiration tip design, with an aspiration lumen of 0.041 in and a crossing profile of 0.068 in. A radiopaque marker is sited 2 mm from the distal tip. Suction is provided by hand with a lockable 20-mL syringe, which allows for a suction rate of 1 mL/s.

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Clinical data and definitions 

Baseline demographic and clinical characteristics 

Baseline characteristics that will be collected include age, sex, time of symptom onset, time of admission, history of coronary artery bypass grafting, previous PCI, stroke and MI, positive family history for cardiovascular diseases, existence of diabetes mellitus, hypertension, smoking status, heart rate, systolic and diastolic blood pressure, weight, length, and the findings of cardiac and pulmonary auscultation. Major Adverse Cardiac Events are defined as the combination of death, reinfarction, and ischemia driven target vessel revascularization and will be recorded at 30 days and at 1 year. Follow-up information will be obtained from hospital records as well as by telephone interviews with the patient.

Coronary angiography 

A coronary angiogram will be obtained at baseline, that is, before the PCI procedure, and after the procedure, ie, after stent placement. Intravenously administered nitroglycerine will be given after the procedure and before the last angiogram in all patients. TIMI flow grades will be estimated as previously described.20 The evaluation of MBG will be performed as described by van' t Hof et al7: 0, no myocardial blush; 1, minimal myocardial blush or contrast density; 2, moderate myocardial blush or contrast density, but less than that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery; and 3, normal myocardial blush or contrast density, comparable with that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery. Persisting myocardial blush (“staining”) suggests leakage of contrast medium into the extravascular space and is graded 0. Distal embolization will be considered to have occurred if new circumscribed filling defects and/or abrupt cutoff of the vessel distal to the target lesion appears.8 Thrombus is assessed according to the criteria summarized by Mabin et al.43 These criteria include the presence of an intraluminal central filling defect or lucency surrounded by contrast material that is seen in multiple projections; the absence of calcium within the defect; and persistence of contrast material within the lumen. TIMI flow grade, the MBG, distal embolization, and thrombus load will be evaluated at baseline and after the PCI procedure.

The coronary angiograms will be analyzed by an independent core laboratory. Evaluations will be performed on spliced films without information regarding device use during the procedure.

Electrocardiography 

A standard 12-lead ECG is acquired at the time of presentation, at 30 to 60 minutes, and at 3-6-9-12 hours after the end of procedure. Mean time interval between pre- and post-intervention will be registered. The magnitude of ST-segment elevation is measured 60 milliseconds from J point. ST-segment score is calculated as the sum of ST-segment elevation >0.1 mV for leads V1 through V6 and I, II, and aVL in anterior infarction and I, II, aVF, V5, and V6 in nonanterior infarction. The first post-intervention ECG will be classified by comparison of the ST segments with those of the ECG at presentation. The percentage ST-segment elevation resolution will be categorized as complete (>70%), partial (30%-70%), or absent (<30%).6 Also, an analysis of persistent ST-segment elevation will be performed. Two observers blinded to study randomization and angiographic findings will analyze all ECG recordings.

Infarct size 

Infarct size will be estimated by serial measurements of cardiac markers in serum, including creatinine kinase (CK), MB fraction of CK (CK-MB), lactate dehydrogenase (LDH), and troponin I. The first measurement is taken as soon as possible after admission. Thereafter, frequent marker determinations are performed according to a schedule that calls for 4 to 6 measurements in the first 24 to 36 hours. To accommodate the problem in practice that exact predefined times for blood sampling are not always followed, the actual times of sampling, expressed as minutes after the moment of randomization, are recorded. To allow optimal comparison of the time courses of marker levels and to best approximate the area under the marker level curves, we use a dedicated algorithm.26, 44 Per patient, the algorithm interpolates the marker levels based on the precise time of measurement. Next, it determines for each of the predefined intervals if an actual measurement has been performed in that interval. Marker levels are determined on a Hitachi 717 automatic analyzer according to the International Federation of Clinical Chemistry recommendation, at 30°C. A peak marker release above the 75% percentile (ie, the highest quartile) is defined as high enzyme release. Time to peak release is also determined.

Histopathologic analysis 

All aspirated material will be processed for histological analysis. After thrombosuction, the aspirated material is placed in formalin and fixed for 24 hours. Cell blocks for paraffin embedding will be prepared. Histological sections will be cut and stained with hematoxylin-eosin for examination with a light microscope. To optimize visualization of smooth muscle cells and macrophage foam cells, additional immunostaining will be performed when applicable.

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End point assessment 

Primary end point 

The primary end point is defined as the frequency of an MBG of <2. We expect this to be 30% in the control group, based on previously published data.7, 22 We hypothesize a reduction of this primary end point to ≤22.5% in the experimental group.

Secondary end points 

Secondary end points are as follows:

˙postprocedural distal embolization;

˙postprocedural TIMI flow;

˙ST-segment elevation resolution and persistent ST-segment elevation at 30 to 60 minutes after the procedure;

˙infarct size as measured by cardiac enzymatic markers (CK, CK-MB, LDH) and troponin I;

˙Major Adverse Cardiac Events at 30 days and 1 year.

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Subgroups 

The primary and secondary end points will be analyzed in prespecified subgroups defined by the following:

1.angiographic evidence of thrombus on the initial pre-PCI coronary angiogram;

2.successful thrombus aspiration defined as the presence of macroscopic or microscopic thrombus in the aspirate confirmed by histopathologic examination.

Additional subgroup analyses will be performed according to age, sex, preinfarction angina, time from symptom onset, infarct-related segment and vessel, and TIMI flow at baseline.

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Statistical analysis 

Statistical methods 

Analyses will be performed according to the intention-to-treat principle for the whole population and in the specified subgroups. An analysis per protocol will also be performed. Differences between group means will be assessed with the 2-tailed Student t test. χ2 Analysis or Fisher exact test is used to test differences between proportions. Survival will be calculated by the Kaplan-Meier product-limit method. The Mantel-Cox (or log-rank) test will be used to evaluate differences in survival between the two treatment groups. The Cox proportional hazards regression model will be used to calculate relative risks and to adjust for differences in baseline characteristics. Statistical significance is considered as a 2-tailed P < .05. The Statistical Package for the Social Sciences (SPSS Inc, Chicago, IL) version 11.0.1 will be used for all statistical analysis.

Calculation of sample size 

A sample size to detect differences between treatment groups has been calculated by a logistic regression binary response variable on a binary independent variable. Based on the estimated reduction in the primary end point, we have selected a target sample size of 1080 subjects. This sample size will provide 80% power at .05 significance level to detect anticipated differences and will offer some protection if accrual is lower, losses are greater, or effect sizes are smaller than anticipated.

Interim analysis 

We will perform an interim analysis using Snapinn's method after the inclusion of approximately 200 patients.45 This method describes a conditional probability procedure that attempts to maintain the overall significance level by balancing the probabilities of false early rejection and false early acceptance. At the time of the interim analysis, we will consider to include more patients when the incidence of the primary end point is <25% in both groups combined.

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Study records 

For each randomized patient, a Case Report Form (CRF) for data recording is provided. Case Report Forms are numbered and should be used in ascending numerical order. All data will be recorded in a dedicated database.

The investigator will ensure that patient anonymity is maintained. On CRFs or other documents, patients are not identified by their names but by the CRF code. The investigator will keep a separate log of patient codes, names, and addresses.

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Appendix 

Investigators

Dr T Svilaas (principal investigator), Prof Dr F Zijlstra (study chairman), Dr ICC van der Horst

Interventional cardiologists

Dr RA Antonio, Dr AFM van den Heuvel, Dr GA Jessurun, Dr BJM de Smet, Dr Y Tan, Dr F Zijlstra

Department of Cardiology, University Medical Centre Groningen, Groningen, The Netherlands

Statistics

Dr H Hillege

Trial Coordination Centre, University Medical Centre Groningen, Groningen, The Netherlands

Pathology

Dr AJH Suurmeijer and Dr GFH Diercks

Department of Pathology, University Medical Centre Groningen, Groningen, The Netherlands

Angiographic core laboratory

Cordinamo, Wezep, The Netherlands

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PII: S0002-8703(05)01040-9

doi:10.1016/j.ahj.2005.11.010

American Heart Journal
Volume 151, Issue 3 , Pages 597.e1-597.e7, March 2006

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