Adjunctive Thrombectomy with Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction: Summary of Rando

Primary percutaneous coronary intervention (PCI) helps to achieve brisk coronary flow (thrombolysis in myocardial infarction [TIMI] 3 flow) in the infarct artery in greater than 90% of patients with ST-elevation myocardial infarction (STEMI) and has achieved excellent outcomes with very low rates of death, re-infarction and stroke.¹ As a consequence, primary PCI has become the preferred reperfusion strategy for STEMI. Despite this, primary PCI is limited by suboptimal myocardial reperfusion (microvascular reperfusion) in many patients as well as limited myocardial salvage. Intracoronary thrombus is thought to be ubiquitous in the infarct artery of patients with STEMI. When visible thrombus embolizes to the distal circulation during primary PCI, outcomes are compromised. The Zwolle group found that macro-embolization occurred in 14% of patients with STEMI treated with primary PCI.² These patients had worse TIMI flow in the infarct artery, worse myocardial reperfusion as evidenced by less frequent grade 2–3 myocardial blush at angiography and less complete ST–segment resolution, larger infarct size, worse left ventricular (LV) function and higher mortality.
Even in patients without macro-embolization, myocardial reperfusion following primary PCI is often suboptimal, as evidenced by persistent ST-segment elevation and abnormal myocardial blush.^3,4 Patients with suboptimal myocardial reperfusion have limited myocardial salvage and increased mortality.^3,4 Distal micro-embolization with primary PCI is thought to be ubiquitous and may contribute to poor myocardial reperfusion. This has stimulated great interest in the use of adjunctive thrombectomy with primary PCI in an attempt to remove thrombus, prevent distal micro-embolization, improve myocardial reperfusion, reduce infarct size and improve outcomes.
There have been a number of thrombectomy devices that have been used as adjunctive therapy with primary PCI. Those that have been most thoroughly studied are the X-Sizer^® Catheter System (ev3, Inc., Plymouth, Minnesota), several aspiration devices and the AngioJet^® System (Possis Medical, Minneapolis, Minnesota).

Thrombectomy with the X-Sizer Catheter System

The X-sizer catheter system is an over-the-wire system with a helical-shaped cutter at the distal tip that rotates at 2100 rpm. The catheter lumen is connected to a 250-cc vacuum bottle that collects aspirated debris. The X-sizer is approved in Europe, but is not approved for coronary use in the United States.
Two small randomized trials have evaluated adjunctive thrombectomy with the X-sizer catheter in patients treated with primary PCI for STEMI (Table 1). Napodano and colleagues randomized 92 patients with STEMI to primary PCI with or without thrombectomy with the X-sizer catheter.5 Patients treated with the X-sizer had similar rates of TIMI 3 flow post-PCI but better myocardial reperfusion as evidenced by more frequent grade 3 myocardial blush and more frequent ST-segment resolution > 50%. In a separate study, Lefevre and colleagues randomized 201 patients with STEMI to primary PCI with or without the X-sizer catheter.⁶ Patients treated with the X-sizer catheter had more frequent TIMI 3 flow post-PCI and better ST-segment resolution, but no difference in myocardial blush.
No large trials have been performed to evaluate infarct size or clinical outcomes.

Aspiration Thrombectomy

There are several aspiration thrombectomy catheters that have been used to remove thrombus in patients with STEMI and all have similar design. Each has a monorail lumen for passage over a coronary wire and each has an aspiration lumen that is connected to a syringe at the proximal end for aspiration. The aspiration devices have been approved for removing fresh thrombus in the arterial system, but have not been specifically approved as safe and effective for coronary use in the United States. There have been four small, randomized trials evaluating aspiration thrombectomy with primary PCI for STEMI (Table 2).
The Randomized evaluation of the effect of MEchanical reduction of DIstal embolization by thrombus-aspiration in primary and rescue Angioplasty (REMEDIA) Trial randomized 100 patients with STEMI treated with primary PCI to aspiration thrombectomy with the Diver CE Catheter (eV3 Inc., Plymouth, Minnesota) versus control.⁷ Patients treated with thrombectomy had better myocardial reperfusion with a higher frequency of Grade 2–3 blush and better ST-segment resolution.
In a second study, De Luca and colleagues randomized 76 patients with anterior STEMI to primary PCI with or without thrombectomy with the Diver catheter.⁸ Thrombectomy patients had better microvascular reperfusion as evidenced by more frequent Grade 3 blush and better ST-segment resolution, and less LV remodeling as assessed by echocardiography.
Morice and colleagues randomized 50 patients with STEMI treated with primary PCI to aspiration thrombectomy with the Export^® catheter (Medtronic, Inc, Minneapolis, Minnesota) versus control.⁹ Patients treated with the Export catheter had better coronary flow and better myocardial reperfusion with better myocardial blush and ST-segment resolution. Export patients also had smaller infarct size by magnetic resonance imaging at 48 hours.
Finally, Kaltoft and colleagues evaluated the Rescue catheter (Boston Scientific, Natick, Massachusetts) in patients with STEMI undergoing primary PCI.¹⁰ Adjunctive use of the Rescue catheter did not improve coronary flow or measures of myocardial reperfusion. Myocardial salvage measured by serial sestimibi imaging was slightly less with the Rescue catheter and final infarct size was significantly more with the Rescue catheter, suggesting possible harm.

Rheolytic Thrombectomy

The AngioJet Rheolytic™ Thrombectomy System consists of a drive unit, a disposable pump set and a Rheolytic Thrombectomy catheter (Possis Medical). The dual-lumen catheter tracks over a guidewire. High velocity saline jets are directed back into the catheter, creating a low-pressure zone at the distal tip (Bernoulli principle), which results in suction, break-up and removal of thrombus through the outflow lumen. The device has been approved for use in removing coronary thrombus in the United States and abroad. There has been one small and one large multi-center randomized trial evaluating thrombectomy using the AngioJet with primary PCI for STEMI (Table 3).
Antoniucci and colleagues randomized 100 patients with STEMI to primary PCI with abciximab (ReoPro^®, Eli Lilly, Indianapolis, Indiana) with or without rheolytic thrombectomy.11 Thrombectomy patients had better coronary flow, better ST-segment resolution and smaller infarct size at 1 month by sestamibi imaging.
The multi-center AngioJet Rheolytic Thrombectomy in Patients Undergoing Primary Angioplasty for Acute MI (AiMI) Trial is by far the largest randomized trial to evaluate the potential benefit of thrombectomy with primary PCI for STEMI.¹² The AiMI trial enrolled high-risk STEMI patients (anterior infarction and large inferior infarction) who were targeted for primary PCI. Patients eligible for PCI and who met angiographic criteria for rheolytic thrombectomy (vessel diameter > 2.0 mm) were randomized to PCI with or without rheolytic thrombectomy. The use of platelet glycoprotein (GP) IIb/IIIa inhibitors was mandated by protocol and temporary pacemakers were strongly encouraged in the AngioJet group. The primary endpoint was infarct size at 14–28 days by sestamibi imaging and the secondary endpoints were TIMI flow post-PCI, corrected TIMI frame count (CTFC), myocardial blush, ST-segment resolution and major adverse cardiac events (MACE) at 30 days. The results were presented at the TCT (Transcatheter Therapeutics) Annual Meeting in Washington, DC in October 2004 and are currently in press.¹² There were no differences in myocardial blush or ST-segment resolution, but TIMI flow post-PCI was worse in the AngioJet arm. Surprisingly, infarct size was greater with rheolytic thrombectomy. This was primarily due to larger infarct size in patients with inferior infarction (10.2% vs. 6.5%, p = 0.001) with no significant difference in infarct size in patients with anterior infarction (16.5% vs. 15.3%, p = 0.58). MACE rates were also higher in the AngioJet group (6.7% vs. 1.7%, p = 0.01) due primarily to a higher mortality (4.6% vs. 0.8%, p = 0.02). The investigators concluded that rheolytic thrombectomy does not reduce infarct size and cannot be recommended for routine use in patients with STEMI undergoing primary PCI.
The reasons for worse outcomes with rheolytic thrombectomy in the AiMI Trial are not clear. The study was not powered to detect differences in clinical endpoints, so the differences in mortality were quite unexpected. These differences were not due to an increased mortality in the AngioJet arm, but rather to an unexpectedly low mortality in the control arm. The 30-day mortality in the control arm (0.8%) was lower than any previous primary PCI trial and occurred in a patient population that was selected to be high risk. The data safety and monitoring committee and the executive committee, after reviewing the data, did not find any indication that any of the 11 deaths in the AngioJet group were directly attributed to the device. The differences in mortality remain unexplained, but could be related to chance.
The reasons for larger infarct size in the AngioJet group are also not clear. The larger infarct size did not translate into worse LV ejection fraction. Ejection fraction measured by sestamibi imaging at 14–28 days was similar in the AngioJet and control groups (51.3% vs. 52.3%, p = 0.38). The frequency of TIMI 3 flow pre-PCI was higher in the control group (27% vs. 19%, p = 0.05), and it is possible that this could influence infarct size favoring smaller infarct size in the control group. Secondly, it is possible that the greater infarct size could be related to the technique used in performing rheolytic thrombectomy. In AiMI, there was no effort to systematically perform thrombectomy with the AngioJet from proximal to distal, and predilation was sometimes performed to facilitate passage of the AngioJet catheter. Both predilation and advancement of the AngioJet catheter across the thrombus laden lesion without activation of the device could predispose to distal embolization. In Dr. Antoniucci’s trial, which reported superior results with the AngioJet, the device was activated during antegrade passage and predilation was avoided except in rare circumstances. Finally, although baseline TIMI flow and operator technique may have influenced the results, the device itself may have contributed to larger infarct size through distal micro-embolization.

Current Role of Thrombectomy with Primary PCI for STEMI

The results of multiple randomized trials evaluating adjunctive thrombectomy with primary PCI for STEMI leave many unanswered questions. Most of the trials were small, and all of the trials evaluated surrogate endpoints rather than clinical endpoints. Six of 8 trials showed improved myocardial reperfusion (better coronary flow, ST-segment resolution and myocardial blush), but the two largest trials did not show improved myocardial reperfusion and showed larger infarct size in patients treated with thrombectomy.
There are several possible reasons for the discordant results from these trials. First, it may be that distal micro-embolization is not a major cause of impaired myocardial reperfusion in patients already infarcted. While there is considerable evidence that macro-embolization occurring with primary PCI is detrimental and leads to impaired LV function and worse clinical outcomes, micro-embolization may not have major detrimental effects. Impaired myocardial reperfusion, which occurs in more than half of patients with successful PCI, may be due to other factors such as reperfusion injury or delayed reperfusion with irreversible microvascular injury. The concept that micro-embolization may not play a major role in causing impaired myocardial reperfusion is supported by the negative results of the Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris (EMERALD) Trial, which showed no benefit of distal protection, despite successful removal of thrombus in the great majority of patients.
Secondly, thrombectomy may be beneficial in subgroups of patients with STEMI treated with primary PCI, but this benefit may be diluted by the larger group of patients who show no benefit. The subgroup thought most likely to benefit from adjunctive thrombectomy are patients with large thrombus burden. Analysis of the subgroup of patients in AiMI with large thrombus burden failed to find benefit with AngioJet, but the number of patients in this subgroup may have been too small to detect differences. Analyses of subgroups with large thrombus burden are limited by difficulty in assessing thrombus burden in patients with total occlusion of the infarct artery on initial angiography, which occurs in over 60% of patients. Better techniques are needed to assess thrombus burden, and new trials targeting patients with large thrombus burden are needed to determine the role of adjunctive thrombectomy in this group of patients.
Finally, it may be that current devices are not optimal for achieving complete thrombectomy without causing distal embolization or other adverse effects. It is certainly possible that the increased infarct size seen in the study by Kaltoft and colleagues with aspiration thrombectomy and the increased infarct size seen in AiMI with rheolytic thrombectomy could be related to distal embolization at the time of thrombectomy. Further research is needed to evaluate this possibility and to modify these devices to achieve optimal thrombus removal while minimizing distal embolization.
To summarize, adjunctive thrombectomy currently cannot be recommended for routine use with primary PCI for STEMI. However, patients with STEMI undergoing primary PCI often have a large thrombus burden and the interventionalist needs guidance in managing these patients (Figure 1). Studies have shown that macro-embolization is harmful and leads to impaired myocardial reperfusion and worse clinical outcomes, and macro-embolization is more likely to occur in patients with large thrombus burden. Thrombectomy devices have proven to be very effective in removing thrombus. Therefore, until we have more data from new trials, it seems reasonable to perform adjunctive thrombectomy in patients with large thrombus burden prior to primary PCI.

References

1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003;361:13–20.
2. Henriques JP, 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.
3. van’t Hof AW, Liem A, de Boer MJ, et al. Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Lancet 1997;350:615–619.
4. van’t Hof AW, Liem A, Suryapranata H, et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: Myocardial blush grade. Circulation 1998;97:2302–2306.
5. Napodano M, Pasquetto G, Sacca S, et al. Intracoronary thrombectomy improves myocardial reperfusion in patients undergoing direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 2003;42:1395–1402.
6. Lefevre T, Garcia E, Reimers B, et al. X-sizer for thrombectomy in acute myocardial infarction improves ST-segment resolution: Results of the X-sizer in AMI for negligible embolization and optimal ST resolution (X AMINE ST) trial. J Am Coll Cardiol 2005;46:246–252.
7. Burzotta F, Trani C, Romagnoli E, et al. Manual thrombus-aspiration improves myocardial reperfusion: The 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.
8. De Luca L, Sardella G, Davidson CJ, et al. Impact of intracoronary aspiration thrombectomy during primary angioplasty on left ventricular remodeling in patients with anterior ST-elevation myocardial infarction. Heart published online October 26, 2005.
9. Noel B, Morice MC, Lefevre T, et al. Thrombus-aspiration in acute ST elevation MI improves myocardial reperfusion. Results of the Export Study. Submitted to J Am Coll Cardiol for publication.
10. Kaltoft A, Bottcher M, Nielsen SS, et al. Thrombectomy as an adjunct to percutaneous coronary intervention in ST-segment elevation myocardial infarction: A prospective randomized controlled trial. Am J Cardiol 2005;95(Supplement):TCT-231.
11. Antoniucci D, Valenti R, Migliorini A, et al. Comparison of rheolytic thrombectomy before direct infarct artery stenting versus direct stenting alone in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol 2004;93(8):1033–1035.
12. Ali A, Cox D, Dib N, et al. Rheolytic thrombectomy with percutaneous coronary intervention for infarct size reduction in acute myocardial infarction: 30 day results from a multicenter randomized study. J Am Coll Cardiol 2006 (In Press).