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Original Contribution
Safety and Efficacy of the AngioJet in Patients with Acute Myocardial Infarction: Results from the Florence Appraisal Study of R
October 2006
Percutaneous coronary intervention (PCI) is a mainstay in the management of acute myocardial infarction (AMI).1 However, despite major improvements in technical and pharmacologic means, including stent implantation and the use of potent antiplatelet agents such as thienopyridines and glycoprotein (GP) IIb/IIIa inhibitors, the current risk of inadequate epicardial or myocardial reperfusion with ensuing clinical complications is not negligible.2,3
A number of strategies to avoid or reduce the risk of embolization of coronary thrombus have been proposed, including direct stenting, distal protection and coronary thrombectomy.4–6 However, the risk-benefit balance of such strategies is still uncertain, as none of these approaches has truly fulfilled its promises.5,7,8 In particular, rheolytic thrombectomy, as provided by the AngioJet® device (Possis Medical, Inc., Minneapolis, Minnesota) was initially found to be superior to urokinase infusion in degenerated saphenous vein grafts.6 Thereafter, a number of registries and a single-center randomized trial performed in high-volume institutions suggested its safety and potential efficacy in selected patients with acute coronary thrombosis.9–11 Unfortunately, a larger multicenter randomized trial in patients with AMI (the AngioJet Rheolytic Thrombectomy in Patients Undergoing Primary Angioplasty for Acute Myocardial Infarction [AiMI] Study) failed to confirm such promising results, and actually showed a significant increase in adverse events with the AngioJet.8 The AiMI Trial, though still unpublished, has nonetheless been largely criticized. Among the most important limitations of the study were the participation of low-volume centers without extensive AngioJet experience, and the enrollment of low-risk patients and lesions with low thrombus burden, which were less likely to benefit from the device.
It is thus timely to reappraise the risk-benefit balance of AngioJet use in patients with AMI, emphasizing the major role of operator volume and experience. The aim of this study was to assess the immediate angiographic and early clinical results of rheolytic thrombectomy in patients with AMI, as well as to define the impact of operator experience on the efficacy and safety of the AngioJet rheolytic thrombectomy device.
Methods
Patients. The study, approved by the local ethics committee, included all consecutive patients with AMI 0.1 mm ST-elevation in > 2 contiguous ECG leads) who were treated with the AngioJet rheolytic thrombectomy device in our institution between 1999 and 2004. Rheolytic thrombectomy was employed at the operator’s discretion, but only provided that angiographic features of grade 3–5 coronary thrombosis (identified by the presence of an irregular filling defect outlined by contrast medium and in the absence of extreme tortuosity or calcifications within the filling defect) were evident in a native coronary vessel with a reference vessel diameter > 2.5 mm that was targeted for PCI.12,13 In particular, patients with initial grade 5 coronary thrombosis were treated with the AngioJet device, provided that grade 3–4 thrombosis was evident after vessel wiring or predilatation. No other explicit exclusion criterion was considered except for the lack of written informed consent.
We also examined, as a control group, all patients treated in our institution with primary PCI within the same time frame and with the same angiographic features and reference vessel diameter as the AngioJet population, but who did not undergo thrombectomy, in order to compare the improvement of angiographic reperfusion parameters in the two populations after PCI. This strategy partially addressed the limitation inherent to the observational study design.
Procedures. Diagnostic and therapeutic interventions were performed via the percutaneous femoral approach. Intravenous heparin (5,000 IU bolus and subsequent doses aimed to maintain an activated clotting time of > 250 seconds) and aspirin (500 mg) were administered before the procedure. After angiographic confirmation of intracoronary thrombus, an 8 Fr guiding catheter was placed in the target vessel and the lesion was crossed with a 300 cm and 0.014 inch floppy guidewire. The AngioJet catheter was then positioned distal to the suspected thrombus. Whenever the operator encountered difficulties in passing the AngioJet catheter, a brief, low-pressure inflation was performed using a 1.5 mm compliant balloon catheter. After appropriate positioning of the AngioJet, the pump unit was activated, and the catheter was passed slowly across the target lesion in a distal-to-proximal or proximal-to-distal direction. Angiography was performed after 3 passes, and additional passes were made until complete or substantial thrombus removal was achieved (14
Angiographic endpoints. The coprimary angiographic endpoints were the changes in the epicardial corrected Thrombolysis In Myocardial Infarction (TIMI) frame count (cTFC) and the TIMI myocardial perfusion grade (TMPG) before and after rheolytic thrombectomy.12,13,15 In the presence of an occluded vessel (visual TIMI flow grade 0–1), the cTFC was set to a value of 100. The epicardial TIMI flow grade, the rate of distal embolization (defined as a new distal cut-off compatible with embolus, residual but displaced filling defects, or TIMI 0–1 flow in a distal branch unresponsive to intracoronary nytroglicerin), the thrombus burden and the no-reflow phenomenon (defined as an acute reduction in coronary flow in the absence of dissection, thrombus, spasm or residual stenosis > 50%) were also assessed.16 Similar measurements were performed after stent implantation and at the end of procedure. Preprocedural and postprocedural reference vessel diameter, minimum lumen diameter (MLD), percentage diameter stenosis and lesion length were also measured with a dedicated software (CMS-QCA 4, Medis, Leiden, The Netherlands). All angiographic measurements were performed off-line by experienced operators unaware of the baseline or procedural characteristics.
Clinical endpoint. The primary safety endpoint was the in-hospital occurrence of major adverse cardiovascular events (MACE), i.e., the composite of cardiac death, recurrent AMI and target vessel revascularization (TVR). The rate of major bleeding was also considered.5Statistical analysis. Continuous variables were expressed as mean (standard deviation), ordinal variables as median (interquartile range) and dichotomic variables as n/N (%). Repeated measures (such as TIMI flow or cTFC) were compared by means of the repeated measures ANOVA, McNemar test, Wilcoxon, Friedman tests and uncorrected Chi-square test, when appropriate. In order to establish the relationship between the operator’s experience with the AngioJet device and angiographic outcomes, we employed a nonparametric correlation (the Spearman rank correlation test) between the time since introduction of the AngioJet in our catheterization laboratory and intraprocedural angiographic parameters. Given the risk of alpha error due to multiple testing, we set significance at the 2-tailed 0.01 level and reported unadjusted crude p-values. Computations were performed with BMDP (Saugus, Massachusetts) and SPSS for Windows (SPSS, Inc., Chicago, Illinois).
Results
Baseline and procedural data. The study cohort consisted of 116 patients whose detailed baseline and procedural characteristics are presented in Table 1. Specifically, there were 100 males (86%), and the mean age was 62 (13) years. Rescue PCI after failed thrombolysis occurred in 6 (5%) patients, while anterior AMI was present in 63 (54%), and Killip class > 3 in 6 (5%) patients. Baseline and procedural characteristics of the control group were not significantly different from the study cohort, as depicted in Table 1, except for family history, use of direct stenting and intracoronary adenosine.
The AngioJet was successfully postioned and employed in all cases, either at first passage or after gentle predilatation with a 1.5 mm balloon. Pacing was utilized in 6 (5%) patients for bradyarrhythmias, and coronary dissections became evident after AngioJet use in 3 (3%) cases, all effectively managed with further stenting. In particular, drug-eluting stents were used in 13 (10%) subjects, while AngioJet use was followed by balloon-only angioplasty in 17 (15%) cases.
Angiographic analysis. The coprimary efficacy endpoints were markedly reduced in patients who received AngioJet treatment, and indeed, rheolytic thrombectomy proved to be the only significant modifying factor for epicardial and myocardial flow parameters. In particular, cTFC decreased from 100 (32–100) preprocedurally, to 18 (11–26) post-AngioJet treatment (p p > 0.05), and to 15 (8–24) as a final result (p > 0.05; each p-value referring to the comparison of the two preceding data elements). Similarly, the number of patients with TMPG >/= 2 changed from 23 (20%) preprocedurally, to 107 (92%) post-AngioJet treatment (p p = 0.03), and to 114 (98%) as a final result (p > 0.05). In addition, the rate of subjects with epicardial TIMI flow >/= 2 increased from 20 (17%) preprocedurally to 106 (91%) post-AngioJet treatment (p p > 0.05), to 114 (98%) as a final result (p > 0.05). As expected, these changes were reflected by the significant effect of rheolytic thrombectomy on the number of patients with thrombus grade >/= 3 [from 116 (100%) preprocedurally to 35 (30%) post-AngioJet treatment (p p p p > 0.05)], and in-segment diameter stenosis [from 96% (11) preprocedurally, to 66% (27) post-AngioJet treatment (p p 9 as a final result (p > 0.05)].
In order to address the question about the risk of embolization secondary to use of the device, we observed that increased anginal symptoms occurred in only 4 patients (3.4%) during AngioJet use, in the absence of any angiographic evidence of distal embolization. No MACE were reported in these patients, and no significant difference was observed for any of the considered endpoints compared with the rest of population.
Clinical outcome. The primary safety endpoint, i.e., the rate of in-hospital MACE, was 8% (9), including 4 (3%) cardiac deaths, 2 (2%) recurrent AMIs, and 5 (4%) percutaneous TVR procedures (Table 3). In addition, 2 (2%) cases of angiographically-adjudicated subacute stent thrombosis were reported, and major bleeding occurred in 3 (3%) patients.
Impact of operator experience on results of rheolytic thrombectomy. The analysis correlating laboratory and operator experience in performing rheolytic thrombectomy with final epicardial and myocardial perfusion results showed that greater experience with the AngioJet device yielded significantly larger reductions in cTFC from preprocedural to post-AngioJet treatment (r = 0.34; p r = -0.55; p Additional analysis. When we compared the study population to the control group defined above, angiographic analysis showed that patients treated with the AngioJet device had a significantly larger increase in TIMI epicardial flow (difference in TIMI flow from baseline to post-balloon dilatation >/= 2: 80% for those treated with AngioJet versus 52% for those who did not undergo thrombectomy; p p /= 2: 15% for those with less thrombus burden versus 96% for those with extensive thrombus; p p Discussion
The present study, which examined a large sample of high-risk patients undergoing rheolytic thrombectomy for AMI, confirms the favorable risk-benefit profile of AngioJet treatment in selected subjects and, to the best of our knowledge, is the first report in the literature on the importance of catheterization laboratory and operator experience in safely and effectively using this device. Indeed, these findings have relevant implications, especially given the recent conflicting evidence on the role of AngioJet treatment in patients with AMI.7,11
Thrombectomy and embolic protection devices in acute myocardial infarction. Since the establishment of percutaneous revascularization as the standard of care in patients with AMI,1 the issue of suboptimal tissue reperfusion has been raised. Indeed, it is well known that even in the presence of adequate (i.e., TIMI 3) epicardial flow, myocardial flow may be impaired, with ominous clinical consequences.2,3 In order to address this problem, a number of drug and device interventions have been proposed and tested clinically, with conflicting results. Only preliminary reports are available in support of medical therapy, even if results may be described as encouraging.17,18
Great interest has been focused instead on coronary devices, including the AngioJet rheolytic thrombectomy device,9 the X-Sizer thrombectomy device (Endicor Medical, Inc., San Clemente, California),19 the pump and manually-operated thrombus aspiration devices,4 and the distal protection devices such as filters7 and occlusive balloons.5 While definitive judgement on their risk and cost-benefit balance is still pending, a number of trials have cooled the initial enthusiasm for these devices. Indeed, Gick et al reported no benefit from the use of filter protection devices in 137 patients with AMI,7 and similarly, Stone et al could not substantiate in the setting of AMI the promising results achieved by the PercuSurge Guidewire (Medtronic, Inc., Minneapolis, Minnesota) occlusive balloon in saphenous vein grafts.5,6 To date, aspiration devices and the X-Sizer thrombectomy catheter have been evaluated only in relatively small trials, employing surrogate primary endpoints, thus their true role in interventional cardiology is still uncertain.4,19,20
At present, the AngioJet device has evidence-based data similar to other devices, but there are also major differences. Indeed, initial registries and randomized trials performed in high-volume and high-expertise centers supported the safety and efficacy of this rheolytic thrombectomy device, which many authors consider the only one capable of truly removing large quantities of thrombus from coronary vessels. Specifically, the promising registry data were reported by Taghizadeh and colleagues,21 Rinfret et al,9 Nagakawa and colleagues22 and Silva et al,10 while Antoniucci et al11 conducted the only randomized trial published to date providing positive results with the AngioJet on surrogate endpoints among 100 patients with AMI. However, recent prepublication reports from the multicenter AiMI trial have showed that across 468 patients with AMI, a significant increase occurred in 1-month adverse events, rate of TIMI flow 8 These differences included a notable excess of deaths in the rheolytic thrombectomy group [11 (5%) versus 2 (1%); p Experience-based recommendations. Consensus exists among several authors that the negative or inconclusive trials performed to date in the field of thrombotic protection/extraction devices may be due to the selective enrollment of low-risk patients with limited coronary thrombus. Indeed, physicians who have experience with the AngioJet know that one of its main advantages is the dramatic increase in the rate of direct stenting, with the ensuing benefits in all cases of extensive thrombotic and/or atherosclerotic burden.11 Recent data suggest that the X-Sizer thrombectomy device may provide similar angiographic results, even if there is still no evidence of the impact of X-Sizer thrombectomy on hard clinical endpoints.19,20 An interesting difference between this device and the AngioJet that favors the latter, is the size, as only the AngioJet can reach distal coronary vessels with a 2.0–3.0 mm reference vessel diameter.
Intriguingly, while a preventive temporary pacemaker was placed in 93% of patients in the registry from Rinfret et al, dating from 1998 to 2000,9 in our experience, only a few cases of bradyarrhythmia occuring in the catheterization laboratory were clinically relevant, as most were transient and successfully managed conservatively with medical therapy. Thus, we advocate very selective, bail-out use of temporary transvenous pacing, and believe that refraining from implanting such pacing catheters in the right ventricle is much safer in patients with AMI undergoing potent antithrombotic therapies. On the other hand, intracoronary aspiration was commonly associated with worsening of chest discomfort, so that liberally employing morphine and other sedating agents is now common practice in our laboratory.
In some cases and during the first passages, there is concern that the bulky AngioJet device might cause distal embolization with vessel or branch occlusion. Although our study was not targeted to appraise this issue, we reported only a few cases of distal embolization and believe that the concomitant use of the AngioJet with GP IIb/IIIa inhibitors may significantly reduce the risk of dislodging such occlusive emboli. On the other hand, since epicardial and myocardial reperfusion after rheolytic thrombectomy in patients with AMI is similar to that achieved after stenting, and while stenting obviously reduces target vessel restenosis, patients eligible for elective CABG could be managed acutely by rheolytic thrombectomy only, without stent implantation and GP IIb/IIIa inhibitors.
We may also envisage a cost-conscious and tailored thrombectomy strategy for patients with AMI so that a simpler aspiration device such as the Export aspiration catheter (Medtronic, Inc., Minneapolis, Minnesota) could be used in coronary vessels with limited thrombus burden (grades 1 and 2), while the more effective AngioJet should be strongly considered in vessels with heavier thrombus burden (grade 3 and beyond).
The above statements, while experience-based, lack thorough evidence-based support. Thus, caution should be exercised in extrapolating them to settings different from the one described in this report. Indeed, we strongly believe that a multicenter clinical outcome research project should be performed to more accurately quantify the learning curve and the minimum required caseload to effectively and safely use the AngioJet device.
Study limitations. Drawbacks of single-center observational studies are well known.23 Nonetheless, in many cases of interventional devices, the design of this study enabled us to accurately identify the potential pitfalls of this novel treatment. Other caveats that should not be dismissed include the risk of alpha error and the lack of long-term clinical follow-up data.
Conclusion
The present observational study, notwithstanding its inherent limitations, supports the favorable risk-benefit profile of the AngioJet in selected patients with AMI, as long as it is utilized in experienced laboratories and by trained operators.
References
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