JETSTENT Trial Results: Impact on ST-Segment Elevation Myocardial Infarction Interventions

Abstract: The results of meta-analyses of studies on manual thrombus aspiration and mechanical thrombectomy support the use of manual aspiration catheters and contraindicate the use of mechanical thrombectomy devices. However, the two largest studies dominate the meta-analysis results, the Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS) for the manual aspiration study group, and the Angiojet rheolytic thrombectomy In patients undergoing primary angioplasty for acute Myocardial Infarction (AIMI) trial for the mechanical thrombectomy group. The first demonstrated a clinical benefit of thrombus removal using the manual aspiration catheter. The AIMI trial, which included 480 patients, showed a negative and harmful impact on survival of rheolytic thrombectomy. The results of the recently concluded AngioJET Rheolytic Thrombectomy Before Direct Infarct Artery STENTing with Direct Stenting Alone in Patients with Acute Myocardial Infarction (JETSTENT) trial, which included 501 patients and showed a strong clinical benefit of rheolytic thrombectomy in the setting of primary PCI for acute myocardial infarction (AMI), adds new arguments in support of rheolytic thrombectomy in AMI. J INVASIVE CARDIOL 2010;22:23B–25B ————————————————————

Routine thrombectomy in the setting of primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) is still a matter of debate, since most concluded randomized studies have produced neutral or conflicting results. The results of meta-analyses of these studies support the use of manual aspiration catheters and contraindicate the use of mechanical thrombectomy devices.^1–5

However, the two largest studies dominate the meta-analysis results: the Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS) and the Angiojet rheolytic thrombectomy In patients undergoing primary angioplasty for acute Myocardial Infarction (AiMI) trial.^6,7 The TAPAS trial, including 1,071 patients, showed a positive impact on survival of manual aspiration catheter, while the AiMI trial of 480 patients showed a negative and harmful impact on survival of rheolytic thrombectomy.

The results of the recently concluded AngioJET Rheolytic Thrombectomy Before Direct Infarct Artery STENTing with Direct Stenting Alone in Patients with Acute Myocardial Infarction (JETSTENT) trial, which included 501 patients, showed a strong clinical benefit of rheolytic thrombectomy in the setting of primary PCI for AMI. These results add new arguments in support of rheolytic thrombectomy in AMI.⁸

Insights from the JETSTENT Trial

The JETSTENT trial included 501 patients with AMI and compared rheolytic thrombectomy plus direct infarct artery stenting with direct stenting alone. The study showed a better clinical outcome for patients randomized to rheolytic thrombectomy with significant differences in major adverse cardiovascular events (death, myocardial infarction, target vessel revascularization, and stroke) at 1-month (3.1% versus 6.9%, p = 0.050), 6-month (11.2% versus 19.4, p = 0.011), and 12- month (14.9% versus 22.7%, p = 0.036) follow-up.⁸ The difference in clinical outcome was driven by death and target vessel revascularization.

By Kaplan-Meier analysis, the 1-year estimated freedom from major adverse cardiovascular events (MACE) was 85.2 ± 2.3% for the AngioJet Rheolytic Thrombectomy (RT) arm, and 75.0 ± 3.1% for the direct stenting (DS) alone arm (p = 0.009) (Figure 1).

An editorial comment to the study, based on a superficial misinterpretation of the data, focused on the fact that the 2 co-primary end-points of the study — early ST-segment resolution and infarct size — were not met. Studies with 2 co-primary endpoints are requested to have an a value = 0.05 for both end-points or an a value = 0.025 for a single primary endpoint. In the JETSTENT trial, early ST-segment resolution was more frequent in the thrombectomy arm, with a p value 0.043 (85.8% of patients randomized to thrombectomy and in 78.8% of patients randomized to control), although the difference in infarct size did not reach the predefined a value of 0.05 (11.8% in the thrombectomy arm and 12.7% in the control, p = 0.398).

However, the editorial commentary neglected to acknowledge that, at multivariable analysis, randomization to thrombectomy results independently related to the primary endpoint early ST-segment resolution (OR 1.70, 95% CI 1.03–2.82, p = 0.039; c-statistic: 0.72; Hosmer-Lemeshow test: P=0.460) and, more importantly, to the occurrence of 1-year major adverse cardiovascular events (HR 0.55, 95% CI 0.35–0.86, p = 0.008) — making the revealed differences between arms statistically significant. Again, from the comment, it is easy to infer that it is not recognized that, in the control arm, patients did much better than expected and that, despite this fact, rheolytic thrombectomy resulted in a significant improvement in clinical outcome.

As a result, several unique features of the JETSTENT trial should be considered to put the results of the study into a proper perspective and to make more complete the comparison with previous trials on manual aspiration catheters or mechanical thrombectomy devices in AMI.⁸

The treatment in the control arm of the JETSTENT study included direct infarct artery stenting; other studies the control arm received standard PCI that includes balloon angioplasty, infarct artery stenting and, eventually, post-dilation. It has been established that, in patients with thrombus containing lesions, pre- and post-dilation increases the risk of embolism. One randomized study and several observational studies have shown that direct stenting in the setting of AMI decreases embolism and the risk of no-reflow.^9,10 One of the major criticism of the TAPAS trial is that many patients (55%) in the thrombus aspiration arm underwent direct stenting while all control-arm patients underwent pre-dilation. This study design could have favored the thrombus aspiration arm because direct stenting without pre- or post-dilation decreases the risk of embolization.⁷

In the JETSTENT trial, direct stenting was successfully performed in 88% of cases without significant difference between arms (90% in the thrombectomy arm, and 86% in the direct-stenting-alone arm), and the potential confounding effect on the results of pre-dilation and, eventually, post-dilation was avoided. Moreover, no difference between groups was revealed in adjunctive antithrombotic therapy with nearly all patients in both arms receiving abciximab, which has a strong protective effect against embolization and no-reflow phenomenon.^11–13 The JETSTENT trial therefore differed from previous studies in that it assessed the potential adjunctive benefit of rheolytic thrombectomy in patients at the top of standard therapy that included routine direct infarct artery stenting without pre- or post-dilation, and routine use of abciximab. This could also explain why patients in the control arm did better than expected in terms of surrogate endpoints with no difference between arms in all surrogate end points and with early ST-segment elevation resolution.

The JETSTENT trial also differed from the TAPAS and AiMI trials because patients were randomized only if there was angiographic evidence of moderate or large thrombus or a persistently occluded infarct artery after coronary wiring. Further, the rate of protocol violation was very low: only 6 patients (1.4%) did not have evidence of thrombus. This compliance to protocol was very high considering that direct stenting had to be attempted in all cases without restriction, based on coronary anatomy (diffuse disease, calcification, and tortuosity), and that pre-dilation before stenting was performed in only 12% of patients.

Another unique feature of the JETSTENT trial is the single-pass anterograde technique used for rheolytic thrombectomy. The technique includes catheter activation proximally to the thrombus, to create a suction vortex before advancing the device and to decrease the risk of embolism and angiographic control after a first pass: In most patients, a single pass is sufficient to restore a TIMI grade flow 2 or 3 with no more evidence of thrombus.

Retrograde technique increases embolism risk, meaning catheter activates only after its tip has been placed distally to the occlusion, and subsequent to distal-to-proximal pullback. It has been hypothesized that, for large pedunculated thrombus extending distally to the target lesion, thrombus fragmentation that happens at the level of its proximal part due to the activated device could result in increased risk of macroembolism. However, no study has validated this concept, and the results of the JETSTENT trial support the routine use of the anterograde technique.

Comparison of the JETSTENT Trial With the AIMI Trial

Table 1 summarizes the major differences between studies in baseline and procedural characteristics.^7,8 Compared to the JETSTENT trial, more of the AiMI trial’s patients did not have angiographic evidence of thrombus, had an already-reperfused infarct artery, underwent pre-dilation before rheolytic thrombectomy, and had higher major bleeding rate. Moreover, nearly 60% of patients randomized to rheolytic thrombectomy and retrograde technique had temporary pacemakers. Finally, the delay from admission to treatment was very long. All these differences negatively affect outcomes and might have superseded any potential benefit of rheolytic thrombectomy, which would explain the difference between AiMI and TAPAS results and those of the JETSTENT trial.

The Role of Manual Thrombus Aspiration and Rheolytic Thrombectomy in the Current Management of Patients With AMI

The available evidence supports the use of manual thrombus aspiration, while the conflicting results of studies on rheolytic thrombectomy in AMI call for further larger trials. Future study designs on the efficacy of devices in removing thrombus before coronary stenting should include a strict patient-treatment uniformity criteria, such as the same stenting technique, the same adjunctive antithrombotic treatment, an acceptable delay from admission to treatment, and inclusion of patients with severe left ventricular dysfunction or cardiogenic shock. In this subset of high-risk patients alone, a no-reflow may be quickly fatal and as a consequence the expected benefit of thrombectomy high.

Meanwhile, as compared to manual aspiration catheters, rheolytic thrombectomy is more expensive but has several important advantages: the lower profile and higher trackability of the device that allows a more easy navigation in tortuous, diffusely diseased and calcified vessels; a predictable efficacy also in large or giant thrombus containing lesions; and a more quick procedure since in most cases the anterograde single-pass technique results in the restoration of a TIMI grade 3 flow and no more angiographic evidence of thrombus.

References

1. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Neumann FJ, Chiariello M. Adjunctive mechanical devices to prevent distal embolization in patients undergoing mechanical revascularization for acute myocardial infarction: a meta-analysis of randomized trials. Am Heart J 2007;153:343–353.
2. De Luca G, Dudek D, Sardella G, et al. Adjunctive manual thrombectomy improves myocardial perfusion and mortality in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis of randomized trials. Eur Heart J 2008;29:3002–3010.
3. Burzotta F, De Vita M, Gu YL, et al. Clinical impact of thrombectomy in acute ST-elevation myocardial infarction: an individual patient-data pooled analysis of 11 trials. Eur Heart J 2009;30:2193–2203.
4. Mongeon FP, Bélisle P, Joseph L, Eisenberg MJ, Rinfret S. Adjunctive thrombectomy for acute myocardial infarction: A bayesian meta-analysis. Circ Cardiovasc Interv 2010;3:6–16.
5. Bavry AA, Kumbhani DJ, Bhatt DL. Role of adjunctive thrombectomy and embolic protection devices in acute myocardial infarction: A comprehensive meta-analysis of randomized trials. Eur Heart J 2008;29:2989–3001.
6. Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet 2008;371:1915–1920.
7. Ali A, Cox D, Dib N, Brodie B, 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;48:244–252.
8. Migliorini A, Stabile A, Rodriguez EA, et al. Comparison of AngioJET Rheolytic Thrombectomy Before Direct Infarct Artery STENTing with Direct Stenting Alone in Patients with Acute Myocardial Infarction: the JETSTENT Trial. J Am Coll Cardiol 29 July 2010. [Epub ahead of print].
9. Loubeyre C, Morice MC, Lefevre T, Pichaud J-F, Louvard Y, Dumas P. A randomized comparison of direct stenting with conventional stent implantation in selected patients with acute myocardial infarction. J Am Coll Cardiol 2002;39:15–21.
10. Antoniucci D, Valenti R, Migliorini A, et al. Direct infarct artery stenting without predilation and no-reflow in patients with acute myocardial infarction. Am Heart J 2001;142:684–690.
11. Neumann F-J, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 1998;98:2695–2701.
12. Antoniucci D, Rodriguez A, Hempel A, et al. A randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction. J Am Coll Cardiol 2003;42:1879–1885.
13. De Luca G, Suryapranata H, Stone GW, et al. Relationship between patient's risk profile and benefits in mortality from adjunctive abciximab to mechanical revascularization for ST-segment elevation myocardial infarction: A meta-regression analysis of randomized trials. J Am Coll Cardiol 2006;47:685–686.

———————————————————— From Careggi Hospital, Florence, Italy. Address for correspondence: David Antoniucci, MD, Division of Cardiology, Careggi Hospital, Viale Morgagni I-50134 Florence, Italy. E-mail: david.antoniucci@virgilio.it. The author reports no conflicts of interest regarding the content herein.